Pemphigus is a group of autoimmune blistering diseases caused by IgG autoantibodies directed against desmosomal adhesion proteins (desmogleins) in the epidermis, resulting in loss of keratinocyte cohesion (acantholysis) and formation of flaccid intraepidermal blisters.

Exam domain	One-glance essentials
Definition / diagnosis	Autoimmune IgG against desmogleins → intraepidermal acantholysis → flaccid blisters ^[1]^[2] Pemphigus vulgaris: anti-Dsg3 ± Dsg1; pemphigus foliaceus: anti-Dsg1 only
Epidemiology / risks	Ask about thiol drugs such as penicillamine and captopril ^[2] Paraneoplastic pemphigus should trigger a search for an underlying lymphoproliferative malignancy ^[3]
Core mechanism	Loss of desmosomal adhesion causes a suprabasal split with a tombstone row in pemphigus vulgaris ^[1]^[2] Desmoglein distribution explains mucosal disease with Dsg3 involvement and skin-only disease with Dsg1
Clinical picture	Painful flaccid bullae and erosions, often beginning in the oral mucosa; Nikolsky sign positive ^[2] Pemphigus foliaceus spares mucosa; paraneoplastic disease causes severe stomatitis and polymorphous lesions ^[3]
Investigations	Lesional H&E → acantholysis; perilesional DIF → *intercellular IgG/C3 in a chicken-wire pattern* ^[2]^[4] Anti-Dsg1/Dsg3 ELISA supports diagnosis and titres track disease activity ^[1]^[2]
Management	*Systemic corticosteroid plus early rituximab or a steroid-sparing agent; rituximab is increasingly first line ^[4]^[5] Prick but do not de-roof blisters; provide wound/oral care and treat infection ^[4] Severe widespread disease needs ICU/burn-style supportive care* ^[1]
Complications	Epidermal barrier loss → sepsis, fluid/protein loss, hypothermia and malnutrition ^[1]^[5] Paraneoplastic pemphigus can cause irreversible bronchiolitis obliterans ^[3]
Prevention / follow-up	Screen HBsAg/anti-HBc before rituximab and monitor immunoglobulins/infection risk ^[4]^[5] Withdraw treatment slowly after disease control; follow clinical activity and anti-Dsg titres ^[1]^[5]
Exam traps	Flaccid + Nikolsky positive + mucosal erosions favours pemphigus; tense + Nikolsky negative favours pemphigoid ^[2] *Antibody titres correlate with activity in pemphigus, unlike pemphigoid* ^[1] Pemphigus foliaceus has no mucosal disease because Dsg3 compensates there

References

^[1] Senior notes: Block A - Dermatology PBL 2.pdf, p1–2, p5 ^[2] Senior notes: Ryan Ho Rheumatology.pdf, p152–153 ^[3] Lecture slides: Derm General Clerkship 2026 Part2.pdf, p28 ^[4] Lecture slides: CFB (MED09) Dermatology (II).pdf, p7–8 ^[5] Senior notes: Block A - Treatments for skin diseases.pdf, p1

Pemphigus

Pemphigus (from Greek pemphix = "blister/bubble") is a group of rare, chronic, potentially life-threatening autoimmune blistering (bullous) diseases characterised by IgG autoantibodies directed against desmosomal adhesion proteins (desmogleins) on keratinocyte cell surfaces, leading to acantholysis (loss of cell-to-cell adhesion between keratinocytes) and the formation of intraepidermal blisters ^[1]^[2].

Core Concept – Why Intraepidermal?

The fundamental distinction: Pemphigus targets intracellular (intercellular) adhesion molecules — desmogleins — which hold epidermal keratinocytes together. This causes the split to occur within the epidermis itself (intraepidermal). Contrast this with pemphigoid, where the target is the dermo-epidermal junction (DEJ) — specifically BP180/BP230 — causing subepidermal blisters. Because the roof of pemphigus blisters is only thin upper epidermis, they are flaccid and fragile, rupturing easily to leave painful erosions. Pemphigoid blisters, having the full-thickness epidermis as a roof, are tense and intact ^[1]^[2].

"Target is intracellular substance (desmoglein 1 and 3) in pemphigus; in contrast to bullous pemphigoid (BP), where target is DEJ (BP180/BP230)" ^[1]

Incidence: Rare — approximately 0.1–0.5 per 100,000 per year globally ^[3]
Highest incidence: Ashkenazi Jews, Indians, Southeast Europe, Middle East ^[3]
Age: Pemphigus vulgaris (PV) typically presents in 40–60 years old (middle-aged adults); Pemphigus foliaceus (PF) has a similar age range for the non-endemic form ^[3]
Sex: M:F ≈ 1:1 ^[3]
Compared with Bullous Pemphigoid (BP): Pemphigus is less common than BP. BP is the most common autoimmune blistering disease overall and tends to affect an older population ( > 60 years) ^[3]
Hong Kong context: Pemphigus is uncommon but not vanishingly rare. The Chinese population has intermediate incidence. Given Hong Kong's ageing population, clinicians must differentiate from the more prevalent BP in elderly patients. Drug-induced pemphigus (e.g. from penicillamine, used historically for rheumatoid arthritis/Wilson disease) should always be considered.

Risk Factor	Explanation
Genetics (HLA-DR4, HLA-DR14)	Specific HLA class II alleles predispose to autoimmune recognition of desmogleins ^[3]
Ethnicity	Ashkenazi Jewish, Indian, Mediterranean, Middle Eastern backgrounds — higher genetic predisposition
Drugs — especially thiol-containing drugs	Penicillamine, captopril, gold, piroxicam, rifampicin can precipitate pemphigus by biochemically disrupting desmoglein sulfhydryl bonds or inducing neoantigen formation ^[3]
UV exposure	Can trigger or exacerbate disease by inducing keratinocyte apoptosis and neoantigen exposure ^[3]
Viral infections	May act as environmental triggers via molecular mimicry or immune dysregulation ^[3]
Underlying malignancy	Specifically associated with paraneoplastic pemphigus — commonly lymphoproliferative disorders (CLL, NHL, Castleman disease, thymoma) ^[3]

Drug-Induced Pemphigus

Always ask about drug history. Thiol drugs (penicillamine, captopril) are the classic culprits. The mechanism: thiol groups (-SH) can directly interfere with the disulfide bonds in desmoglein molecules, causing acantholysis even without autoantibodies initially, though autoantibodies may subsequently develop. Non-thiol drugs (e.g. ACE inhibitors without thiol groups like enalapril) can also rarely cause it. Drug withdrawal alone may lead to remission.

4. Anatomy and Relevant Structural Biology

The epidermis (from deepest to most superficial) consists of:

Stratum basale (basal layer) — single layer of columnar keratinocytes anchored to the basement membrane zone (BMZ) via hemidesmosomes
Stratum spinosum (spinous/prickle cell layer) — several layers of polyhedral keratinocytes connected by abundant desmosomes
Stratum granulosum (granular layer) — contains keratohyalin granules
Stratum corneum (cornified/horny layer) — dead, anucleate squames

Desmosomes are the primary cell-cell adhesion junctions between keratinocytes. They are "spot welds" that mechanically link adjacent cells.

Key components:

Transmembrane cadherins: Desmoglein (Dsg) 1, 2, 3 and Desmocollin (Dsc) 1, 2, 3
- These are calcium-dependent adhesion glycoproteins whose extracellular domains interdigitate with those on the neighbouring cell
Intracellular plaque proteins: Plakoglobin, plakophilin → link to desmoplakin → which anchors to the intermediate filament (keratin) cytoskeleton

This is the single most important concept for understanding the clinical presentations of different pemphigus subtypes:

Layer	Dsg1	Dsg3
Skin — superficial (stratum granulosum/corneum)	+++++	+
Skin — deep (suprabasal)	++	++++
Mucous membranes (oral, genital, oesophageal)	+	+++++

Key principle: Where both Dsg1 and Dsg3 are expressed, loss of one can be "compensated" by the other, maintaining adhesion. Where only one is present, its loss causes acantholysis.

Desmoglein Compensation Theory — High Yield

This theory explains why:

PF (anti-Dsg1 only) → superficial cutaneous blisters only, NO mucosal involvement (Dsg3 compensates in mucosa and deep skin)
Mucosal PV (anti-Dsg3 only) → mucosal erosions only, skin spared (Dsg1 compensates on skin surface)
Mucocutaneous PV (anti-Dsg1 + Dsg3) → both skin and mucosal involvement

This also explains why PF blisters are more superficial (subcorneal/granular layer split) while PV blisters are suprabasal (deeper split).

Not directly targeted in pemphigus, but understanding it helps distinguish from pemphigoid:

Hemidesmosomes anchor basal keratinocytes to the lamina lucida of the BMZ
Key antigens here: BP180 (type XVII collagen) and BP230 — targets in bullous pemphigoid
This is NOT the target in pemphigus ^[1]

5. Aetiology and Pathophysiology

Pemphigus is an organ-specific autoimmune disease where pathogenic IgG autoantibodies (predominantly IgG4 in the active phase, IgG1 in some contexts) bind to the extracellular domains of desmogleins.

Acantholysis = separation of keratinocytes from each other due to loss of intercellular adhesion ^[2]

Multiple mechanisms contribute:

Steric hindrance / Direct interference: Autoantibody binding to Dsg extracellular domains physically blocks the trans-adhesion (handshake) between Dsg molecules on adjacent cells
Signal transduction: Antibody binding activates intracellular signalling cascades (p38 MAPK, Src kinases) → keratin filament retraction from the desmosomal plaque → weakening of the desmosome
Dsg internalisation/depletion: Antibody-bound Dsg molecules are endocytosed and degraded, reducing the number of functional desmosomes on the cell surface
Complement activation: Plays a minor role; pemphigus can occur in the absence of complement fixation, confirming that the antibody itself is directly pathogenic
Apoptosis (apoptolysis): Some evidence suggests that antibody binding triggers keratinocyte apoptosis, contributing to acantholysis

The fact that IgG autoantibodies are directly pathogenic (proven by passive transfer experiments — injecting patient serum into neonatal mice reproduces blistering) makes pemphigus a type II hypersensitivity reaction (cytotoxic antibody-mediated).

Intraepidermal cleavage with acantholysis ^[3]
- PV: cleavage primarily at the suprabasal level → "tombstone row" = a single row of basal keratinocytes remaining attached to the basement membrane, looking like tombstones ^[2]
- PF: cleavage primarily beneath stratum corneum or in the granular layer (subcorneal/granular) ^[3]
Dislodged keratinocytes (acantholytic cells) = rounded-up, free-floating keratinocytes within the blister cavity ("Tzanck cells" on cytology) ^[2]

"Dislodged keratinocyte, acantholysis... Tombstone row, one single layer of basal keratinocytes on top of the dermis" ^[2]

When pemphigus is severe (extensive erosions), the patient essentially loses the epidermal barrier — analogous to a burn patient:

"80% of body surface area involved → all red area is dermis exposed, no more epidermis → very prone to infection, thermoregulation defects resulting in hypothermia, fluid loss" ^[2]

This is why severe pemphigus requires ICU and burn-unit-like management ^[2].

