Pemphigus Vulgaris

1. Clinical Overview

Summary

Pemphigus Vulgaris (PV) is a potentially life-threatening autoimmune blistering disease characterised by flaccid blisters and erosions on the skin and mucous membranes. It is caused by IgG autoantibodies targeting Desmoglein 3 (and 1), causing loss of adhesion between keratinocytes (Acantholysis). [1,2]

Unlike Bullous Pemphigoid, the blisters are superficial (intra-epidermal) and rupture easily, often leaving large, painful, raw areas that are prone to infection. The disease typically begins with oral mucosal involvement, followed weeks to months later by cutaneous manifestations. [3]

Historical Context

The term "pemphigus" derives from the Greek word pemphix, meaning bubble or blister. Prior to the introduction of systemic corticosteroids in the 1950s, pemphigus vulgaris was almost universally fatal, with mortality rates approaching 75-90%. The advent of immunosuppressive therapy revolutionised outcomes, reducing mortality to approximately 5-10%. [4] The most recent paradigm shift occurred with the introduction of rituximab, which has become first-line therapy based on landmark trials. [5]

Clinical Pearls

Pemphigus means "Bubble": From the Greek pemphix.

The "Asboe-Hansen" Sign: If you press on the roof of a blister, the fluid dissects laterally into the surrounding seemingly normal skin, extending the blister size. This demonstrates the lack of cohesion in the epidermis.

Paraneoplastic Pemphigus: A severe variant associated with underlying malignancy (Non-Hodgkin Lymphoma, CLL, Castleman disease). Suspect this if the stomatitis is exceptionally severe, refractory, and involves respiratory epithelium causing bronchiolitis obliterans.

Desmoglein Compensation Theory: Why oral lesions often precede skin lesions: Dsg3 is predominantly expressed in mucosa, while both Dsg3 and Dsg1 are present in skin. Anti-Dsg3 antibodies alone cause mucosal disease. When anti-Dsg1 antibodies develop, skin involvement occurs because Dsg1 cannot compensate in the superficial epidermis.

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2. Epidemiology

Demographics

• Incidence: Rare, 0.1-0.5 per 100,000 population per year in most populations. [6]
• Geographic Variation: Higher incidence in certain regions (Mediterranean, Middle East, Southeast Asia) with rates up to 1.6 per 100,000. [7]
• Age: Peak incidence 40-60 years (mean age 50-60 years). Younger than Bullous Pemphigoid (70+ years).
• Sex: Slight female predominance (1.2-1.5:1 female to male ratio). [6]
• Ethnicity: Significantly higher prevalence in:
  • Ashkenazi Jews (incidence 1.6-4.2 per 100,000)
  • Mediterranean populations (Greeks, Italians, Turks)
  • Indian subcontinent populations
  • "HLA associations: HLA-DR4 (DRB10402) and HLA-DR14 (DRB11401) in Ashkenazi Jews; HLA-DR4 and HLA-DQ1 in other populations. [8]"

Burden of Disease

• Mortality: Historical (pre-1950s) mortality > 75%. Current mortality 5-10% with modern immunosuppression. [4]
• Morbidity: Significant impact on quality of life due to chronic pain, difficulty eating, risk of infection, and treatment-related complications.
• Healthcare Costs: High due to hospitalisation requirements, expensive biologics (rituximab), and long-term immunosuppression monitoring.

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3. Pathophysiology

Molecular Mechanisms

Desmosomes and Intercellular Adhesion

Keratinocytes are connected by desmosomes, complex protein structures that provide mechanical integrity to the epidermis. The key desmosomal cadherins are:

• Desmoglein 1 (Dsg1): Predominantly in superficial epidermis and skin
• Desmoglein 3 (Dsg3): Predominantly in basal/suprabasal layers and mucous membranes
• Desmoglein 2 (Dsg2): Present in cardiac and simple epithelia
• Desmoglein 4 (Dsg4): Hair follicles

Desmogleins are calcium-dependent adhesion molecules that interact in trans (between adjacent cells) to form strong intercellular bonds. [9]

Autoantibody Production

In pemphigus vulgaris, B cells produce IgG4 autoantibodies (predominantly) that target the extracellular domains of Dsg3 and/or Dsg1. The autoantibody profile determines clinical phenotype: [10]

1. Anti-Dsg3 only: Mucosal-dominant pemphigus (oral lesions only)
2. Anti-Dsg3 + Anti-Dsg1: Mucocutaneous pemphigus (oral + skin lesions)
3. Anti-Dsg1 only: Rare in PV, typically seen in pemphigus foliaceus

Desmoglein Compensation Theory

This elegant theory explains the clinical-serological correlation: [11]

• In oral mucosa: Dsg3 is the main adhesion molecule. Anti-Dsg3 antibodies → loss of adhesion → blistering.
• In skin: Both Dsg3 (basal) and Dsg1 (superficial) are present. Anti-Dsg3 alone does not cause blistering because Dsg1 compensates. Only when anti-Dsg1 antibodies also develop does skin blistering occur.

This explains why PV typically begins with oral lesions (anti-Dsg3 phase) and later develops skin lesions (anti-Dsg3 + anti-Dsg1 phase).