6. Classification

Subtype	Age	Target Antigen	Antibody Class	Clinical Features	Key Distinguishing Points
Pemphigus Vulgaris (PV)	40–60y	Dsg3 ± Dsg1	IgG	Flaccid blisters → painful erosions; mucosal involvement in almost all patients	Most common form (~70% of pemphigus); suprabasal acantholysis
Pemphigus Foliaceus (PF)	40–60y	Dsg1 only	IgG	Superficial, scaly, crusted erosions; NO mucosal involvement	Superficial (subcorneal/granular) acantholysis; "foliaceus" = leaf-like scale
Paraneoplastic Pemphigus (PNP)	Adults	Anti-envoplakin, anti-periplakin (also anti-desmoplakin, anti-Dsg3)	IgG	Severe stomatitis + variable cutaneous findings (polymorphous — may mimic EM, LP, SJS)	Associated with underlying malignancy (lymphoproliferative — CLL, NHL, Castleman disease, thymoma); worst prognosis; bronchiolitis obliterans may occur ^[3]
IgA Pemphigus	Any age	Anti-desmocollin (subcorneal pustular dermatosis type); poorly defined Ab for intraepidermal neutrophilic dermatosis type	IgA	Grouped pustules/vesicles, crusting erythematous plaques	Looks exactly like subcorneal pustular dermatosis (SPD) → only differentiated by skin biopsy ^[4]; neutrophilic infiltrate

"SPD looks exactly like IgA pemphigus → only can be differentiated by skin biopsy" ^[4]

Based on antibody profile and clinical presentation:

PV Subtype	Antibodies	Sites	Histology
Mucosal-dominant PV	Anti-Dsg3 only	Oral mucosa ± other mucosal surfaces; skin spared	Suprabasal acantholysis
Mucocutaneous PV	Anti-Dsg3 + anti-Dsg1	Mucosa AND skin	Suprabasal acantholysis

Found in rural Brazil and other parts of South America
Clinically and histologically identical to non-endemic PF
Associated with insect bites (sand flies — Simulium species) — possibly through molecular mimicry
Tends to affect younger individuals, including children
Not relevant to Hong Kong practice but occasionally tested

7. Clinical Features

Symptom	Pathophysiological Basis
Oral pain (often the FIRST symptom in PV)	Mucosal erosions due to anti-Dsg3; mucosal blisters rupture almost immediately because mucosa is a wet, friction-rich environment → raw erosions exposed to food, saliva, microbes → intense pain
Pain exacerbated by chewing or swallowing	Mechanical disruption of mucosal erosions during mastication ^[3]
Poor nutrition and weight loss	Secondary to severe oral pain preventing adequate oral intake ^[3]
Skin pain/burning	Erosions expose nerve endings in the superficial dermis to the external environment
Pruritus (uncommon in PV; may occur in PF)	PF superficial erosions may have more itch component; PV typically presents with pain rather than itch
Dysphagia/odynophagia	Oesophageal mucosal involvement (pharyngeal/oesophageal erosions)
Eye irritation/tearing	Conjunctival mucosal erosions
Dyspareunia / genital discomfort	Vulvovaginal/genital mucosal erosions

Clinical Pearl — Oral Erosions Come First

In >50% of PV patients, the disease begins with oral mucosal erosions weeks to months before any skin lesions appear. Patients often see dentists repeatedly before the diagnosis is made. If a middle-aged patient has chronic, non-healing oral ulcers unresponsive to standard treatments — think pemphigus and biopsy.

7.2 Signs

Sign	Description	Pathophysiological Basis
Flaccid blisters	Thin-roofed, easily ruptured blisters on normal or erythematous skin	Suprabasal acantholysis → blister roof = only upper epidermis (thin) → cannot withstand gravity or friction → flaccid and fragile ^[3]
Painful erosions with erythematous base	Where blisters have ruptured; moist, red, raw surfaces; may have serous crusting	Loss of epidermis exposes dermis → no re-epithelialisation without treatment ^[3]
Nikolsky sign POSITIVE	Blistering can be induced by mechanical pressure at edge of blister or on normal skin — sliding pressure on uninvolved skin causes the epidermis to shear off ^[3]	Widespread acantholysis means even "normal-looking" skin has weakened intercellular adhesion. Mechanical force is enough to separate the already-compromised epidermis
Asboe-Hansen sign (bulla-spread sign)	Pressing on intact blister causes it to spread laterally	Fluid dissects along the plane of acantholysis
Mucosal erosions — oral	Most common site of involvement; erosions on buccal mucosa, palate, gingiva, lips, tongue	Anti-Dsg3 targets mucosa where Dsg1 is insufficient to compensate ^[2]^[3]
Mucosal erosions — other sites	Conjunctiva, nose, oesophagus, vulvovaginal area, anus ^[3]	Same mechanism as oral; any stratified squamous epithelium with desmoglein expression
Distribution	Often starts on the oral mucosa → spreads to scalp, face, trunk, axillae, groin (intertriginous areas) ^[2]	Sites of friction and moisture → blisters rupture easily
No scarring (unless secondary infection)	Intraepidermal split → basal layer intact → regeneration possible	Unlike some mucosal diseases (e.g. mucous membrane pemphigoid) that damage the BMZ and cause scarring

"Erosions very extensive — buccal mucosa, lips, gums... Axilla → erosions, superficial, some crusting" ^[2]

Sign	Description	Pathophysiological Basis
Superficial, scaly, crusted erosions	"Cornflake-like" or "leaf-like" scales and crusts	Very superficial (subcorneal) acantholysis → blister roof is just the stratum corneum → extremely fragile → blisters are almost never seen intact, only the resultant erosions/crusts
Seborrhoeic distribution	Scalp, face, upper trunk, back	These are sun-exposed and sebaceous-gland-rich areas; the reason for this predilection is not entirely clear but may relate to Dsg1 expression patterns and UV triggering
NO mucosal involvement	Mucosa is spared	Dsg3 compensates in mucosa (anti-Dsg1 alone cannot cause mucosal acantholysis because Dsg3 is abundantly expressed there)
Nikolsky sign +ve	Over affected or perilesional skin	Same mechanism as PV

Sign	Description	Pathophysiological Basis
Severe, treatment-resistant stomatitis	Extensive, painful mucosal erosions (lips, buccal mucosa, tongue) — often the dominant feature	Multiple autoantibodies against plakin proteins and Dsg3
Polymorphous skin eruption	May look like erythema multiforme (target lesions), lichen planus, or SJS/TEN	Multiple target antigens → diverse histological and clinical patterns
Bronchiolitis obliterans	Progressive dyspnoea → respiratory failure	Anti-plakin antibodies target respiratory epithelium → small airway inflammation and obliterative fibrosis; a major cause of mortality
Signs of underlying malignancy	Lymphadenopathy, hepatosplenomegaly, constitutional symptoms	CLL, NHL, Castleman disease, thymoma

Sign	Description	Pathophysiological Basis
Grouped pustules and vesicles	Annular or circinate ("sunflower-like") arrangement	IgA-mediated neutrophil recruitment to the epidermis → pustule formation (neutrophilic infiltrate)
Crusting erythematous plaques	On trunk and proximal extremities	Superficial intraepidermal neutrophilic infiltration

Feature	Mechanism
Secondary bacterial infection	Loss of epidermal barrier → colonisation by S. aureus, Pseudomonas, etc. → cellulitis, sepsis ^[2]
Hypothermia	Thermoregulation defects — loss of skin barrier → increased evaporative heat loss (same principle as burns) ^[2]
Fluid and electrolyte loss	Weeping erosions → transepidermal water loss, protein loss (hypoalbuminaemia) ^[2]
Malnutrition	Severe oral pain → inability to eat → weight loss, nutritional deficiency ^[3]

"When seeing these patients, must consult ICU + burn environment" ^[2]

"Titer correlates with disease activity in pemphigus" ^[1]

This is in contrast to bullous pemphigoid, where "titer does not correlate with disease activity" ^[1]

This means that anti-Dsg1 and anti-Dsg3 ELISA titres can be used to:

Monitor response to treatment
Predict flares (rising titres precede clinical relapse)
Guide decisions on tapering immunosuppression

Before the advent of corticosteroids, pemphigus vulgaris had a mortality rate of ~75% within 1 year, mostly from sepsis and fluid/electrolyte imbalance. The case described in the PBL illustrates this starkly:

"Patient presented to A&E due to rapid progressive worsening → 80% of body surface area involved... Ultimately died — even after starting treatment with prednisolone and rituximab" ^[2]

With modern treatment:

Mortality: Reduced to ~5–10% (mainly from complications of immunosuppression: infections, metabolic complications of corticosteroids)
Course: Chronic relapsing-remitting; some patients achieve complete long-term remission off therapy, others require lifelong immunosuppression

This comparison is extremely high-yield and tested repeatedly:

Feature	Pemphigus	Bullous Pemphigoid
Target	Intercellular (Dsg1/3)	DEJ (BP180/BP230)
Level of split	Intraepidermal	Subepidermal
Blister type	Flaccid	Tense
Mucosal involvement	Common (PV)	Uncommon (~10-30%)
Nikolsky sign	Positive	Usually negative
Histology	Acantholysis, suprabasal cleft	Subepidermal cleft, eosinophilic infiltrate
DIF pattern	Intercellular "chicken wire" IgG	Linear IgG/C3 at BMZ
Ab titre correlation	Correlates with disease activity	Does not correlate
Age	40–60y	> 60y (elderly)
Prognosis	Worse (historically fatal)	Better

"Antibody levels do not correlate with disease activity, as in pemphigus" — this line from the notes refers to BP antibodies NOT correlating, whereas pemphigus antibodies DO correlate ^[5]

"I hardly ever give systemic steroids to patients — only those with pemphigus / pemphigoid" ^[6]

This quote from the lecturer highlights that autoimmune blistering diseases are among the few dermatological conditions that genuinely warrant systemic corticosteroids as first-line treatment. Most other common dermatological conditions (eczema, psoriasis, acne) are managed with topical therapies and targeted systemic agents, not systemic steroids.

High Yield Summary

Pemphigus — Key Points for Exams:

Definition: Autoimmune blistering disease; IgG against desmogleins → intraepidermal acantholysis → flaccid blisters
PV (most common): Anti-Dsg3 ± Dsg1 → mucosal + cutaneous erosions; suprabasal split; "tombstone row"
PF: Anti-Dsg1 only → superficial cutaneous erosions only; NO mucosa; subcorneal split
PNP: Anti-envoplakin/periplakin → severe stomatitis + polymorphous skin + bronchiolitis obliterans; always search for malignancy
IgA Pemphigus: Anti-desmocollin → grouped pustules; looks like SPD clinically
Desmoglein compensation theory: Explains pattern of involvement in each subtype
Nikolsky sign positive: Mechanical pressure → shearing of epidermis
Antibody titres (ELISA) correlate with disease activity in pemphigus (NOT in pemphigoid)
Untreated: Fatal — sepsis, fluid loss, hypothermia (burn-like pathophysiology)
DIF: "Chicken wire" / intercellular IgG in epidermis
Treatment: Systemic corticosteroids ± steroid-sparing agents (azathioprine, MMF); rituximab increasingly first-line
Drug causes: Thiol drugs (penicillamine, captopril) — always ask drug history

Active Recall - Pemphigus

^[1] Senior notes: Block A - Dermatology PBL 2.pdf (p.2, pemphigus vs pemphigoid targets and titre correlation) ^[2] Senior notes: Block A - Dermatology PBL 2.pdf (p.2, case 3 clinical description, acantholysis, tombstone row, ICU management) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (p.152-153, pemphigus epidemiology, pathogenesis, classification, clinical features, diagnosis, management) ^[4] Senior notes: Block A - Dermatology PBL 1.pdf (p.21, SPD vs IgA pemphigus) ^[5] Senior notes: Block A - It is red and painful.pdf (p.25, antibody levels in pemphigoid vs pemphigus) ^[6] Senior notes: Block A - I have an itchy rash.pdf (p.1, systemic steroids in dermatology)

Differential Diagnosis of Pemphigus

When a patient presents with blisters, erosions, or widespread skin denudation, the clinician must systematically work through a differential diagnosis. The key clinical features that point towards pemphigus — flaccid blisters, painful erosions, mucosal involvement, Nikolsky sign positive — overlap with several other conditions. The approach to the differential depends on:

Level of skin splitting (intraepidermal vs. subepidermal)
Blister morphology (flaccid vs. tense; vesicle vs. pustule vs. bulla)
Mucosal involvement (present or absent)
Distribution (generalised vs. localised; mucosal vs. cutaneous vs. both)
Systemic illness (febrile, drug history, malignancy)
Histology and immunofluorescence (ultimately confirmatory)

Differential diagnoses for a patient presenting with widespread erosions: Pemphigus vulgaris / Stevens-Johnson syndrome / Toxic epidermal necrolysis / Bullous pemphigoid / Paraneoplastic pemphigus ^[7]

Dermatological emergencies include: SJS/TEN, Pemphigus vulgaris, Extensive bullous pemphigoid ^[8]

This table from the approach to vesiculoblistering diseases is extremely high-yield ^[9]:

Level of Split	Clinical Features	Examples
Intracorneal / subcorneal	Only erosions with NO intact blisters, Nikolsky +ve	Staphylococcal scalded skin syndrome (SSSS), bullous impetigo, IgG/IgA pemphigus foliaceus
Intraepidermal / suprabasilar	Occasional intact flaccid blisters with erosions, Nikolsky +ve	Pemphigus vulgaris, Hailey-Hailey disease
Subepidermal	Tense, intact blisters; Nikolsky usually −ve	Bullous pemphigoid, dermatitis herpetiformis, epidermolysis bullosa acquisita, linear IgA bullous dermatosis

Why does the level of split determine blister morphology?

A subcorneal/intraepidermal split has a thin, fragile roof → blisters are flaccid or rupture so quickly they are never seen intact (only erosions remain)
A subepidermal split has the full-thickness epidermis as roof → blisters are tense, dome-shaped, and remain intact longer

Major Differentials — Detailed Comparison

This is the single most important differential for pemphigus, and their distinction is tested repeatedly.