Mechanisms of Acantholysis

Autoantibody binding triggers multiple pathogenic mechanisms beyond simple steric hindrance: [12,13]

1. Direct Interference: Antibodies block homophilic trans-interaction between desmogleins
2. Steric Hindrance: IgG molecules physically disrupt desmoglein clustering
3. Desmoglein Depletion: Antibody-induced endocytosis and degradation of desmogleins
4. Cell Signaling Disruption:
   • Activation of p38 MAPK pathway
   • Increased intracellular calcium
   • Phosphorylation of intermediate filaments (keratin retraction)
   • Activation of proteases (plasminogen activator system)
5. Complement Activation: C3 deposition contributes to inflammation and keratinocyte damage (though acantholysis can occur without complement)
6. Apoptotic Signaling: Activation of caspases and apoptotic pathways (controversial)

Genetic Susceptibility

• HLA Associations: Strong association with specific HLA-DR alleles varies by ethnicity. [8]
• Non-HLA Genes: Polymorphisms in genes encoding:
  • ST18 (suppression of tumorigenicity 18)
  • TRAF3IP2 (IL-17 signaling)
  • TNFRSF6B (apoptosis regulation)

Environmental Triggers

• Drugs: Thiol-containing drugs (penicillamine, captopril, enalapril) can induce pemphigus
• Viral Infections: Potential role of herpes viruses in triggering autoimmunity (controversial)
• UV Radiation: May trigger disease in predisposed individuals

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4. Classification of Pemphigus Subtypes

Pemphigus encompasses several distinct clinical and immunological entities:

Pemphigus Vulgaris (PV)

• Most common form (70% of all pemphigus cases)
• Anti-Dsg3 ± anti-Dsg1 antibodies
• Mucosal and/or mucocutaneous involvement
• Suprabasal acantholysis

Pemphigus Foliaceus (PF)

• Anti-Dsg1 antibodies only
• Superficial blistering (subcorneal)
• No mucosal involvement (Dsg3 compensation in mucosa)
• Geographic distribution: Endemic form in Brazil (fogo selvagem)

Paraneoplastic Pemphigus (PNP)

• Associated with underlying neoplasm (NHL, CLL, Castleman, thymoma)
• Complex autoantibody profile: anti-Dsg3, anti-Dsg1, anti-plakin proteins (envoplakin, periplakin, desmoplakin, BP230)
• Severe mucosal involvement (stomatitis, conjunctivitis)
• Lichenoid skin lesions
• Bronchiolitis obliterans (life-threatening)
• Poor prognosis

IgA Pemphigus

• Rare variant with IgA (not IgG) autoantibodies
• Two subtypes:
  • Subcorneal pustular dermatosis type (anti-desmocollin 1)
  • Intraepidermal neutrophilic IgA dermatosis type
• Pustular rather than bullous lesions
• Better prognosis than PV

Drug-Induced Pemphigus

• Triggered by medications (especially thiol-containing: penicillamine, captopril)
• Clinically and histologically identical to idiopathic pemphigus
• May resolve after drug discontinuation

Endemic Pemphigus (Fogo Selvagem)

• Pemphigus foliaceus endemic to rural Brazil
• Environmental trigger (black fly Simulium) hypothesized
• Anti-Dsg1 antibodies
• Young age of onset

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5. Clinical Presentation

Timeline of Disease Progression

Phase 1: Mucosal Phase (Weeks to Months)

• Painful oral erosions and ulcers
• Often misdiagnosed as aphthous stomatitis, herpes, or candidiasis
• Difficulty eating and swallowing
• 50-70% of patients present with oral lesions as first manifestation [14]

Phase 2: Mucocutaneous Phase (Variable)

• Development of skin blisters weeks to months after oral lesions
• Flaccid bullae that rupture easily
• Widespread erosions
• Positive Nikolsky sign

Phase 3: Generalised Phase (Without Treatment)

• Progressive extension of erosions
• Risk of fluid loss, electrolyte imbalance
• Secondary infection
• Potential for mortality without treatment

Mucosal Involvement

Oral Cavity (90% of patients)

• Sites: Buccal mucosa, palate, gingiva, tongue, lips
• Appearance: Painful erosions with irregular borders, often without intact blisters
• "Desquamative Gingivitis": Diffuse gingival erythema and erosions
• Pain: Severe odynophagia, difficulty eating
• Complications: Weight loss, malnutrition

Other Mucosal Sites

• Esophagus: Dysphagia, odynophagia (10-20% of patients)
• Nasopharynx: Nasal crusting, epistaxis
• Conjunctiva: Rare, can cause scarring and symblepharon
• Genital Mucosa: Erosions on glans penis, vulva, vagina (20-30%)
• Larynx: Hoarseness (rare)

Cutaneous Involvement

Morphology

• Primary Lesion: Flaccid (limp), thin-walled bullae containing clear fluid
• Secondary Lesions: Erosions (most common presentation), crusts, scales
• Size: Variable, from small (less than 1 cm) to large (> 5 cm)
• Intact Blisters: Rarely seen because they rupture spontaneously

Distribution

• Favoured Sites:
  • Scalp
  • Face (especially perioral)
  • Chest and back (seborrheic areas)
  • Axillae
  • Groin and intertriginous areas
  • Pressure points
• Palms and Soles: Usually spared

Associated Features

• Nikolsky Sign: Positive (see Examination section)
• Asboe-Hansen Sign: Lateral extension of blister with gentle pressure
• Post-inflammatory Hyperpigmentation: Common, especially in darker skin types
• Vegetating Lesions: Rare, seen in intertriginous areas (pemphigus vegetans variant)

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6. Clinical Examination

General Approach

1. Assess Extent: Estimate body surface area (BSA) involved
2. Mucosal Examination: Thorough examination of all mucosal surfaces
3. Skin Examination: Identify intact blisters, erosions, crusts
4. Elicit Clinical Signs: Nikolsky, Asboe-Hansen
5. Assess Complications: Signs of infection, dehydration

Key Clinical Signs

Nikolsky Sign (Positive in PV)

Technique: Apply firm sliding pressure with finger on normal-appearing perilesional skin

Positive Result: Epidermis shears off, creating an erosion

Interpretation:

• Indicates intraepidermal loss of cohesion (acantholysis)
• Positive in pemphigus (intraepidermal split)
• Negative in bullous pemphigoid (subepidermal split)
• Can also be positive in SJS/TEN, staphylococcal scalded skin syndrome

Sensitivity/Specificity: Not absolute; false negatives occur in inactive disease

Asboe-Hansen Sign (Bulla Spread Sign)

Technique: Apply gentle pressure to the top of an intact blister

Positive Result: Blister fluid extends laterally into adjacent normal-appearing skin

Interpretation: Demonstrates plane of cleavage is within viable epidermis with poor intercellular adhesion

Disease Activity Assessment

Pemphigus Disease Area Index (PDAI)

• Standardised scoring system for disease activity
• Assesses 12 anatomical sites
• Scores erosions/blisters separately
• Maximum score: 263
• Used in clinical trials and monitoring

Autoimmune Bullous Skin Disorder Intensity Score (ABSIS)

• Alternative scoring system
• Includes extent, disease course, symptoms
• Maximum score: 206

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7. Differential Diagnosis

Intraepidermal Blistering Disorders

Subepidermal Blistering Disorders

Other Important Differentials

• Stevens-Johnson Syndrome/TEN: Acute onset, drug-related, targetoid lesions, epidermal necrosis
• Erythema Multiforme: Target lesions, acute, often HSV-triggered
• Hailey-Hailey Disease: Familial, flexural, bacterial overgrowth, "dilapidated brick wall" histology
• Bullous Drug Eruption: Drug history, resolves with cessation
• Staphylococcal Scalded Skin Syndrome: Neonates/children, toxin-mediated, subcorneal split

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8. Investigations

Biopsy Protocol (Two Samples Required)

Sample 1: Lesional Skin for Histopathology (H&E)

Site Selection:

• Fresh, small, intact blister (ideal)
• Edge of fresh erosion (if no intact blisters)
• Avoid old, crusted, or infected lesions

Technique:

• 4 mm punch biopsy or small shave biopsy
• Include blister roof and adjacent skin
• Place in formalin

Expected Findings:

1. Intraepidermal Split: Suprabasal cleavage plane
2. Acantholysis: "Free-floating" rounded keratinocytes with perinuclear halo
3. "Row of Tombstones": Basal keratinocytes remain attached to basement membrane like tombstones
4. Minimal Inflammation: Sparse lymphocytic infiltrate
5. Eosinophils: May be present in blister cavity

Diagnostic Sensitivity: High (> 90% if adequate sample)

Sample 2: Perilesional Skin for Direct Immunofluorescence (DIF)

Site Selection:

• Normal-appearing or erythematous perilesional skin
• Within 1-2 cm of active lesion
• NOT from blister or erosion itself

Technique:

• 4 mm punch biopsy
• Place in Michel's medium or immunofluorescence transport medium (NOT formalin)
• Can be stored at room temperature for days to weeks in Michel's medium

Expected Findings:

• IgG Deposition: Intercellular (cell surface) pattern in epidermis
• "Chicken Wire" or "Fishnet" Pattern: IgG outlining keratinocytes
• C3 Complement: Also intercellular (70-80% of cases)
• IgG Subclass: Predominantly IgG4

Diagnostic Sensitivity: 80-90%

False Negatives: Can occur with:

• Improper specimen handling
• Very early or treated disease
• Technical factors

Indirect Immunofluorescence (IIF)

Substrate: Monkey esophagus (gold standard) or guinea pig esophagus

Technique: Patient serum applied to substrate; detects circulating anti-desmoglein antibodies

Findings:

• Intercellular staining pattern
• Titre often correlates with disease activity

Sensitivity: 70-80% (lower than DIF)

Use: Can supplement DIF, monitor disease activity

ELISA (Enzyme-Linked Immunosorbent Assay)

Targets: Recombinant human Dsg1 and Dsg3

Advantages:

• Highly specific (> 95%)
• Quantitative (antibody titre)
• Differentiates anti-Dsg1 vs anti-Dsg3
• Titre correlates with disease activity
• Useful for monitoring treatment response

Clinical Correlation: [15]

• Anti-Dsg3 only: Mucosal disease
• Anti-Dsg3 + anti-Dsg1: Mucocutaneous disease
• Rising titres: Predict relapse
• Falling titres: Indicate treatment response

Availability: Increasingly available commercially

Additional Laboratory Tests

Baseline (Pre-Treatment)

• FBC: Baseline WBC (prior to immunosuppression)
• U&E: Baseline renal function
• LFTs: Baseline hepatic function
• Glucose: Screen for diabetes (steroid risk)
• HBV/HCV Serology: Mandatory before rituximab
• HIV Test: If risk factors
• Tuberculosis Screening: QuantiFERON or PPD before immunosuppression
• Immunoglobulins: Baseline IgG levels (risk of hypogammaglobulinemia with rituximab)

Disease Activity Monitoring

• Dsg ELISA Titres: Every 3-6 months
• Inflammatory Markers: CRP/ESR (non-specific)

Treatment Monitoring

• FBC, U&E, LFTs: Monthly initially, then every 3 months on stable therapy
• Glucose: Monitor for steroid-induced diabetes
• Bone Density: DEXA scan if prolonged steroid use
• IgG Levels: Monitor after rituximab (risk of hypogammaglobulinemia)

Imaging

Not routinely required unless:

• Chest X-ray: If paraneoplastic pemphigus suspected (mediastinal mass)
• CT Chest/Abdomen/Pelvis: If malignancy screen needed for PNP

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9. Management

Principles of Management

1. Suppress Autoimmunity: Stop autoantibody production and eliminate pathogenic B cells
2. Induce Remission: Achieve complete disease control
3. Maintain Remission: Prevent relapse while minimising treatment toxicity
4. Supportive Care: Wound care, nutrition, infection prevention
5. Monitor for Complications: Treatment-related and disease-related

Management Algorithm

        PEMPHIGUS VULGARIS DIAGNOSED
    (Confirmed by Biopsy/DIF/ELISA)
                ↓
        ASSESS SEVERITY
                ↓
    ┌───────────┴───────────┐
    ↓                       ↓
MILD-MODERATE          SEVERE/EXTENSIVE
- Limited oral/skin    - > 30% BSA involved
- Able to eat/drink    - Unable to eat
- No systemic upset    - Dehydration
                       - Infection risk
    ↓                       ↓
OUTPATIENT             HOSPITAL ADMISSION
MANAGEMENT            - Burn unit/HDU if extensive
                       - Fluid resuscitation
                       - Infection control
                       - Nutritional support
                       ↓
        ┌───────────────┴───────────────┐
        ↓                               ↓
    FIRST-LINE                    ADJUVANT MEASURES
RITUXIMAB + STEROIDS           - Wound care
                               - Pain management
    ↓                          - Oral hygiene
Rituximab Protocols:           - Nutrition
                               - Prophylaxis
1) Lymphoma Protocol              (PCP, fungal)
   - 375 mg/m² weekly × 4
   OR
2) Rheumatoid Arthritis Protocol
   - 1000 mg IV day 0 and day 14
   