Feature	Pemphigus (PV)	Bullous Pemphigoid
Age	40–50y (younger)	> 70y (older); a/w neurological deficit e.g. Parkinson's, stroke ^[10]
Level	Intraepidermal (superficial)	Subepidermal (deep) ^[10]
Pathogenesis	AutoAb against desmosomes between keratinocytes → cleft within epidermis	AutoAb against hemidesmosomes at DEJ (BP180/BP230) → complement-mediated attack → cleft between epidermis and dermis ^[10]
Blister	Flaccid, ruptures easily	Tense, firm, dome-shaped, does not rupture easily ^[10]
Mucosal	Skin + mucosa	Skin only (mostly); ~17% may have oral mucosal erosions ^[8]^[10]
Nikolsky sign	+ve	−ve ^[10]
Pre-bullous phase	No specific pre-bullous phase	Urticaria-like non-specific rash, can last several months — urticaria > 24 hours should raise suspicion ^[8]^[10]
DIF	IgG/C3 deposits between keratinocytes in "chicken wire pattern"	IgG/C3 deposits along dermo-epidermal junction ^[10]
Ab–disease correlation	Titre correlates with disease activity ^[1]	Titre does NOT correlate with disease activity ^[1]^[5]
Drug associations	Thiol drugs (penicillamine, captopril)	DPP4 inhibitors, frusemide, spironolactone, sulfasalazine, penicillin, penicillamine, β-blockers ^[10]

Pre-bullous BP — A Common Trap

Must recognise early signs of bullous pemphigoid → appears eczematous beforehand, very non-specific and can be missed. Urticaria > 24 hours should raise suspicion — another DDx would be urticarial vasculitis ^[8]. Elderly patients in nursing homes with "itchy eczema unresponsive to treatment" may actually have pre-bullous BP. If you see unexplained urticaria lasting > 24 hours in an elderly patient, biopsy for DIF.

Why does BP affect older patients with neurological disease? Neuronal isoforms of BP180 and BP230 are expressed in the CNS. Neurodegeneration may expose these antigens, triggering cross-reactive autoimmunity against skin BP180/BP230 — a form of "epitope spreading."

This is a critical differential because both SJS/TEN and severe pemphigus can present with widespread epidermal loss, positive Nikolsky sign, and mucosal involvement.

Feature	Pemphigus Vulgaris	SJS/TEN
Mechanism	Autoimmune (anti-Dsg IgG)	Drug-induced cytotoxic T-cell-mediated keratinocyte apoptosis (Type IV HSR)
Onset	Gradual (weeks to months)	Acute — days to weeks after drug exposure
Drug history	May have thiol drug history	Almost always drug-related (sulphonamides, anticonvulsants, allopurinol, NSAIDs) ^[9]
Skin morphology	Flaccid blisters → erosions on normal/erythematous skin	Dusky red/purpuric macules → confluent erythema → full-thickness epidermal necrosis → sheet-like denudation
Key distinguishing sign	Blisters arise on otherwise normal skin	"Dusky red is important, indicates that there is a degree of damage being done already → epidermal necrosis is present. No blanching when pressed" — contrast with erythema (vasodilation) which blanches ^[8]
Mucosal	Yes (oral predominant)	Yes — ≥2 mucosal sites (oral, conjunctival, genital)
Histology	Acantholysis, suprabasal cleft	Full-thickness epidermal necrosis, subepidermal split (keratinocyte apoptosis), no acantholysis
DIF	Intercellular IgG ("chicken wire")	Negative
BSA classification	Not classified by BSA in the same way	< 10% = SJS; 10–30% = overlap; > 30% = TEN ^[9]

Why is SJS/TEN non-blanching but pemphigus erythema is blanching? In SJS/TEN, the "dusky red" colour reflects epidermal necrosis and extravasation of blood — dead tissue does not blanch because the vasculature is destroyed. In pemphigus, the surrounding erythema is due to inflammation/vasodilation — pressing on it compresses the dilated vessels, causing blanching.

Feature	Pemphigus	SSSS
Age	Adults (40–60y)	Neonates and young children (rarely adults) ^[8]
Cause	Autoimmune	*Exfoliative toxins (ETA, ETB) produced by S. aureus* — these toxins specifically cleave Dsg1**
Level of split	Intraepidermal (suprabasal in PV)	Subcorneal/intragranular (same as PF) — because the toxin targets Dsg1
Mucosal	Common in PV	NOT involved (because Dsg3 compensates in mucosa, same logic as PF)
Nikolsky	+ve	+ve
Biopsy	Acantholysis + autoantibodies on DIF	Superficial split only, NO acantholysis (toxin-mediated cleavage), DIF negative

Key insight: SSSS toxins and PF antibodies target the same molecule (Dsg1) — hence the same level of split and same clinical pattern (no mucosal involvement). The difference is infectious vs. autoimmune.

Feature	Pemphigus	EM
Morphology	Flaccid blisters, erosions	Typical "target lesions" (central papule surrounded by erythematous ring) — acral distribution (palms, soles, extremities) ^[11]
Cause	Autoimmune	90% associated with HSV infection; rarely drugs ^[9]
BSA	Variable	Limited bullae + skin shedding involving < 10% BSA ^[9]
Mucosal	Common	Possible but limited
Histology	Acantholysis	Interface dermatitis with keratinocyte necrosis; NO acantholysis

Must be differentiated from PV because management is entirely different (treat the underlying malignancy).

Feature	PV	PNP
Stomatitis	Oral erosions	Severe, treatment-resistant stomatitis — often the most prominent feature ^[3]
Skin	Flaccid blisters	Polymorphous — may mimic EM, lichen planus, or SJS/TEN ^[3]
Antibodies	Anti-Dsg1/3	Anti-envoplakin, anti-periplakin (± anti-desmoplakin, Dsg3) ^[3]
Malignancy	Not inherently associated	Always associated — CLL, NHL, Castleman disease, thymoma ^[3]
Respiratory	Not involved	Bronchiolitis obliterans — major cause of death ^[3]
Prognosis	Moderate	Worst of all pemphigus subtypes

Pustular eruption differential diagnoses: Subcorneal pustular dermatosis (SPD), Pustular psoriasis, Acute generalised exanthematous pustulosis (AGEP), IgA pemphigus ^[7]

Condition	Key Distinguishing Features
Subcorneal Pustular Dermatosis (SPD)	Looks exactly like IgA pemphigus → only can be differentiated by skin biopsy ^[4]; no autoantibodies on DIF; treated with dapsone or retinoids
Generalised Pustular Psoriasis (GPP, Von Zumbusch type)	More merged pustules ("lakes of pus"); extremity predilection; fever, deranged LFT; history of psoriasis ^[12]
AGEP	Drug history (commonly β-lactam antibiotics); onset 3–4 days after drug exposure; more discrete pustules; abdomen predilection; self-limiting (resolves 1–2 weeks after drug withdrawal) ^[9]^[12]

"GPP vs AGEP: Both are medical emergencies, require hospital admission. Very difficult to differentiate clinically — more discrete pustules in AGEP, more merged together (lakes of pus) in GPP. Abdomen in AGEP, extremities in GPP" ^[12]

Condition	Why It Enters the DDx	Key Distinguishing Feature
Dermatitis herpetiformis (DH)	Vesicles, itchy	Grouped vesicles on extensor surfaces; associated with coeliac disease; IgA granular deposits at dermal papillae on DIF (NOT intercellular)
Linear IgA bullous dermatosis	Vesicles/blisters, may have mucosal involvement	"String of pearls" arrangement; linear IgA at BMZ on DIF; drug-associated (vancomycin classic)
Epidermolysis bullosa acquisita (EBA)	Blisters, may mimic BP or pemphigus	Autoantibodies against type VII collagen (anchoring fibrils); skin fragility at trauma-prone sites; scarring and milia
Hailey-Hailey disease	Intraepidermal blistering, acantholysis	Genetic (AD mutation in ATP2C1); flexural predilection; "dilapidated brick wall" on histology; NOT autoimmune (DIF negative)
Erythroderma	Can be caused by pemphigus (as a complication)	Generalised erythema and scaling involving > 90% BSA; causes include pre-existing dermatoses (including immunobullous disorders), drugs, malignancy (CTCL/Sézary), infection, idiopathic ^[11]
Fixed drug eruption	Round, dusky patches	"Multiple round dusky patches over buttocks and thighs = some extent of epidermal necrosis. Spot diagnosis → fixed drug eruption" ^[8]; recurs at the same site with re-exposure

Condition	Blister	Nikolsky	Mucosa	DIF	Age	Key Clue
Pemphigus vulgaris	Flaccid	+ve	++	Intercellular IgG	40–60	Oral erosions first
Pemphigus foliaceus	Erosions only	+ve	−	Intercellular IgG (upper)	40–60	Seborrhoeic distribution
Bullous pemphigoid	Tense	−ve	±	Linear IgG at BMZ	> 70	Pre-bullous urticaria
SJS/TEN	Sheet-like	+ve	++	Negative	Any	Drug Hx, dusky red
SSSS	Flaccid	+ve	−	Negative	Children	S. aureus infection
EM	Targets	−ve	±	Negative	Any	HSV association
PNP	Polymorphous	+ve	+++	Mixed pattern	Adults	Malignancy, refractory stomatitis
IgA pemphigus	Pustules	±	−	Intercellular IgA	Any	Identical to SPD clinically
DH	Grouped vesicles	−ve	−	Granular IgA at papillae	Young adults	Coeliac disease
Linear IgA	"String of pearls"	−ve	±	Linear IgA at BMZ	Any	Vancomycin

High Yield Summary — Pemphigus Differential Diagnosis

The Big Five DDx for widespread erosions (per GC lecture slides): Pemphigus vulgaris, SJS/TEN, Bullous pemphigoid, Paraneoplastic pemphigus ^[7]
PV vs. BP: Flaccid vs. tense; intraepidermal vs. subepidermal; Nikolsky +ve vs. −ve; intercellular IgG vs. linear IgG at BMZ; titre correlates in PV but NOT in BP
PV vs. SJS/TEN: Gradual autoimmune vs. acute drug-induced; acantholysis vs. full-thickness necrosis; "dusky non-blanching" = SJS/TEN
Pustular eruption DDx: SPD, GPP, AGEP, IgA pemphigus — SPD and IgA pemphigus can only be differentiated by biopsy ^[4]
SSSS vs. PF: Both target Dsg1 (toxin vs. antibody); both spare mucosa; differentiated by age (children vs. adults) and DIF (negative vs. positive)
Dermatological emergencies: SJS/TEN, Pemphigus vulgaris, Extensive bullous pemphigoid ^[8]
Pre-bullous BP trap: Elderly patient with persistent urticaria (> 24h) or "eczema" unresponsive to treatment → think BP and biopsy

Active Recall - Pemphigus Differential Diagnosis

References

^[1] Senior notes: Block A - Dermatology PBL 2.pdf (p.2, titre correlation in pemphigus vs. pemphigoid) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (p.152, pemphigus subtypes including PNP) ^[4] Senior notes: Block A - Dermatology PBL 1.pdf (p.21, SPD vs. IgA pemphigus) ^[5] Senior notes: Block A - It is red and painful.pdf (p.25, antibody levels in pemphigoid) ^[7] Lecture slides: Derm General Clerkship 2026 Part2.pdf (p.2, DDx list for pemphigus presentation) ^[8] Senior notes: Block A - Dermatology PBL 2.pdf (p.3 and p.6, pre-bullous BP, urticaria > 24h, dermatological emergencies, dusky red/non-blanching, fixed drug eruption) ^[9] Senior notes: Ryan Ho Rheumatology.pdf (p.147–150, approach to blistering disease DDx, SJS/TEN, EM, AGEP) ^[10] Senior notes: Maksim Medicine Notes.pdf (p.71, pemphigus vs. BP comparison table) ^[11] Senior notes: Maksim Medicine Notes.pdf (p.77, erythroderma, erythema multiforme) ^[12] Senior notes: Block A - Dermatology PBL 1.pdf (p.18, GPP vs. AGEP)

Diagnosis of Pemphigus — Criteria, Algorithm, and Investigations

There is no single universally agreed "diagnostic criteria" checklist for pemphigus in the way that, say, the Jones criteria exist for rheumatic fever. Instead, the diagnosis rests on a convergence of clinical, histological, and immunological evidence. In practice, a confident diagnosis of pemphigus requires at least clinical features PLUS confirmatory histopathology PLUS immunofluorescence (direct or serological).