PLUS

Prednisolone
- 0.5-1 mg/kg/day initially
- Taper slowly over 6-12 months

    ↓

MAINTENANCE THERAPY
- Rituximab maintenance infusions
  (e.g., 500-1000 mg every 6 months)
  OR
- Steroid-sparing agents:
  • Mycophenolate mofetil 2-3 g/day
  • Azathioprine 1-3 mg/kg/day
  • Dapsone 50-200 mg/day (adjunct)

    ↓

REFRACTORY DISEASE
- IVIG 2 g/kg per cycle
- Immunoadsorption
- Cyclophosphamide
- Emerging: Anti-CD19, BTK inhibitors

First-Line Therapy: Rituximab + Corticosteroids

Rituximab (Anti-CD20 Monoclonal Antibody)

Mechanism: Depletes CD20+ B cells, eliminating autoantibody-producing B cell clones

Evidence Base: [5,16]

• Ritux 3 Trial (Joly et al., Lancet 2017): Landmark RCT
  • Rituximab + short-term steroids vs. steroids alone
  • 89% complete remission (off therapy) at 24 months with rituximab vs. 34% with steroids alone
  • Lower cumulative steroid dose
  • Established rituximab as first-line therapy

Dosing Protocols:

1. Lymphoma Protocol (more common in dermatology):

   • 375 mg/m² IV weekly for 4 weeks
   • Repeat cycles at 12 and 18 months (some protocols)

2. Rheumatoid Arthritis Protocol:

   • 1000 mg IV on day 0 and day 14
   • Can repeat cycles every 6-24 months based on clinical response and B cell counts

Premedication:

• Paracetamol 1 g
• Chlorphenamine 10 mg
• Hydrocortisone 100 mg IV
• (To reduce infusion reactions)

Monitoring:

• FBC: Monitor for cytopenias
• Immunoglobulins: Check every 3-6 months (risk of hypogammaglobulinemia)
• CD19+ B cell count: Can guide re-treatment timing
• Dsg ELISA: Monitor antibody titres

Contraindications:

• Active infection (including hepatitis B reactivation risk)
• Severe heart failure
• Live vaccines (avoid during and for 6 months after)

Adverse Effects:

• Infusion Reactions: Fever, chills, hypotension (usually first infusion, reduced with premedication)
• Infections: Increased risk during B cell depletion phase
• Hypogammaglobulinemia: Late complication, may require IVIG replacement
• Progressive Multifocal Leukoencephalopathy (PML): Extremely rare
• Hepatitis B Reactivation: Screen and treat/monitor HBsAg+ patients

Corticosteroids

Role: Rapidly suppress inflammation while rituximab takes effect (B cell depletion occurs over weeks)

Dosing:

• Induction: Prednisolone 0.5-1 mg/kg/day (modern protocols favour lower doses with rituximab)
• Duration: Taper over 6-12 months
• Tapering Schedule (example):
  • Maintain initial dose until disease controlled (new lesions stop appearing)
  • Reduce by 10 mg every 2 weeks to 40 mg/day
  • Reduce by 5 mg every 2 weeks to 20 mg/day
  • Reduce by 2.5 mg every 2 weeks to 10 mg/day
  • Reduce by 1 mg every 4 weeks to cessation
  • (Adjust based on disease activity)

Steroid-Sparing: Rituximab allows for faster steroid taper and lower cumulative doses

Adjunctive Measures:

• Bone Protection: Calcium, vitamin D, bisphosphonates
• PCP Prophylaxis: Co-trimoxazole if prednisolone > 20 mg for > 1 month
• Gastric Protection: PPI if high risk
• Glucose Monitoring: Screen for steroid-induced diabetes

Second-Line and Steroid-Sparing Agents

Mycophenolate Mofetil (MMF)

Dose: 2-3 g/day (1-1.5 g twice daily)

Mechanism: Inhibits inosine monophosphate dehydrogenase, reducing lymphocyte proliferation

Evidence: Effective steroid-sparing agent; inferior to rituximab in head-to-head trials [5]

Monitoring: FBC, LFTs, U&E every 2-4 weeks initially, then every 3 months

Adverse Effects: GI upset, cytopenias, increased infection risk

Pregnancy: Teratogenic (avoid)

Azathioprine

Dose: 1-3 mg/kg/day

Mechanism: Purine analogue, immunosuppressive

Monitoring:

• TPMT Activity: Check before starting (risk of severe myelosuppression if deficient)
• FBC, LFTs: Weekly for 4 weeks, then every 3 months

Adverse Effects: Cytopenias, hepatotoxicity, GI upset, increased malignancy risk (long-term)

Onset: Slow (8-12 weeks)

Dapsone

Dose: 50-200 mg/day

Mechanism: Anti-inflammatory (not fully understood)

Role: Adjunctive therapy, not monotherapy

Monitoring:

• G6PD Status: Check before starting (contraindicated if deficient)
• FBC: Monitor for hemolysis, methemoglobinemia

Adverse Effects: Hemolysis, methemoglobinemia, peripheral neuropathy

Refractory Disease Management

Intravenous Immunoglobulin (IVIG)

Dose: 2 g/kg per cycle (divided over 3-5 days), repeated monthly

Mechanism: Multiple (Fc receptor blockade, anti-idiotypic antibodies, immune modulation)

Indications: Refractory disease, rituximab failure, contraindication to other agents

Evidence: Case series and small RCTs show efficacy [17]

Adverse Effects: Headache, aseptic meningitis, thromboembolism, renal impairment

Cost: Extremely expensive

Immunoadsorption/Plasmapheresis

Technique: Extracorporeal removal of autoantibodies

Indications: Severe, rapidly progressive disease; short-term bridge therapy

Protocol: 3-5 cycles over 1-2 weeks

Limitations: Temporary effect (antibody rebound); requires central venous access

Cyclophosphamide

Dose: Pulse IV (500-1000 mg monthly) or oral (1-2 mg/kg/day)

Indications: Refractory disease

Monitoring: FBC, U&E, urine microscopy

Adverse Effects: Cytopenias, hemorrhagic cystitis, infertility, malignancy risk

Precautions: Mesna (uroprotection), adequate hydration

Emerging Therapies

• Anti-CD19 Agents: Broader B cell depletion than rituximab
• Bruton Tyrosine Kinase (BTK) Inhibitors: Ibrutinib (in trials)
• Neonatal Fc Receptor (FcRn) Inhibitors: Efgartigimod (reduces IgG levels)
• Chimeric Antigen Receptor (CAR) T Cells: Anti-CD19 CAR-T (case reports of dramatic responses)

Supportive and Adjunctive Care

Wound Care

• Gentle Handling: Avoid trauma (Nikolsky positive skin)
• Non-Adherent Dressings: Silicone-based dressings, petroleum gauze
• Topical Antibiotics: If signs of infection (e.g., mupirocin)
• Antiseptic Baths: Dilute bleach or potassium permanganate baths

Oral Care

• Oral Hygiene: Soft toothbrush, alcohol-free mouthwashes
• Topical Anesthetics: Viscous lidocaine, benzocaine gels (before meals)
• Topical Corticosteroids: Triamcinolone in Orabase for oral lesions
• Antiseptic Rinses: Chlorhexidine (caution: can stain)

Nutritional Support

• Soft/Liquid Diet: For severe oral involvement
• Nutritional Supplements: High-calorie, high-protein
• Feeding Tube: Nasogastric or PEG if unable to maintain oral intake

Pain Management

• Oral Analgesia: Paracetamol, NSAIDs, opioids (if severe)
• Topical Analgesia: Lidocaine gels/viscous preparations
• Neuropathic Pain: Gabapentin/pregabalin if needed

Infection Prevention and Management

• Prophylaxis:

  • "PCP prophylaxis: Co-trimoxazole 480 mg daily or 960 mg three times weekly"
  • "Fungal prophylaxis: Consider fluconazole if high risk"
  • "Herpes prophylaxis: Aciclovir if history of recurrent HSV"

• Treatment of Infection:

  • Low threshold for antibiotics if signs of superinfection
  • Swabs for culture
  • Staph aureus most common organism (consider MRSA risk)

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10. Complications

Disease-Related Complications

Infection and Sepsis

• Risk: Loss of skin barrier function
• Organisms: Staphylococcus aureus (most common), Streptococcus pyogenes, Pseudomonas aeruginosa, Candida
• Presentation: Increased pain, purulent discharge, fever, systemic upset
• Management: Swabs, blood cultures, broad-spectrum antibiotics, sepsis protocol if systemic
• Historical Significance: Sepsis was leading cause of death pre-immunosuppression era [4]

Fluid and Electrolyte Imbalance

• Mechanism: Extensive erosions → transepidermal water loss (like burns)
• Consequences: Dehydration, hyponatremia, hypokalemia, hypoalbuminemia
• Management: IV fluids, electrolyte replacement, albumin if severe

Malnutrition

• Causes: Severe oral involvement → odynophagia, poor oral intake
• Consequences: Weight loss, hypoalbuminemia, impaired healing
• Management: Nutritional support, feeding tubes if necessary

Ocular Complications

• Frequency: Rare in PV (more common in mucous membrane pemphigoid)
• Complications: Conjunctival erosions, symblepharon (scarring), vision loss
• Management: Ophthalmology referral, topical steroids

Treatment-Related Complications

Corticosteroid Complications

• Metabolic: Diabetes, weight gain, dyslipidemia
• Musculoskeletal: Osteoporosis, avascular necrosis, myopathy
• Cardiovascular: Hypertension
• Gastrointestinal: Peptic ulcer
• Psychiatric: Mood changes, psychosis
• Ophthalmologic: Cataracts, glaucoma
• Dermatologic: Striae, acne, easy bruising
• Immunologic: Increased infection risk

Mitigation: Use lowest effective dose, rapid taper with rituximab, bone protection, monitoring

Rituximab Complications

• Infusion Reactions: Managed with premedication
• Infections: Bacterial, viral, fungal (during B cell depletion)
• Hypogammaglobulinemia: Late complication, may require IVIG replacement
• PML: Extremely rare, catastrophic
• Hepatitis B Reactivation: Screen and prophylax

Other Immunosuppression Complications

• Cytopenias: MMF, azathioprine, cyclophosphamide
• Hepatotoxicity: Azathioprine, MMF
• Malignancy: Increased risk with long-term immunosuppression (especially cyclophosphamide, azathioprine)
• Opportunistic Infections: PCP, CMV, fungal

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11. Prognosis and Outcomes

Natural History (Untreated)

• Mortality: > 75% within 1 year (historical data from pre-corticosteroid era) [4]
• Causes of Death: Sepsis (most common), fluid/electrolyte imbalance, malnutrition

Prognosis with Modern Treatment

• Mortality: 5-10% (predominantly treatment-related complications) [18]
• Remission Rates: [5]
  • "Complete remission off therapy: 50-89% (higher with rituximab)"
  • "Complete remission on minimal therapy: Additional 20-30%"
• Relapse Rates: 30-50% over 10 years

Prognostic Factors

Favourable Prognosis

• Younger age
• Limited disease at presentation
• Rapid response to treatment
• Rapid decline in Dsg antibody titres
• Use of rituximab