The diagnostic pillars are:

Pillar	What It Shows	Why It Is Necessary
1. Clinical features	Flaccid blisters / erosions ± mucosal involvement, Nikolsky +ve	Raises suspicion — but insufficient alone because SJS/TEN, SSSS, and other conditions mimic pemphigus
2. Histopathology (H&E)	Intraepidermal acantholysis at the appropriate level	Confirms the pathological process (acantholysis) and the level of split (suprabasal vs. subcorneal) — but cannot alone prove autoimmune aetiology
3. Direct immunofluorescence (DIF)	Intercellular IgG ± C3 deposition in the epidermis	Gold standard — confirms autoimmune antibody deposition at the site of disease. This is what definitively separates pemphigus from non-autoimmune mimics (SSSS, SJS/TEN)
4. Serology (ELISA / Indirect IF)	Circulating anti-Dsg1/Dsg3 antibodies	Identifies the specific target antigen; correlates with disease activity and can be used for monitoring ^[1]

Diagnostic Standard — GC Lecture Slide High Yield

"Skin biopsy — Histology: Loss of the intracellular adhesion, supra-basal splitting, acantholysis of keratinocyte cells; IMF: intercellular pattern IgG/C3" ^[13]

This is the core diagnostic finding. You need both H&E histology AND direct immunofluorescence (IMF) from the skin biopsy to make the diagnosis. A biopsy sent for only one of these is incomplete.

The overall approach when pemphigus is suspected:

Investigations to order (GC lecture slide): "CBC, LRFT, anti-skin, anti-dsg1 & 3, HBsAg, anti-HBc, G6PD, HbA1c, IgGAM; Wound swab × aerobic culture, HSV/VZV PCR; CXR; Skin biopsy" ^[7]

Why These Specific Baseline Bloods?

The investigation panel is not random — each test serves a purpose in the context of a patient about to receive potent immunosuppression:

HBsAg, anti-HBc: Screen for hepatitis B before immunosuppression (risk of reactivation with rituximab, steroids, azathioprine)
G6PD: Screen before dapsone (used occasionally; G6PD deficiency → haemolytic crisis with dapsone/sulphonamides)
HbA1c: Baseline glycaemic status before systemic corticosteroids (which cause hyperglycaemia)
IgGAM: Baseline immunoglobulin levels; relevant if considering rituximab (B-cell depletion → hypogammaglobulinaemia) or IVIg
CBC: Baseline haematological parameters; monitor for drug-induced cytopenias with azathioprine/MMF
LRFT: Baseline liver and renal function for drug dosing and monitoring hepatotoxicity/nephrotoxicity
HSV/VZV PCR, wound swab × aerobic culture: Important to rule out primary/secondary skin infection ^[13] — secondary infection complicates management and must be treated; HSV/VZV can mimic or co-exist with pemphigus erosions
CXR: Baseline before immunosuppression; rule out TB, lymphoma (relevant for PNP)

3. Investigation Modalities — Detailed Breakdown

This is the cornerstone investigation. Two key principles:

A. Biopsy technique and site:

Perilesional biopsy — take the biopsy from the edge of an active blister (or from perilesional uninvolved skin, within 1 cm of a fresh lesion) ^[3]
- Why perilesional and not from the centre of a lesion? The centre of an old erosion may show only non-specific inflammation, necrosis, and secondary infection. The perilesional area captures the advancing edge where the autoimmune process is actively occurring — this is where you see acantholysis in evolution and where antibody deposition is best demonstrated on DIF
The biopsy should ideally be a punch biopsy (≥ 4 mm) taking full-thickness tissue
Split the biopsy into TWO specimens ^[3]:
1. One piece in formalin → for H&E histology
2. One piece in Michel's transport medium (or snap-frozen) → for direct immunofluorescence

Common Exam Mistake — Biopsy Handling

A very common error is sending only one specimen for histology and forgetting DIF, or vice versa. You MUST split the biopsy and send for BOTH. DIF requires unfixed (fresh/Michel's medium) tissue — putting everything in formalin destroys the immunoreactants and makes DIF impossible. This is a practical point that is tested.

B. Histopathology (H&E) findings:

Subtype	Histological Features	Explanation
Pemphigus vulgaris	Intraepithelial cleavage with acantholysis, primarily at the suprabasal region ^[3]	Anti-Dsg3 targets the deep epidermis where Dsg3 is most concentrated → basal cells detach from each other but remain attached to the basement membrane via hemidesmosomes → "tombstone row" (a single row of basal keratinocytes sitting on the dermis like headstones in a graveyard) ^[2]
Pemphigus foliaceus	Intraepithelial cleavage with acantholysis, primarily beneath stratum corneum or in the granular layer ^[3]	Anti-Dsg1 targets the superficial epidermis → subcorneal/granular split
IgA pemphigus	Intraepidermal neutrophilic infiltrate ± subcorneal pustules	IgA-mediated neutrophil chemotaxis into the epidermis
PNP	Suprabasal acantholysis + interface dermatitis (lichenoid pattern with keratinocyte necrosis)	Combined desmosomal and BMZ targeting → mixed pattern

Key histological terms to understand:

Acantholysis: Loss of intercellular adhesion between keratinocytes → rounded-up, free-floating cells ("acantholytic cells" or "Tzanck cells") within the cleft cavity ^[2]
"Tombstone row": "One single layer of basal keratinocytes on top of the dermis" ^[2] — pathognomonic for PV
"Dislodged keratinocyte": The acantholytic cell that has lost all desmosomal connections ^[2]

C. Direct Immunofluorescence (DIF) — the gold standard:

Subtype	DIF Pattern	Location
Pemphigus vulgaris	Intercellular IgG deposition throughout epidermis — "chicken wire" or "fishnet" pattern ^[3]	Throughout all layers of the epidermis
Pemphigus foliaceus	Intercellular IgG deposition mainly at the upper epidermis ^[3]	Concentrated in the superficial layers (correlating with Dsg1 distribution)
IgA pemphigus	Intercellular IgA (not IgG) deposition	Variable level depending on subtype
PNP	Combined intercellular + linear BMZ staining	Reflects antibodies targeting both desmosomal and plakin proteins

"DIF shows intercellular IgG deposition throughout the epidermis" (PV) vs. "mainly at the upper epidermis" (PF) ^[3]

Why "chicken wire" pattern? On DIF, the antibodies bound to the keratinocyte surface outline each individual cell. Because keratinocytes are polygonal and packed together, the staining outlines a honeycomb/meshwork pattern that looks like chicken wire fencing when viewed under the fluorescence microscope. This is pathognomonic for pemphigus.

Sensitivity of DIF: > 90% (highest sensitivity of all pemphigus investigations; considered the gold standard).

Three serological modalities are used:

A. Anti-skin antibody (Indirect Immunofluorescence — IIF):

Available in all public hospitals ^[14]
Method: Patient's serum is incubated with a substrate epithelium (classically monkey oesophagus or guinea pig oesophagus) → if circulating anti-keratinocyte surface antibodies are present, they bind to the substrate epithelium → detected by fluorescein-tagged anti-human IgG
Result: Intercellular IgG deposition on the substrate epithelium = positive
Sensitivity: > 80% positive for intercellular IgG ^[3]
Limitation: Cannot be used alone to distinguish between PV and PF (both show intercellular pattern) ^[3]
"Antiskin antibody +ve, highly positive" confirms circulating autoantibodies ^[14]

B. ELISA for IgG to Desmoglein 1 and Desmoglein 3:

The most specific serological test — directly measures antibodies against the specific target antigens
Sensitivity > 90% (better sensitivity and specificity than IIF) ^[3]
Can be used to monitor disease activity and response to treatment — titre correlates with disease severity ^[1]^[3]
Clinical utility for subtyping:

Anti-Dsg3	Anti-Dsg1	Interpretation
+	−	Mucosal-dominant PV
+	+	Mucocutaneous PV
−	+	Pemphigus foliaceus

"ELISA for IgG to desmoglein 1/3: Sens > 90% (better Sens/Spec over IIF), can be used to monitor disease activity and response to Tx (correlate with disease severity)" ^[3]

C. IgGAM (total immunoglobulin levels):

Included in the GC investigation panel ^[7]
Why? Baseline immunoglobulin quantification before initiating rituximab (anti-CD20, depletes B cells → risk of secondary hypogammaglobulinaemia) or before considering IVIg replacement

Method: Scrape the base of a fresh blister or erosion → smear on glass slide → stain (Wright or Giemsa stain)
Finding: Acantholytic cells (Tzanck cells) — rounded, enlarged keratinocytes with large nuclei and prominent nucleoli, that have lost their intercellular connections
Utility: Rapid bedside test; can provide early supportive evidence for pemphigus within minutes
Limitations: Not specific — Tzanck cells are also seen in herpes virus infections (HSV/VZV) where they represent multinucleated giant cells and balloon degeneration; does not distinguish pemphigus subtypes; does not replace skin biopsy

GC Lecture Slide Investigation Panel: "CBC, LRFT, anti-skin, anti-dsg1 & 3, HBsAg, anti-HBc, G6PD, HbA1c, IgGAM; Wound swab × aerobic culture, HSV/VZV PCR; CXR; Skin biopsy" ^[7]

Investigation	Purpose	Key Findings / Interpretation
CBC	Baseline; monitor for cytopenias with treatment (azathioprine, MMF)	Anaemia (chronic disease or blood loss from erosions); leukocytosis (secondary infection); eosinophilia possible
LRFT	Baseline renal and liver function; monitor drug toxicity	↓Albumin (protein loss through weeping erosions); electrolyte imbalance (transdermal fluid loss); baseline for steroid/azathioprine/MMF monitoring
Anti-skin antibody	Screening serological test (IIF)	+ve intercellular pattern supports pemphigus; available in all HA hospitals ^[14]
Anti-Dsg1 and anti-Dsg3	Specific diagnosis and subtyping; disease monitoring	See ELISA interpretation table above
HBsAg, anti-HBc	Hepatitis B screening before immunosuppression	Positive → risk of HBV reactivation with rituximab/steroids → start antiviral prophylaxis (e.g. entecavir) BEFORE immunosuppression
G6PD	Screen before dapsone use	Deficient → dapsone contraindicated (causes oxidative haemolysis)
HbA1c	Baseline glycaemic control before steroids	Elevated → closer glucose monitoring during steroid therapy; adjust diabetic medications
IgGAM	Baseline immunoglobulin levels	Low IgG → increased infection risk with rituximab; may need IVIg supplementation
Wound swab × aerobic culture	Rule out secondary bacterial infection ^[13]	Positive → targeted antibiotics; S. aureus and Pseudomonas are common colonisers of denuded skin
HSV/VZV PCR	Rule out primary/secondary viral skin infection ^[13]	HSV/VZV can co-exist with or mimic pemphigus erosions; herpetic infections may flare during immunosuppression
CXR	Baseline before immunosuppression; screen for TB, lymphoma	Abnormal → investigate further before starting treatment; PNP may have mediastinal mass (thymoma, lymphoma)

Subtype	Additional Investigations	Rationale
Paraneoplastic pemphigus	CT thorax/abdomen/pelvis; PET-CT; bone marrow biopsy; peripheral blood flow cytometry	Must work out for any underlying malignancy as symptoms/age directed ^[13]; CLL, NHL, Castleman disease, thymoma
PNP	Anti-envoplakin, anti-periplakin antibodies; immunoprecipitation for plakin proteins	Confirm specific PNP antibodies; standard anti-Dsg may be positive but plakin antibodies are key
PNP	Pulmonary function tests	Screen for bronchiolitis obliterans (restrictive/obstructive pattern, ↓DLCO)
IgA pemphigus	DIF for IgA (not IgG); consider desmocollin antibodies	Distinguish from SPD — only differentiable by skin biopsy ^[4]

Parameter	Method	Interpretation
Clinical	Track new blister formation, Nikolsky sign, healing of old lesions	Response to Tx assessed by cessation of new blister formation, absent Nikolsky sign, healing of old lesions ^[3]
Anti-Dsg ELISA titres	Serial blood tests (e.g. monthly during active treatment)	Dropping ELISA titres used as adjunct to clinical monitoring ^[3]; rising titres may herald flare → pre-emptive treatment adjustment
CBC, LRFT	Regular bloods during immunosuppression	Monitor for drug-induced cytopenias (azathioprine), hepatotoxicity, renal impairment
TPMT / NUDT15 genotype	Before starting azathioprine	TPMT/NUDT15 deficiency → accumulation of thioguanine nucleotides → severe myelosuppression; especially important in East Asian populations (higher NUDT15 variant frequency)