Unfavourable Prognosis

• Extensive disease (> 30% BSA)
• Advanced age (> 60 years)
• Paraneoplastic pemphigus
• Persistently high Dsg antibody titres
• Multiple relapses
• Treatment non-adherence

Definitions of Disease States

Complete Remission Off Therapy: No new or established lesions while off all systemic therapy for ≥2 months [19]

Complete Remission On Therapy: No new or established lesions while on minimal therapy (e.g., ≤10 mg/day prednisolone)

Partial Remission: Presence of transient new lesions that heal within 1 week without treatment while on minimal therapy

Relapse: Appearance of ≥3 new lesions per month or extension of established lesions in patient in remission

Long-Term Outcomes

• Quality of Life: Significantly impaired during active disease; improves with remission [20]
• Scarring: Minimal (unlike cicatricial pemphigoid); post-inflammatory pigmentation common
• Functional Impairment: Resolves with disease control
• Psychological Impact: Chronic disease burden, treatment anxiety, body image concerns

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12. Special Populations

Pediatric Pemphigus

• Frequency: Rare (5% of PV cases)
• Presentation: Similar to adults; mucosal involvement common
• Management: Rituximab increasingly used; steroid-sparing strategies critical for growth
• Prognosis: Generally good with treatment
• Challenges: Adherence, school attendance, psychosocial impact

Pregnancy and Lactation

Pemphigus in Pregnancy

• Disease Activity: May flare, remain stable, or improve (unpredictable)
• Fetal Risk: Transplacental transfer of maternal IgG → neonatal pemphigus (rare, self-limited)
• Obstetric Complications: Increased risk if severe disease

Management in Pregnancy

• Preconception Counselling: Ideally achieve remission before pregnancy

• Medications:

  • "Safe: Systemic corticosteroids (prednisolone preferred; minimal placental transfer), IVIG"
  • "Avoid: MMF (teratogenic), methotrexate (teratogenic), cyclophosphamide (teratogenic)"
  • "Limited Data: Rituximab (case reports suggest relative safety, but avoid if possible)"
  • "Azathioprine: Use only if benefits outweigh risks (crosses placenta but may be used)"

• Monitoring: Dermatology + high-risk obstetrics, fetal monitoring

Neonatal Pemphigus

• Mechanism: Transplacental IgG transfer
• Presentation: Blisters at birth or within first weeks
• Course: Self-limited (resolves as maternal antibodies clear over 6-12 weeks)
• Management: Supportive care, gentle skin care, rarely requires treatment

Elderly Patients

• Frequency: Onset typically 40-60 years, but can occur in elderly
• Challenges:
  • Increased comorbidities
  • Polypharmacy interactions
  • Higher risk of steroid complications (osteoporosis, diabetes)
  • Frailty
• Management: Aggressive steroid-sparing strategies, careful monitoring

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13. Evidence Base and Guidelines

Key Clinical Trials

1. Ritux 3 Trial (Joly et al., Lancet 2017) [5]

Design: Multicentre, randomised, controlled, open-label trial

Participants: 90 patients with newly diagnosed pemphigus (74 with PV)

Intervention:

• Rituximab Group: Rituximab (1000 mg IV on days 0 and 14, repeated at months 12 and 18) + short-course prednisolone (0.5-1 mg/kg/day for 3-6 months)
• Control Group: Prednisolone alone (1-1.5 mg/kg/day for ≥12 months)

Primary Outcome: Complete remission off therapy at 24 months

Results:

• Complete remission off therapy: 89% rituximab vs. 34% control (pless than 0.0001)
• Cumulative steroid dose: Significantly lower in rituximab group (median 8085 mg vs. 20,430 mg)
• Adverse events: Similar between groups

Conclusion: Rituximab + short-term steroids superior to steroids alone

Impact: Established rituximab as first-line therapy for pemphigus

2. Ritux 1 Trial (Joly et al., JAMA Dermatol 2019)

Design: Phase 3 RCT comparing two rituximab protocols

Participants: 64 patients with moderate-to-severe pemphigus

Results: Both protocols effective; no significant difference in outcomes

3. Immunoadsorption Studies

Findings: Effective as adjunct therapy in severe disease; antibody rebound limits long-term efficacy

Clinical Practice Guidelines

British Association of Dermatologists (BAD) 2017 [1]

Key Recommendations:

• Diagnostic biopsy (lesional H&E + perilesional DIF) mandatory
• Rituximab recommended as first-line for moderate-severe disease
• Systemic corticosteroids for induction
• Steroid-sparing agents (MMF, azathioprine) for maintenance if rituximab not used
• IVIG for refractory disease

European Academy of Dermatology and Venereology (EADV) 2020

Key Recommendations:

• Rituximab first-line for moderate-severe pemphigus
• Lymphoma protocol (4 weekly infusions) preferred
• Combination with short-course steroids

American Academy of Dermatology (AAD) Guidelines

Key Recommendations:

• Systemic corticosteroids + adjuvant immunosuppression
• Rituximab increasingly recommended
• Wound care and supportive measures critical

Systematic Reviews and Meta-Analyses

• Rituximab Efficacy: Multiple meta-analyses confirm superior outcomes vs. conventional immunosuppression [16]
• IVIG: Cochrane review shows benefit but limited by small studies [17]

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14. Patient and Layperson Explanation

What is Pemphigus Vulgaris?

Pemphigus Vulgaris is a rare autoimmune condition where your immune system mistakenly attacks the "glue" that holds your skin cells together. This causes the skin to become extremely fragile and blister with minimal friction or pressure.

What Causes It?

Your immune system produces antibodies (proteins that normally fight infections) that mistakenly target proteins called desmogleins, which act like molecular "Velcro" holding skin cells together. When these connections break down, the skin layers separate, causing blisters.

How is it Different from Other Blister Conditions?

Unlike other blistering diseases (like bullous pemphigoid), pemphigus causes very superficial, fragile blisters that break almost immediately, leaving painful raw areas. It often starts in the mouth before affecting the skin.

What are the Symptoms?