Scenario	H&E	DIF	Anti-Dsg1	Anti-Dsg3	Anti-skin IIF	Diagnosis
Oral erosions → suprabasal acantholysis	Suprabasal cleft, tombstone row	Intercellular IgG/C3 throughout epidermis	−	+	+ (intercellular)	Mucosal-dominant PV
Oral + skin erosions → suprabasal acantholysis	Suprabasal cleft, tombstone row	Intercellular IgG/C3 throughout	+	+	+ (intercellular)	Mucocutaneous PV
Scaly crusted lesions, no mucosa → subcorneal acantholysis	Subcorneal/granular cleft	Intercellular IgG upper epidermis	+	−	+ (intercellular)	Pemphigus foliaceus
Severe stomatitis + polymorphous skin + lymphoma found	Suprabasal acantholysis + interface dermatitis	Intercellular + linear BMZ	±	±	+ (mixed pattern)	Paraneoplastic pemphigus
Grouped pustules → subcorneal neutrophilic infiltrate	Subcorneal pustules	Intercellular IgA	−	−	±	IgA pemphigus

High Yield Summary — Pemphigus Diagnosis

Diagnosis requires convergence: Clinical features + Histopathology (H&E) + Direct Immunofluorescence (DIF) + Serology
Skin biopsy: Perilesional, split into two — one for H&E (formalin), one for DIF (Michel's medium / fresh)
H&E key findings: Suprabasal acantholysis with tombstone row (PV) or subcorneal acantholysis (PF)
DIF gold standard: Intercellular IgG/C3 "chicken wire" pattern — pathognomonic
Serology: Anti-Dsg1/Dsg3 ELISA > 90% sensitivity; correlates with disease activity (for monitoring); anti-skin antibody (IIF) > 80% sensitivity, available in all HA hospitals
GC investigation panel: CBC, LRFT, anti-skin, anti-Dsg1 & 3, HBsAg, anti-HBc, G6PD, HbA1c, IgGAM; wound swab × aerobic culture + HSV/VZV PCR; CXR; skin biopsy
Pre-treatment rationale: HBsAg/anti-HBc (HBV reactivation risk), G6PD (dapsone safety), HbA1c (steroid-induced diabetes), IgGAM (rituximab safety)
Monitoring: Clinical (new blisters, Nikolsky sign, healing) + dropping ELISA titres
Rule out infection: Important to rule out primary/secondary skin infection — swab for HSV, bacterial culture

Active Recall - Pemphigus Diagnosis

References

^[1] Senior notes: Block A - Dermatology PBL 2.pdf (p.2, titre correlation in pemphigus) ^[2] Senior notes: Block A - Dermatology PBL 2.pdf (p.2, acantholysis, tombstone row, dislodged keratinocyte) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (p.152–153, diagnosis — biopsy, DIF patterns, ELISA, IIF, monitoring) ^[4] Senior notes: Block A - Dermatology PBL 1.pdf (p.21, SPD vs IgA pemphigus differentiation by biopsy) ^[7] Lecture slides: Derm General Clerkship 2026 Part2.pdf (p.2, investigation panel) ^[13] Lecture slides: CFB (MED09) Dermatology (II).pdf (p.7, pemphigus investigation — blood workup, skin biopsy, histology, IMF, rule out infection, malignancy workup) ^[14] Senior notes: Block A - Dermatology PBL 2.pdf (p.1, anti-skin antibody available in all public hospitals, highly positive)

Management of Pemphigus

The management of pemphigus follows a structured, phased approach. Understanding why each phase exists is crucial:

Treatment always indicated at disease onset even for mild disease to ↓ complications ^[3]

Why treat even mild disease? Pemphigus is a progressive autoimmune disease. Without treatment, autoantibody production continues unchecked → ongoing acantholysis → expansion of erosions → eventually massive epidermal loss with life-threatening complications (sepsis, fluid loss, hypothermia). The PBL case illustrates the catastrophic consequences of delayed treatment — a patient who refused treatment progressed to 80% BSA involvement and died ^[2].

The three phases of treatment (as taught in the lecture):

"Induce remission, consolidate remission, withdraw medication slowly" ^[15]

Phase	Goal	Duration	Key Principle
1. Induction	Stop new blister formation; control disease	Weeks to months	High-dose immunosuppression
2. Consolidation	Heal existing lesions; maintain disease control	Months	Begin tapering while maintaining control
3. Maintenance / Withdrawal	Taper to minimal effective dose → eventual withdrawal	Months to years	Withdraw medication slowly to prevent relapse ^[15]

"Problem is that lots of side effects, toxicity" from prolonged steroids — this is the fundamental rationale for steroid-sparing agents and the shift towards biologics ^[15]

3. Treatment Modalities — Detailed Breakdown

These measures apply to every pemphigus patient, regardless of severity. They are frequently overlooked but are critical for outcomes.

A. Basic Skin / Wound Care:

"Basic skin care, e.g. sterile puncture and drainage of large blisters, leave blister roof in situ to ↓ infection risk, sterile wound dressing" ^[3]

Measure	Rationale
Sterile puncture and drainage of large blisters	Relieves tension and discomfort; prevents lateral extension of blister by removing the hydrostatic pressure that dissects along the acantholytic plane
Leave blister roof in situ	The collapsed blister roof acts as a biological dressing — it protects the exposed dermis from infection, desiccation, and mechanical trauma. De-roofing removes this protection and increases infection risk ^[3]^[10]
Sterile, non-adhesive wound dressings	Protects erosions; adhesive dressings would tear off fragile epithelium when removed
Antibiotics if concomitant infection	"Antibiotics if there is concomitant infection" ^[13] — secondary bacterial infection (S. aureus, Pseudomonas) is a major cause of morbidity and mortality

Blister Management — Do NOT De-roof

A common clinical mistake is de-roofing blisters. Prick but do NOT de-roof ^[10]. The blister roof, though fragile, is the patient's only remaining barrier against the environment. Removing it exposes the raw dermis to bacteria, fluid loss, and pain.

B. Oral Symptom Management:

"Oral symptom Mx: avoid irritating food, apply topical LA as needed, oral hygiene, consider topical steroid (associated with ↓ symptoms)" ^[3]

Measure	Explanation
Avoid irritating food	Spicy, acidic, crunchy, or very hot food mechanically and chemically irritates mucosal erosions → worsens pain
Topical local anaesthetic	E.g. lidocaine gel/spray applied before meals → numbs mucosal surface → allows eating
Oral hygiene	Gentle brushing, antiseptic mouthwash (chlorhexidine) → reduces bacterial load on mucosal erosions → reduces secondary infection risk
Topical steroid	E.g. triamcinolone acetonide in orabase, or dexamethasone mouthwash → local anti-inflammatory effect on oral erosions
Nutritional support	If oral intake is severely impaired → consider soft/liquid diet, nutritional supplements, or NG feeding in extreme cases

C. Severe / Extensive Disease — Burn-Unit Approach:

"When seeing these patients, must consult ICU + burn environment" ^[2]

Measure	Rationale
ICU consultation	For monitoring: fluid balance, temperature, haemodynamics, infection surveillance
Sterile/burn-unit environment	Minimise nosocomial infection risk — extensive epidermal loss = loss of the primary barrier against pathogens
Fluid and electrolyte replacement	Transepidermal water and protein loss → hypovolaemia, hypoalbuminaemia, electrolyte imbalance
Temperature management	Thermoregulation failure → hypothermia (lost epidermis = lost insulation + increased evaporative heat loss)
Nutritional support	Catabolism + inability to eat (oral erosions) → caloric and protein deficiency → impaired wound healing

"Systemic corticosteroid — mainstay of initial treatment" ^[13]

"I hardly ever give systemic steroids to patients — only those with pemphigus / pemphigoid" ^[6] — emphasising that pemphigus is one of the few dermatological conditions genuinely warranting systemic steroids

Mechanism: Corticosteroids suppress the autoimmune response broadly — they inhibit T-cell activation, reduce cytokine production, suppress B-cell function (reducing autoantibody production), and have anti-inflammatory effects that reduce tissue damage at the blister site.

Regimen:

Parameter	Detail
Drug	Oral prednisone / prednisolone
Dose	1–1.5 mg/kg/day ^[3]
When to start tapering	Begin tapering ≥ 1 week after the last formation of new lesions ^[3]
Taper rate	Gradual — typically reduce by 5–10 mg every 1–2 weeks initially, then slower (2.5–5 mg every 2–4 weeks) as the dose decreases; no fixed protocol — guided by clinical response

Monitoring response to treatment:

"Response to Tx assessed by cessation of new blister formation, absent Nikolsky sign, healing of old lesions and dropping ELISA titres (as adjunct)" ^[3]

Response Marker	Significance
No new blisters	Primary clinical endpoint — indicates disease control
Nikolsky sign becomes negative	Indicates restoration of intercellular adhesion in uninvolved skin
Healing of existing erosions	Indicates re-epithelialisation
Dropping anti-Dsg ELISA titres	Correlates with disease activity ^[1] — confirms immunological response

Side effects of prolonged systemic steroids (the reason steroid-sparing agents are essential):

"Problem is that lots of side effects, toxicity" ^[15]

System	Side Effect	Mechanism
Metabolic	Hyperglycaemia / steroid-induced diabetes	Glucocorticoids ↑ hepatic gluconeogenesis + ↑ peripheral insulin resistance
Skeletal	Osteoporosis, avascular necrosis	↓ Osteoblast activity + ↑ osteoclast activity; impaired blood supply to femoral head
GI	Peptic ulcer (especially with concurrent NSAIDs)	↓ Prostaglandin-mediated mucosal protection
Cardiovascular	Hypertension, fluid retention	Mineralocorticoid effect (Na⁺/water retention)
Immune	Increased infection susceptibility	Broad immunosuppression
Endocrine	Adrenal suppression, Cushingoid features	Exogenous cortisol suppresses HPA axis
Psychiatric	Insomnia, mood changes, psychosis	Direct CNS effects of glucocorticoids
Ophthalmic	Cataracts, glaucoma	Altered lens protein metabolism; ↑ intraocular pressure

Prophylaxis during steroid therapy:

Bone protection: Calcium + Vitamin D supplementation; consider bisphosphonate if prolonged high-dose use
GI protection: PPI if high dose or concurrent risk factors
Infection: Monitor for signs; consider PJP prophylaxis (co-trimoxazole) if on high-dose steroids + other immunosuppression
Glucose monitoring: Regular blood glucose / HbA1c (reason for pre-treatment HbA1c in investigation panel)

"Now biologics used more recently — Rituximab as first line, landmark paper — changed the way we treat pemphigus" ^[15]

"Rituximab (anti-CD20 B cell depleting agent)" ^[13]

"Alternative: upfront rituximab + prednisone gaining popularity recently" ^[3]

What is rituximab? The name breaks down as: "ri-" (chimeric antibody prefix) + "-tu-" (for tumour) + "-xi-" (chimeric) + "-mab" (monoclonal antibody). It is a chimeric anti-CD20 monoclonal antibody that depletes CD20-positive B cells.

Mechanism in pemphigus:

CD20 is expressed on pre-B cells through to mature B cells (but NOT on plasma cells or stem cells)
Rituximab binds CD20 → depletes the B-cell lineage that produces pathogenic anti-Dsg autoantibodies
This is essentially a "factory reset" of the B-cell compartment ^[2] — the autoreactive B-cell clones are destroyed, and when B cells regenerate from stem cells, they may not re-develop the same autoreactivity
Spares long-lived plasma cells initially → existing antibodies persist temporarily → clinical improvement is not immediate (takes weeks)

"Remember that rituximab takes time to factory reset, so need prednisolone / IVIg" ^[2] — this explains why rituximab is combined with corticosteroids for initial disease control

The Landmark RITUX 3 Trial (Joly et al., Lancet 2017):

Showed that first-line rituximab + low-dose prednisone achieved complete remission off therapy in 89% vs. 34% with prednisone alone at 24 months
Patients in the rituximab arm required significantly less cumulative corticosteroid
This trial fundamentally changed practice → rituximab is now considered a first-line option in many centres, not just for refractory disease

Regimen options:

Rheumatology protocol: 1000 mg IV on Day 1 and Day 15 (two infusions)
Lymphoma protocol: 375 mg/m² IV weekly × 4 weeks
Either protocol is acceptable; the rheumatology protocol is simpler and commonly used in dermatology

Monitoring and cautions:

Concern	Action
HBV reactivation	Must screen HBsAg and anti-HBc BEFORE rituximab — if positive, start antiviral prophylaxis (entecavir)
Hypogammaglobulinaemia	B-cell depletion → ↓ immunoglobulin production over time → check IgG levels; may need IVIg supplementation
Infusion reactions	Pre-medicate with paracetamol, antihistamine, IV methylprednisolone; slow initial infusion rate
Progressive multifocal leukoencephalopathy (PML)	Extremely rare but reported; caused by JC virus reactivation in severely immunosuppressed patients
Infection risk	Impaired humoral immunity → increased susceptibility to encapsulated organisms and viral infections

Contraindications to rituximab:

Active severe infection
Severe hypogammaglobulinaemia (IgG < 4 g/L) — relative contraindication
Known hypersensitivity
Pregnancy / breastfeeding

"Immunosuppressive agents: azathioprine / Mycophenolate; Rituximab (anti-CD20 B cell depleting agent)" ^[13]

"Steroid-sparing adjunct, e.g. azathioprine (preferred), MMF, cyclophosphamide (refractory only)" ^[3]

The rationale for steroid-sparing agents: prolonged high-dose steroids cause unacceptable toxicity. These agents allow earlier and faster steroid tapering while maintaining disease control.

A. Azathioprine (AZA) — Preferred first-line steroid-sparing agent:

Parameter	Detail
Mechanism	Purine analogue → metabolised to 6-mercaptopurine → inhibits purine synthesis → suppresses lymphocyte proliferation (T and B cells)
Dose	1–3 mg/kg/day (adjusted based on TPMT/NUDT15 activity)
Onset	Slow — 4–8 weeks to reach full efficacy
When to start	Routine upfront use in conjunction with steroid in some centres; start at flares during steroid tapering or when refractory to steroids in others ^[3]
When to stop	Start tapering 8 weeks after completely off steroids ^[3]
Pre-treatment testing	TPMT and NUDT15 genotyping — deficiency → accumulation of toxic thioguanine nucleotides → severe myelosuppression. NUDT15 variants are particularly common in East Asian populations (including HK Chinese — ~20% carry at least one risk allele)
Monitoring	Regular CBC (weekly initially, then monthly) → watch for leukopenia, pancytopenia; LFT for hepatotoxicity
Contraindications	TPMT/NUDT15 homozygous deficiency (absolute); pregnancy (teratogenic — category D); concurrent allopurinol (inhibits xanthine oxidase → blocks AZA metabolism → toxicity; must reduce AZA dose by 75% if co-prescribed)

B. Mycophenolate Mofetil (MMF) — Alternative to AZA:

Parameter	Detail
Mechanism	Prodrug → active metabolite mycophenolic acid → inhibits inosine monophosphate dehydrogenase (IMPDH) → selectively blocks de novo purine synthesis in lymphocytes (lymphocytes uniquely depend on the de novo pathway, unlike other cells that have a salvage pathway)
Dose	2–3 g/day in divided doses
Advantage over AZA	Does not require TPMT/NUDT15 testing; more selective lymphocyte suppression
Side effects	GI disturbance (diarrhoea, nausea — common), leukopenia, infections
Contraindications	Pregnancy (teratogenic — category D); breastfeeding

C. Cyclophosphamide — Reserved for Refractory Disease:

"Cyclophosphamide (refractory only)" ^[3]

Parameter	Detail
Mechanism	Alkylating agent → cross-links DNA → cytotoxic to rapidly dividing cells including lymphocytes
Use in pemphigus	Refractory disease only — when AZA/MMF/rituximab fail
Side effects	Haemorrhagic cystitis (due to acrolein metabolite — prevent with mesna and hydration), bone marrow suppression, gonadal toxicity (infertility), secondary malignancy (bladder cancer, leukaemia)
Contraindications	Pregnancy, active infection, severe bone marrow suppression

"Consider Intravenous immunoglobulin for severe / refractory type" ^[13]

"Need prednisolone / IVIg" while waiting for rituximab to take effect ^[2]

Parameter	Detail
Mechanism	Multiple proposed mechanisms: neutralisation of pathogenic autoantibodies; Fc receptor blockade on macrophages → ↓ antibody-mediated damage; immunomodulation of B/T cells; accelerated catabolism of IgG (including pathogenic IgG) via FcRn saturation
Dose	2 g/kg divided over 3–5 days per cycle; repeated monthly as needed
Indications	Severe or refractory pemphigus; bridge therapy while awaiting rituximab effect; acute deterioration requiring rapid antibody reduction
Advantages	Rapid onset (within days); does not further immunosuppress the patient (unlike cyclophosphamide)
Side effects	Headache, fever, chills (infusion-related); aseptic meningitis; thromboembolic events (IVIg increases blood viscosity); renal impairment (sucrose-containing preparations); anaphylaxis in IgA-deficient patients
Contraindications	Selective IgA deficiency with anti-IgA antibodies (anaphylaxis risk); severe renal impairment (use non-sucrose preparations)

"Other immunosuppressive therapy for refractory disease: rituximab, IVIg, immunoadsorption, plasmapheresis, cyclophosphamide, topical steroids" ^[3]

Modality	Mechanism	Role
Immunoadsorption	Selectively removes IgG (including pathogenic anti-Dsg) from plasma using protein A columns	Rapid reduction of pathogenic antibodies; avoids removal of clotting factors (cf. plasmapheresis)
Plasmapheresis	Non-selective removal of plasma (including antibodies, clotting factors, complement)	Rapid reduction in circulating autoantibodies; used as bridge in acute severe disease
Dapsone	Anti-inflammatory (inhibits neutrophil chemotaxis); especially useful in IgA pemphigus	IgA pemphigus, mild PF; must check G6PD first (haemolytic anaemia in G6PD deficiency)
Topical steroids	Local anti-inflammatory effect	Adjunct for localised lesions; not sufficient alone for moderate-severe disease

Principle	Detail
Identify and withdraw the culprit drug	Especially thiol drugs (penicillamine, captopril); non-thiol drugs (e.g. other ACE inhibitors, NSAIDs, antibiotics)
Observation	Some cases resolve spontaneously after drug withdrawal (especially if no true autoantibodies develop)
If persistent	Treat as autoimmune pemphigus with standard immunosuppressive regimen

Principle	Detail
Treat underlying malignancy	Tumour resection (if possible, e.g. Castleman disease) may lead to remission
Standard immunosuppression	Often poorly responsive to conventional treatment
Bronchiolitis obliterans	Progressive and often irreversible; monitor with PFTs; may require lung transplant consideration

Phase	Clinical Markers	Steroid Status	Steroid-Sparing Agent	Monitoring
Induction	Active new blisters, Nikolsky +ve	Full dose: 1–1.5 mg/kg/day	Start upfront or within first few weeks	Weekly CBC, fortnightly LRFT, anti-Dsg titres at baseline
Disease control achieved	No new blisters for ≥ 1 week	Begin tapering ^[3]	Continue / uptitrate if needed	Clinical review; anti-Dsg titres monthly
Consolidation	Existing lesions healing, Nikolsky −ve	Gradual taper (aim ~0.5 mg/kg/day)	Maintain therapeutic dose	Monthly CBC/LRFT; anti-Dsg titres
Maintenance	All lesions healed, titres low/negative	Continue tapering → aim to stop	Continue at stable dose	2–3 monthly reviews
Remission off steroids	No active disease, off steroids	STOPPED	Start tapering 8 weeks after completely off steroids ^[3]	Continue monitoring for relapse
Complete remission off therapy	No disease, off all medications	OFF	OFF	Annual review; re-check titres if symptoms recur

Parameter	Pemphigus	Bullous Pemphigoid
Steroid dose	Higher: 1–1.5 mg/kg/day	Lower: 0.5–0.75 mg/kg/day
Topical steroid role	Adjunct only	First-line for localised BP (superpotent topical clobetasol) ^[10]
Rituximab	First-line or early second-line	Reserved for refractory disease
Treatment goal	Complete remission (no blisters)	Presence of 5–10 blisters once every 1–2 weeks is acceptable ^[10]
Steroid-sparing agents	AZA preferred, MMF alternative	Dapsone, MTX, AZA, tetracyclines + nicotinamide

Treatment Goals Differ!

In pemphigus, the goal is complete cessation of new blisters. In BP, the threshold is more lenient — "presence of blisters (5–10) once every 1–2 weeks" is considered acceptable disease control ^[10]. This is because BP is generally a less aggressive disease in terms of individual blister severity, and over-treating elderly, frail BP patients with heavy immunosuppression may cause more harm than the disease itself.

High Yield Summary — Pemphigus Management

Treatment is ALWAYS indicated, even for mild disease — do not adopt a watch-and-wait approach ^[3]
Three phases: Induce remission → consolidate remission → withdraw medication slowly ^[15]
Supportive care: Prick but do NOT de-roof blisters; leave roof in situ; sterile dressings; oral care with topical LA and hygiene
Systemic corticosteroids: Mainstay of initial treatment — prednisolone 1–1.5 mg/kg/day ^[13]; begin taper ≥ 1 week after last new blister ^[3]
Rituximab: Anti-CD20 B-cell depleting agent — now first-line (landmark paper) ^[15]; takes time to work → bridge with prednisolone / IVIg ^[2]; must screen HBV before starting
Steroid-sparing agents: Azathioprine (preferred) or MMF ^[3]^[13]; check TPMT/NUDT15 for AZA; taper 8 weeks after off steroids ^[3]
IVIg: For severe / refractory disease ^[13]; rapid onset; bridge therapy
Antibiotics if concomitant infection ^[13]
Severe/extensive: Consult ICU + burn environment ^[2]
Monitor: Clinical (new blisters, Nikolsky, healing) + dropping ELISA titres ^[3]

Active Recall - Pemphigus Management

References

^[1] Senior notes: Block A - Dermatology PBL 2.pdf (p.2, titre correlates with disease activity in pemphigus) ^[2] Senior notes: Block A - Dermatology PBL 2.pdf (p.2, case 3 — fatal outcome, rituximab factory reset, ICU/burn consult) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (p.153, pemphigus management — steroid regimen, tapering, steroid-sparing agents, monitoring, refractory therapy) ^[6] Senior notes: Block A - I have an itchy rash.pdf (p.1, systemic steroids only for pemphigus/pemphigoid) ^[10] Senior notes: Maksim Medicine Notes.pdf (p.71, blister care, BP management and treatment goals) ^[13] Lecture slides: CFB (MED09) Dermatology (II).pdf (p.8, pemphigus management — systemic corticosteroid, immunosuppressive agents, rituximab, antibiotics, IVIg, oral and wound care) ^[15] Senior notes: Block A - Treatments for skin diseases.pdf (p.1, treatment phases, rituximab as first-line, landmark paper)

Complications of Pemphigus

Complications of pemphigus can be divided into two broad categories: disease-related complications (arising from the pathology of pemphigus itself — essentially the consequences of losing the epidermal barrier) and treatment-related complications (arising from the immunosuppressive therapies used to manage the disease). Both categories contribute significantly to morbidity and mortality. In the modern era, treatment-related complications have actually overtaken disease-related complications as the leading cause of morbidity, reflecting both improved disease control and the toxicity burden of chronic immunosuppression.

These complications all stem from the same fundamental problem: loss of the epidermal barrier. The epidermis normally provides protection against infection, fluid loss, temperature dysregulation, and mechanical trauma. When acantholysis destroys this barrier across large areas, the patient is in a situation physiologically analogous to a major burn.

"80% of body surface area involved → all red area is dermis exposed, no more epidermis → very prone to infection, thermoregulation defects resulting in hypothermia, fluid loss" ^[2]

Aspect	Detail
Mechanism	Loss of the physical barrier of intact epidermis → direct exposure of the dermis and its vasculature to environmental microorganisms → colonisation → local wound infection → bacteraemia → sepsis
Common organisms	Staphylococcus aureus (most common coloniser of denuded skin), Pseudomonas aeruginosa (thrives in moist wound environments), Streptococcus species, Candida (especially in intertriginous or mucosal areas)
Clinical clues	Increasing wound erythema, warmth, purulent discharge ("juicy lesions"), fever, rising inflammatory markers (CRP, WCC), positive wound/blood cultures
Significance	Main cause of death in uncontrolled pemphigus — analogous to sepsis being the leading cause of death in burn patients ^[2]^[16]
Prevention	Sterile wound care, leave blister roofs in situ (biological dressing), antiseptic washes (chlorhexidine), surveillance wound swabs, early targeted antibiotics at first sign of infection
Compounding factor	Once immunosuppressive treatment is started (steroids, rituximab, azathioprine), the already-compromised barrier defence is further impaired by pharmacological immunosuppression → double hit

"Erosions have progressed, may be secondarily infected, juicy lesions" ^[2] — illustrating the rapid progression of uncontrolled disease with superimposed infection

Infection vs. Disease Flare — A Clinical Dilemma

In a pemphigus patient on immunosuppression who deteriorates, you must distinguish between disease flare (requiring more immunosuppression) and secondary infection (requiring antibiotics and potentially less immunosuppression). The two can co-exist. Always take wound swabs and blood cultures before empirically escalating immunosuppression. Worsening erosions with systemic sepsis signs point towards infection.