• Painful mouth sores that don't heal
• Fragile blisters on the skin that rupture easily
• Raw, oozing areas on skin
• Difficulty eating and swallowing
• Skin that peels off with gentle rubbing

How Serious is It?

Before modern treatments, pemphigus was almost always fatal. With today's medications, most people can achieve long-term remission (where the disease is controlled or goes into "sleep" mode). However, it remains a serious condition requiring expert treatment.

How is it Diagnosed?

Diagnosis requires:

1. Skin biopsy: A small sample of affected skin examined under a microscope
2. Immunofluorescence test: A special test showing antibodies in the skin
3. Blood test: ELISA test to measure antibody levels

What Treatments are Available?

Modern First-Line Treatment:

• Rituximab: A "targeted" medication given as an IV infusion that selectively removes the immune cells making the harmful antibodies. This is now the best treatment, with high success rates.
• Steroids (prednisolone): Used initially to rapidly control inflammation while rituximab takes effect

Other Treatments:

• Steroid-sparing medications (mycophenolate, azathioprine)
• Intravenous immunoglobulin (IVIG) for difficult cases
• Supportive care (wound care, pain management, nutritional support)

Will I Get Better?

Yes, most people achieve remission with treatment. Studies show that:

• About 89% of people treated with rituximab achieve complete remission off all medications
• Treatment usually continues for 1-2 years
• Some people may need occasional maintenance treatment
• Relapses can occur but are usually manageable

What Should I Expect During Treatment?

• First Few Months: Intensive treatment with regular hospital visits, blood tests, and monitoring
• Gradual Improvement: Blisters stop forming within weeks; existing lesions heal over months
• Medication Tapering: Steroids are gradually reduced over 6-12 months
• Long-Term Monitoring: Regular follow-up to detect early relapse

Living with Pemphigus

• Avoid skin trauma (use soft fabrics, gentle washing)
• Maintain good oral hygiene
• Attend all medical appointments
• Report new blisters early
• Join support groups for emotional support

Will It Affect My Life Expectancy?

With modern treatment, life expectancy is near normal. The main risks come from complications of the disease (like infection) or side effects of medications, which are carefully monitored.

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15. Clinical Cases

Case 1: Classic Presentation

Presentation: A 52-year-old woman of Mediterranean descent presents with a 3-month history of painful mouth ulcers. She initially saw her dentist who treated her for aphthous stomatitis without improvement. Over the past 4 weeks, she developed fragile blisters on her chest and back that rupture easily, leaving painful raw areas.

Examination:

• Multiple painful erosions on buccal mucosa, palate, and gingiva
• Scattered flaccid bullae and erosions on trunk (approximately 15% BSA)
• Positive Nikolsky sign

Investigations:

• Skin biopsy (H&E): Suprabasal acantholysis, "row of tombstones"
• DIF: Intercellular IgG and C3 deposition ("chicken wire" pattern)
• ELISA: Anti-Dsg3 170 U/mL (positive), anti-Dsg1 90 U/mL (positive)

Diagnosis: Pemphigus vulgaris, mucocutaneous type

Management:

• Rituximab 1000 mg IV on day 0 and day 14
• Prednisolone 60 mg/day (1 mg/kg), tapered over 9 months
• Co-trimoxazole prophylaxis
• Calcium, vitamin D, bisphosphonate for bone protection
• Viscous lidocaine for oral pain
• Gentle wound care with non-adherent dressings

Outcome: No new blisters after 4 weeks. Prednisolone tapered to 5 mg/day by month 9. Complete remission off therapy achieved at 18 months. Anti-Dsg titres normalized.

Case 2: Refractory Disease

Presentation: A 68-year-old man diagnosed with pemphigus vulgaris 2 years ago. Initially treated with high-dose prednisolone (80 mg/day) and azathioprine. Partial response but unable to taper steroids below 40 mg/day without flare. Now developing steroid-induced diabetes and cushingoid features.

Current Disease Activity: Persistent oral erosions, intermittent new skin blisters (5-10% BSA)

Previous Treatments:

• Prednisolone (ongoing, 40 mg/day)
• Azathioprine 150 mg/day (inadequate response)
• Dapsone 100 mg/day added (minimal benefit)

Management Plan:

• Switch to rituximab (375 mg/m² weekly × 4 weeks)
• Continue prednisolone initially, then taper aggressively
• Discontinue azathioprine and dapsone
• Add IVIG 2 g/kg monthly × 3 cycles as bridge therapy
• Intensive monitoring

Outcome: Dramatic improvement after rituximab. Prednisolone tapered to 10 mg/day over 6 months. IVIG discontinued after 3 cycles. Maintained on rituximab 500 mg every 6 months. Diabetes improved with steroid reduction.

Case 3: Paraneoplastic Pemphigus

Presentation: A 61-year-old man with known chronic lymphocytic leukemia (CLL) develops severe, intractable mouth ulcers involving tongue, buccal mucosa, and lips. Progressive dysphagia and odynophagia. Subsequently develops polymorphous skin lesions (bullae, erosions, targetoid lesions, lichenoid papules). Progressive dyspnea.

Examination:

• Severe confluent mucosal erosions
• Polymorphous cutaneous lesions (unusual for PV)
• Bilateral lung crackles

Investigations:

• Skin biopsy: Interface dermatitis with acantholysis (unusual combination)
• DIF: Intercellular + linear basement membrane zone IgG
• ELISA: Anti-Dsg3 positive, anti-Dsg1 positive
• Indirect IF: Staining on rat bladder epithelium (characteristic of PNP)
• Immunoprecipitation: Antibodies to envoplakin, periplakin (confirms PNP)
• CT chest: Mediastinal lymphadenopathy (CLL)
• Pulmonary function tests: Obstructive pattern, reduced DLCO

Diagnosis: Paraneoplastic pemphigus associated with CLL

Management:

• Hematology consultation: Treat underlying CLL with chemoimmunotherapy
• Rituximab for both CLL and PNP
• High-dose steroids
• IVIG
• Pulmonology involvement for bronchiolitis obliterans

Outcome: Partial response. Persistent mucosal disease despite treatment. Developed progressive bronchiolitis obliterans requiring oxygen therapy. Poor prognosis.