Aspect	Detail
Mechanism	Extensive epidermal loss → massive transepidermal water loss (TEWL) through exposed dermis → dehydration. Weeping erosions also lose protein-rich serous exudate (albumin, immunoglobulins) → hypoalbuminaemia → reduced oncotic pressure → oedema, further intravascular volume depletion
Electrolyte disturbances	Hyponatraemia (dilutional or from losses), hypokalaemia, metabolic derangements; electrolyte imbalance ^[16]
Laboratory findings	↓ Albumin, electrolyte imbalance, ↑ urea (pre-renal azotaemia from hypovolaemia + hypercatabolic state) ^[16]
Clinical consequence	Hypovolaemia → pre-renal acute kidney injury; peripheral oedema (paradoxically, due to low oncotic pressure despite intravascular depletion); poor wound healing
Management	Aggressive IV fluid resuscitation (guided by clinical assessment); albumin replacement if severely hypoalbuminaemic; electrolyte monitoring and correction; nutritional support

Why is this like a burn patient? In burns, the destroyed skin loses its barrier function in exactly the same way. The fluid resuscitation formulae used in burns (e.g. Parkland formula: 4 mL/kg × %BSA over 24 hours for burns; approximately 2/3 of this for SJS/TEN ^[9]) provide a conceptual framework, though formal formulae are less commonly applied to pemphigus given that epidermal loss tends to be more gradual.

Aspect	Detail
Mechanism	Intact skin is a critical thermoregulatory organ — it insulates, controls evaporative heat loss, and mediates vasomotor responses. Loss of epidermis → uncontrolled evaporative heat loss → hypothermia ^[2]
Clinical consequence	Thermoregulation defects resulting in hypothermia ^[2]; in severe cases, patients require a warm, controlled environment (burn-unit temperature: 30–32°C)
Management	Ambient temperature control; warming blankets; regular temperature monitoring

Aspect	Detail
Mechanism	Severe oral and oesophageal mucosal erosions → oral pain exacerbated by chewing or swallowing → poor nutrition, weight loss ^[3]; combined with a hypercatabolic state (ongoing inflammation, protein loss through wounds)
Clinical consequence	Weight loss, sarcopenia, impaired wound healing (protein-calorie malnutrition slows keratinocyte proliferation and immune function), micronutrient deficiencies (iron, zinc, vitamin C — all essential for wound repair)
Management	Dietary modification (soft, non-irritating, high-calorie, high-protein diet); oral nutritional supplements; topical local anaesthetic before meals; NG tube or PEG feeding if oral intake is impossible

Aspect	Detail
Mechanism	After erosions heal, melanocytes in the recovering epidermis may produce excess melanin in response to the preceding inflammation → deposition of melanin in the upper dermis (melanophages)
Clinical significance	Cosmetically distressing, especially in darker skin types (including Chinese patients in HK); may persist for months to years
Note	"When lesions heal, will leave scarring → post-inflammatory hyperpigmentation. Rule of thumb, lesions don't leave scars if injury is above dermis" ^[14] — true scars (fibrosis) are uncommon in pemphigus because the split is intraepidermal (above the dermis), but hyperpigmentation is common

Aspect	Detail
Mechanism	If pemphigus is extensive enough (approaching > 90% BSA), it can evolve into erythroderma — generalised erythema and scaling/erosion of the entire skin surface
Consequences	"Skin failure" — a medical emergency with hypothermia, dehydration, electrolyte disturbance, secondary infection, and potentially high-output cardiac failure (massively increased cutaneous blood flow in an attempt to thermoregulate) ^[16]

2.1 Paraneoplastic Pemphigus (PNP) — Unique Complications

"Think of BO" (bronchiolitis obliterans) when PNP is diagnosed ^[8]

Complication	Mechanism	Clinical Features	Prognosis
Bronchiolitis obliterans (BO)	Anti-plakin antibodies (envoplakin, periplakin) cross-react with respiratory epithelium → inflammation and fibrosis of small airways → progressive irreversible airway obstruction	Progressive dyspnoea, non-productive cough, declining FEV1/FVC on PFTs, air trapping on HRCT	Poor prognosis from BOS ^[17]; often the cause of death in PNP even after skin disease is controlled; may progress despite treatment
Underlying malignancy progression	PNP is by definition associated with malignancy (haematological in >80%)	Constitutional symptoms, lymphadenopathy, organomegaly; one third undiagnosed at time of PNP onset ^[17]	Depends on tumour type; Castleman disease has best prognosis if resectable

"Paraneoplastic pemphigus — associated cancers: Non-Hodgkin lymphoma, Chronic lymphocytic leukemia, Castleman disease, Thymoma, Waldenström macroglobulinemia, Solid organ tumours (breast, colon), Sarcoma" ^[17]

PNP — Always Screen for Malignancy and Monitor Lungs

When PNP is diagnosed: (1) Search for an underlying malignancy — CT TAP, PET-CT, bone marrow biopsy, flow cytometry — one third are undiagnosed at PNP onset ^[17]. (2) Monitor for bronchiolitis obliterans with serial PFTs — this can develop insidiously and is the major determinant of long-term prognosis.

These complications are a direct consequence of the immunosuppressive medications used to control pemphigus. In the modern treatment era, they are the leading cause of morbidity and a significant contributor to mortality.

"Problem is that lots of side effects, toxicity" ^[15]

Prolonged high-dose corticosteroid use (often months to years in pemphigus) causes a broad spectrum of adverse effects:

System	Complication	Mechanism	Prevention / Monitoring
Metabolic	Steroid-induced diabetes / hyperglycaemia	↑ Hepatic gluconeogenesis + ↑ peripheral insulin resistance	Pre-treatment HbA1c; regular glucose monitoring; early diabetic medication if needed
Skeletal	Osteoporosis → pathological fractures	↓ Osteoblast activity + ↑ osteoclast activity + ↓ intestinal Ca²⁺ absorption	Calcium + Vitamin D supplementation; DEXA scan; bisphosphonates if prolonged use
Skeletal	Avascular necrosis (femoral head)	Impaired blood supply to bone (fat embolism of intraosseous vessels, endothelial dysfunction)	Clinical suspicion if new hip/knee pain; MRI for diagnosis
GI	Peptic ulcer disease	↓ Prostaglandin synthesis → mucosal vulnerability (especially with concurrent NSAIDs)	PPI co-prescription if risk factors present
Cardiovascular	Hypertension, fluid retention	Mineralocorticoid cross-reactivity → Na⁺/water retention	Blood pressure monitoring; dietary Na⁺ restriction
Immune	Opportunistic infections	Broad immunosuppression → susceptibility to TB, Pneumocystis jirovecii (PJP), fungal infections, viral reactivation (HSV, VZV, HBV)	PJP prophylaxis (co-trimoxazole) if high-dose steroids + another immunosuppressant; HBV screening
Endocrine	Adrenal suppression → adrenal crisis on abrupt withdrawal	Exogenous cortisol suppresses ACTH → adrenal atrophy; abrupt withdrawal → acute cortisol deficiency	Withdraw medication slowly ^[15]; stress-dose steroids during illness/surgery
Ophthalmological	Posterior subcapsular cataracts, glaucoma	Altered lens protein metabolism; ↑ trabecular meshwork resistance → ↑ IOP	Regular ophthalmological review
Psychiatric	Insomnia, mood disturbance, psychosis	Direct CNS glucocorticoid receptor effects	Anticipate and counsel patients; dose reduction if severe
Dermatological	Skin atrophy, striae, acneiform eruption, poor wound healing	Corticosteroids inhibit fibroblast collagen synthesis and keratinocyte proliferation	Use minimum effective dose; aim for steroid-free remission
Cushing syndrome	Cushingoid habitus (moon face, truncal obesity, buffalo hump)	Redistribution of fat due to altered lipogenesis	Cosmetically distressing; reinforces the need for steroid-sparing

Complication	Mechanism	Prevention / Monitoring
Infusion reactions	Cytokine release from B-cell lysis; type I hypersensitivity	Pre-medication (paracetamol, antihistamine, IV methylprednisolone); slow initial infusion
HBV reactivation	B-cell depletion impairs immune control of latent HBV → viral rebound → hepatitis flare, potentially fulminant hepatic failure	Must screen HBsAg and anti-HBc before rituximab; antiviral prophylaxis (entecavir) if positive
Hypogammaglobulinaemia	Prolonged B-cell depletion → ↓ immunoglobulin production	Monitor IgG levels; IVIg replacement if recurrent infections + low IgG
Late-onset neutropenia	Mechanism not fully understood; occurs weeks to months after rituximab	Regular CBC monitoring
Progressive multifocal leukoencephalopathy (PML)	JC virus reactivation in severely immunosuppressed patients → demyelination	Extremely rare; clinical vigilance for new neurological symptoms; brain MRI if suspected
Increased infection risk	Impaired humoral immunity → ↓ antibody responses to pathogens (especially encapsulated bacteria)	Vaccinate before rituximab if possible (live vaccines contraindicated); early treatment of infections

Complication	Mechanism	Prevention / Monitoring
Myelosuppression (leukopenia, pancytopenia)	Thioguanine nucleotide accumulation → cytotoxicity to rapidly dividing bone marrow cells; especially severe in TPMT/NUDT15 deficient patients	TPMT/NUDT15 genotyping before starting; regular CBC (weekly initially, then monthly)
Hepatotoxicity	Drug-induced hepatocellular injury	Regular LFT monitoring
GI intolerance	Nausea, vomiting, diarrhoea	Dose titration; take with food
Increased infection risk	Immunosuppression	Clinical vigilance
Long-term malignancy risk	↑ Risk of non-melanoma skin cancer (NMSC) and lymphoma with prolonged use	Sun protection advice; annual skin cancer screening
Drug interaction with allopurinol	Allopurinol inhibits xanthine oxidase → blocks metabolism of 6-mercaptopurine → toxic accumulation → severe myelosuppression	Reduce AZA dose by 75% if co-prescribed with allopurinol; or avoid combination

Complication	Mechanism	Prevention / Monitoring
GI effects (most common)	Direct mucosal irritation + inhibition of rapidly dividing GI epithelial cells	Dose reduction; consider enteric-coated mycophenolate sodium
Myelosuppression	Inhibition of lymphocyte and other haematopoietic cell proliferation	Regular CBC
Teratogenicity	Category D; associated with congenital malformations (external ear, cleft lip/palate, cardiac defects)	Effective contraception mandatory; discontinue ≥ 6 weeks before planned pregnancy
Infection risk	Immunosuppression; particularly CMV, BK virus	Vigilance; viral PCR monitoring in high-risk patients

Complication	Mechanism
Headache, fever, chills	Infusion-related; common and usually mild
Aseptic meningitis	Immune complex deposition in meninges; self-limiting
Thromboembolic events (DVT, PE, stroke)	IVIg increases blood viscosity; especially in patients with cardiovascular risk factors
Renal impairment	Sucrose-containing IVIg preparations cause osmotic nephropathy
Anaphylaxis in IgA-deficient patients	Patients with selective IgA deficiency may develop anti-IgA antibodies → anaphylaxis to IgA-containing IVIg

Aspect	Detail
Pre-steroid era mortality	~75% within 1 year (from sepsis, fluid loss, hypothermia)
Modern era mortality	~5–10% (now mainly from treatment-related complications — infections, cardiovascular disease from chronic steroids)
Relapse	Common — pemphigus follows a chronic, relapsing-remitting course; complete sustained remission off all therapy is achievable in a subset (especially with rituximab — up to 85% at 2 years in trials) but many require long-term low-dose immunosuppression
Quality of life	Significantly impaired — chronic pain (oral/skin erosions), cosmetic distress (post-inflammatory hyperpigmentation, Cushingoid features from steroids), dietary restrictions, psychological burden (depression, anxiety, social isolation)
Monitoring for relapse	Titre correlates with disease activity in pemphigus ^[1] — rising anti-Dsg ELISA titres may precede clinical relapse by weeks → allows pre-emptive treatment adjustment

Category	Complications	Key Points
Disease — Infection	Secondary bacterial infection → sepsis	Main cause of death; S. aureus, Pseudomonas
Disease — Fluid	Dehydration, hypoalbuminaemia, electrolyte imbalance	Transepidermal fluid + protein loss
Disease — Thermal	Hypothermia	Loss of skin barrier → evaporative heat loss
Disease — Nutritional	Malnutrition, weight loss	Oral erosions → inability to eat
Disease — Cosmetic	Post-inflammatory hyperpigmentation	Common in darker skin; not true scarring
Disease — Extreme	Erythroderma ("skin failure")	> 90% BSA; ICU emergency
PNP — specific	Bronchiolitis obliterans	Poor prognosis; may be fatal
PNP — specific	Underlying malignancy	1/3 undiagnosed at PNP onset
Treatment — Steroids	DM, osteoporosis, AVN, infections, Cushing, adrenal suppression	"Lots of side effects, toxicity"
Treatment — Rituximab	HBV reactivation, hypogammaglobulinaemia, PML, infections	Screen HBV before; monitor IgG
Treatment — AZA	Myelosuppression, hepatotoxicity, malignancy risk	TPMT/NUDT15; allopurinol interaction
Treatment — MMF	GI effects, myelosuppression, teratogenicity	Contraception mandatory
Treatment — IVIg	Thromboembolism, renal impairment, anaphylaxis	Avoid sucrose preparations in renal impairment

High Yield Summary — Complications of Pemphigus

Disease-related: The fundamental problem is loss of the epidermal barrier → sepsis (main cause of death), fluid/protein loss, hypothermia, malnutrition
Severe pemphigus = burn patient physiology → consult ICU + burn environment ^[2]
PNP-specific: Bronchiolitis obliterans — progressive, irreversible, major cause of death; always screen for underlying malignancy (1/3 undiagnosed at PNP onset) ^[17]
Treatment-related complications are now the leading cause of morbidity in the modern era → rationale for steroid-sparing strategies and rituximab as first-line
Steroid toxicity: "Lots of side effects, toxicity" ^[15] — DM, osteoporosis, AVN, Cushing, infections, adrenal suppression → never withdraw abruptly
Rituximab: Screen HBV (reactivation risk), monitor IgG (hypogammaglobulinaemia), watch for infections
Azathioprine: TPMT/NUDT15 genotyping essential (East Asian population); never co-prescribe allopurinol at full dose
Anti-Dsg ELISA titres correlate with disease activity — rising titres may predict relapse before clinical deterioration ^[1]

Active Recall - Pemphigus Complications

References

^[1] Senior notes: Block A - Dermatology PBL 2.pdf (p.2, titre correlates with disease activity) ^[2] Senior notes: Block A - Dermatology PBL 2.pdf (p.2, case 3 — infection, fluid loss, hypothermia, 80% BSA, ICU/burn environment, death) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (p.152, oral pain exacerbated by chewing/swallowing, poor nutrition, weight loss) ^[8] Senior notes: Block A - Dermatology PBL 2.pdf (p.5, PNP — think of BO, associated cancers) ^[9] Senior notes: Ryan Ho Rheumatology.pdf (p.150, SJS/TEN fluid management formula for context) ^[14] Senior notes: Block A - Dermatology PBL 2.pdf (p.1, post-inflammatory hyperpigmentation, lesions above dermis do not scar) ^[15] Senior notes: Block A - Treatments for skin diseases.pdf (p.1, side effects and toxicity of steroids, rituximab as first-line, withdraw medication slowly) ^[16] Senior notes: Maksim Medicine Notes.pdf (p.75, complications of epidermal loss — infection, dehydration, thermal dysregulation, electrolyte disturbance) ^[17] Lecture slides: Derm General Clerkship 2026 Part2.pdf (p.28, PNP — bronchiolitis obliterans, poor prognosis from BOS, associated cancers, one third undiagnosed at onset)

High Yield Summary

Pemphigus — Key Points for Exams:

Definition: Autoimmune blistering disease; IgG against desmogleins → intraepidermal acantholysis → flaccid blisters
PV (most common): Anti-Dsg3 ± Dsg1 → mucosal + cutaneous erosions; suprabasal split; "tombstone row"
PF: Anti-Dsg1 only → superficial cutaneous erosions only; NO mucosa; subcorneal split
PNP: Anti-envoplakin/periplakin → severe stomatitis + polymorphous skin + bronchiolitis obliterans; always search for malignancy
IgA Pemphigus: Anti-desmocollin → grouped pustules; looks like SPD clinically
Desmoglein compensation theory: Explains pattern of involvement in each subtype
Nikolsky sign positive: Mechanical pressure → shearing of epidermis
Antibody titres (ELISA) correlate with disease activity in pemphigus (NOT in pemphigoid)
Untreated: Fatal — sepsis, fluid loss, hypothermia (burn-like pathophysiology)
DIF: "Chicken wire" / intercellular IgG in epidermis
Treatment: Systemic corticosteroids ± steroid-sparing agents (azathioprine, MMF); rituximab increasingly first-line
Drug causes: Thiol drugs (penicillamine, captopril) — always ask drug history

High Yield Summary — Pemphigus Differential Diagnosis

The Big Five DDx for widespread erosions (per GC lecture slides): Pemphigus vulgaris, SJS/TEN, Bullous pemphigoid, Paraneoplastic pemphigus ^[7]
PV vs. BP: Flaccid vs. tense; intraepidermal vs. subepidermal; Nikolsky +ve vs. −ve; intercellular IgG vs. linear IgG at BMZ; titre correlates in PV but NOT in BP
PV vs. SJS/TEN: Gradual autoimmune vs. acute drug-induced; acantholysis vs. full-thickness necrosis; "dusky non-blanching" = SJS/TEN
Pustular eruption DDx: SPD, GPP, AGEP, IgA pemphigus — SPD and IgA pemphigus can only be differentiated by biopsy ^[4]
SSSS vs. PF: Both target Dsg1 (toxin vs. antibody); both spare mucosa; differentiated by age (children vs. adults) and DIF (negative vs. positive)
Dermatological emergencies: SJS/TEN, Pemphigus vulgaris, Extensive bullous pemphigoid ^[8]
Pre-bullous BP trap: Elderly patient with persistent urticaria (> 24h) or "eczema" unresponsive to treatment → think BP and biopsy

High Yield Summary — Pemphigus Diagnosis

Diagnosis requires convergence: Clinical features + Histopathology (H&E) + Direct Immunofluorescence (DIF) + Serology
Skin biopsy: Perilesional, split into two — one for H&E (formalin), one for DIF (Michel's medium / fresh)
H&E key findings: Suprabasal acantholysis with tombstone row (PV) or subcorneal acantholysis (PF)
DIF gold standard: Intercellular IgG/C3 "chicken wire" pattern — pathognomonic
Serology: Anti-Dsg1/Dsg3 ELISA > 90% sensitivity; correlates with disease activity (for monitoring); anti-skin antibody (IIF) > 80% sensitivity, available in all HA hospitals
GC investigation panel: CBC, LRFT, anti-skin, anti-Dsg1 & 3, HBsAg, anti-HBc, G6PD, HbA1c, IgGAM; wound swab × aerobic culture + HSV/VZV PCR; CXR; skin biopsy
Pre-treatment rationale: HBsAg/anti-HBc (HBV reactivation risk), G6PD (dapsone safety), HbA1c (steroid-induced diabetes), IgGAM (rituximab safety)
Monitoring: Clinical (new blisters, Nikolsky sign, healing) + dropping ELISA titres
Rule out infection: Important to rule out primary/secondary skin infection — swab for HSV, bacterial culture

High Yield Summary — Pemphigus Management

Treatment is ALWAYS indicated, even for mild disease — do not adopt a watch-and-wait approach ^[3]
Three phases: Induce remission → consolidate remission → withdraw medication slowly ^[15]
Supportive care: Prick but do NOT de-roof blisters; leave roof in situ; sterile dressings; oral care with topical LA and hygiene
Systemic corticosteroids: Mainstay of initial treatment — prednisolone 1–1.5 mg/kg/day ^[13]; begin taper ≥ 1 week after last new blister ^[3]
Rituximab: Anti-CD20 B-cell depleting agent — now first-line (landmark paper) ^[15]; takes time to work → bridge with prednisolone / IVIg ^[2]; must screen HBV before starting
Steroid-sparing agents: Azathioprine (preferred) or MMF ^[3]^[13]; check TPMT/NUDT15 for AZA; taper 8 weeks after off steroids ^[3]
IVIg: For severe / refractory disease ^[13]; rapid onset; bridge therapy
Antibiotics if concomitant infection ^[13]
Severe/extensive: Consult ICU + burn environment ^[2]
Monitor: Clinical (new blisters, Nikolsky, healing) + dropping ELISA titres ^[3]

High Yield Summary — Complications of Pemphigus

Disease-related: The fundamental problem is loss of the epidermal barrier → sepsis (main cause of death), fluid/protein loss, hypothermia, malnutrition
Severe pemphigus = burn patient physiology → consult ICU + burn environment ^[2]
PNP-specific: Bronchiolitis obliterans — progressive, irreversible, major cause of death; always screen for underlying malignancy (1/3 undiagnosed at PNP onset) ^[17]
Treatment-related complications are now the leading cause of morbidity in the modern era → rationale for steroid-sparing strategies and rituximab as first-line
Steroid toxicity: "Lots of side effects, toxicity" ^[15] — DM, osteoporosis, AVN, Cushing, infections, adrenal suppression → never withdraw abruptly
Rituximab: Screen HBV (reactivation risk), monitor IgG (hypogammaglobulinaemia), watch for infections
Azathioprine: TPMT/NUDT15 genotyping essential (East Asian population); never co-prescribe allopurinol at full dose
Anti-Dsg ELISA titres correlate with disease activity — rising titres may predict relapse before clinical deterioration ^[1]

Pemphigus

1. Definition

2. Epidemiology

3. Risk Factors

4. Anatomy and Relevant Structural Biology

4.1 Normal Epidermal Architecture

4.2 Desmosomes and Desmogleins

4.3 Distribution of Desmogleins — The Desmoglein Compensation Theory

4.4 The Dermo-Epidermal Junction (DEJ)

5. Aetiology and Pathophysiology

5.1 Autoimmune Basis

5.2 Mechanism of Acantholysis

5.3 Histopathological Consequences

5.4 Consequences of Extensive Epidermal Loss

6. Classification

6.1 Major Subtypes

6.2 PV Subclassification (Clinically Important)

6.3 Endemic Pemphigus Foliaceus (Fogo Selvagem)

7. Clinical Features

7.1 Symptoms

7.2 Signs

7.2.1 Pemphigus Vulgaris (PV)

7.2.2 Pemphigus Foliaceus (PF)

7.2.3 Paraneoplastic Pemphigus (PNP)

7.2.4 IgA Pemphigus

7.3 Complications Presenting as Clinical Features (Before Formal Management)

8. Disease Activity and Monitoring

9. Natural History and Prognosis (Untreated)

10. Key Distinguishing Features: Pemphigus vs. Pemphigoid

11. Systemic Steroids in Dermatology — Context

Active Recall - Pemphigus

References

Framing the Problem

Approach to Differential by Level of Split and Nikolsky Sign

Major Differentials — Detailed Comparison

1. Bullous Pemphigoid (BP)

2. Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis (SJS/TEN)

3. Staphylococcal Scalded Skin Syndrome (SSSS)

4. Erythema Multiforme (EM)

5. Paraneoplastic Pemphigus (PNP)

6. Pustular Eruption Differentials (for IgA Pemphigus / PF)

7. Other Differentials to Consider

Diagnostic Algorithm — Approach to Blistering Disease

Summary of Key Differentials — Quick-Reference Table

Active Recall - Pemphigus Differential Diagnosis

1. Diagnostic Criteria

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3.1 Skin Biopsy

3.2 Serology — Blood-Based Antibody Testing

3.3 Tzanck Smear (Cytology)

3.4 Baseline and Pre-Treatment Investigations

3.5 Additional Investigations for Specific Subtypes

3.6 Monitoring Disease Activity During Treatment

4. Putting It All Together — Diagnostic Interpretation Framework

Active Recall - Pemphigus Diagnosis

1. Principles of Management

2. Management Algorithm

3. Treatment Modalities — Detailed Breakdown

3.1 Supportive Care (All Patients)

3.2 Systemic Corticosteroids — Mainstay of Initial Treatment

3.3 Rituximab — The Paradigm Shift

3.4 Steroid-Sparing Immunosuppressive Agents

3.5 IVIg (Intravenous Immunoglobulin) — Rescue Therapy

3.6 Other Modalities for Refractory Disease

3.7 Drug-Induced Pemphigus — Specific Management

3.8 Paraneoplastic Pemphigus — Specific Considerations

4. Treatment Phases — Detailed Timeline

5. Comparison: Pemphigus vs. BP Management

Active Recall - Pemphigus Management

1. Disease-Related Complications

1.1 Secondary Infection and Sepsis

1.2 Fluid and Electrolyte Imbalance

1.3 Thermoregulatory Failure

1.4 Malnutrition and Cachexia

1.5 Post-Inflammatory Hyperpigmentation

1.6 Erythroderma ("Skin Failure")

2. Complications Specific to Pemphigus Subtypes

3. Treatment-Related Complications

3.1 Complications of Systemic Corticosteroids