Teaching Points: PNP is distinct from PV, has complex autoantibody profile targeting multiple antigens (desmogleins + plakin proteins), associated with malignancy, and has worse prognosis due to bronchiolitis obliterans.

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16. Investigation Interpretation Examples

Example 1: Classic PV Histology

Clinical Scenario: Punch biopsy from edge of fresh blister on chest

H&E Findings:

• Low Power: Intraepidermal blister, suprabasal cleavage
• High Power:
  • Basal keratinocytes remain attached to dermis ("row of tombstones")
  • Rounded, acantholytic keratinocytes with perinuclear halos floating in blister cavity
  • Minimal dermal inflammation
  • Sparse eosinophils in blister cavity

Interpretation: Classic findings for pemphigus vulgaris

Example 2: Direct Immunofluorescence

Clinical Scenario: Perilesional skin from normal-appearing area 1 cm from erosion

DIF Findings:

• Strong intercellular IgG deposition throughout epidermis
• "Chicken wire" or "fishnet" pattern outlining keratinocytes
• Intercellular C3 deposition (weaker than IgG)
• No linear basement membrane zone staining

Interpretation: Diagnostic for pemphigus. The intercellular pattern distinguishes pemphigus from subepidermal blistering diseases (which show linear BMZ staining).

Example 3: ELISA Results and Clinical Correlation

Case A (Mucosal-Dominant PV):

• Anti-Dsg3: 180 U/mL (high positive)
• Anti-Dsg1: less than 20 U/mL (negative)
• Clinical Correlation: Isolated oral involvement, no skin lesions

Case B (Mucocutaneous PV):

• Anti-Dsg3: 210 U/mL (high positive)
• Anti-Dsg1: 150 U/mL (high positive)
• Clinical Correlation: Extensive oral and skin involvement

Case C (Monitoring Treatment Response):

• Baseline: Anti-Dsg3 200 U/mL, Anti-Dsg1 140 U/mL
• Month 6 (on rituximab): Anti-Dsg3 45 U/mL, Anti-Dsg1 30 U/mL
• Clinical Correlation: Complete clinical remission, falling titres predict sustained response

Case D (Predicting Relapse):

• Month 18 (in remission): Anti-Dsg3 25 U/mL
• Month 20: Anti-Dsg3 90 U/mL (rising titre)
• Month 21: Clinical relapse with new oral erosions
• Interpretation: Rising titres predict clinical relapse by 4-8 weeks

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17. Examination Focus

Common Exam Questions

1. Differentiator: "Pemphigus vs Pemphigoid?"

Model Answer:

2. Clinical Sign: "Describe and demonstrate Nikolsky Sign"

Model Answer: "The Nikolsky sign is elicited by applying firm sliding pressure with a finger on normal-appearing perilesional skin. A positive sign occurs when the epidermis shears off, creating an erosion. This indicates intraepidermal loss of cohesion due to acantholysis and is characteristic of pemphigus. It can also be positive in other blistering conditions like SJS/TEN and staphylococcal scalded skin syndrome, but is negative in subepidermal blistering diseases like bullous pemphigoid."

3. Target Antigen: "What is the autoantigen in pemphigus vulgaris?"

Model Answer: "The primary autoantigens are Desmoglein 3 and Desmoglein 1. These are transmembrane glycoproteins of the cadherin family that form the adhesive core of desmosomes. Dsg3 is predominantly expressed in mucosa and basal epidermis, while Dsg1 is mainly in superficial epidermis. Autoantibodies to Dsg3 alone cause mucosal-dominant pemphigus, while antibodies to both Dsg3 and Dsg1 cause mucocutaneous disease. This is explained by the desmoglein compensation theory."

4. Histological Finding: "Describe acantholysis"

Model Answer: "Acantholysis is the loss of intercellular adhesion between keratinocytes, resulting from disruption of desmosomes. Histologically, acantholytic keratinocytes appear as rounded cells with perinuclear halos, losing their polygonal shape and intercellular bridges. They can be seen floating freely in the blister cavity. The characteristic histological finding in pemphigus vulgaris is suprabasal acantholysis with the 'row of tombstones' sign, where the basal keratinocytes remain attached to the basement membrane while overlying cells have lost cohesion."

5. Management: "First-line treatment for pemphigus vulgaris?"

Model Answer: "The current first-line treatment for moderate-to-severe pemphigus vulgaris is rituximab combined with short-term corticosteroids, based on the landmark Ritux 3 trial (Joly et al., Lancet 2017). Rituximab is an anti-CD20 monoclonal antibody that depletes B cells, eliminating the autoantibody-producing cell population. The regimen typically involves rituximab 1000 mg IV on days 0 and 14, combined with prednisolone 0.5-1 mg/kg/day tapered over 6-12 months. This approach achieves superior remission rates (89% vs 34%) and requires lower cumulative steroid doses compared to steroids alone."

Viva Scenarios

Scenario 1: "Why does pemphigus typically start with mouth ulcers?"

Model Answer: "This is explained by the desmoglein compensation theory. Desmoglein 3 is the predominant adhesion molecule in oral mucosa, whereas skin expresses both Dsg3 (basal layers) and Dsg1 (superficial layers). In early disease, patients develop anti-Dsg3 antibodies first. In the mouth, loss of Dsg3 function directly causes blistering because there's no compensatory adhesion molecule. In the skin, Dsg1 can compensate for Dsg3 loss, preventing blistering. Later, when anti-Dsg1 antibodies also develop, skin involvement occurs because Dsg1 can no longer provide adequate adhesion. This explains the typical progression from mucosal-only disease to mucocutaneous disease."

Scenario 2: "Describe the 'Row of Tombstones' finding"

Model Answer: "The 'row of tombstones' is a characteristic histological finding in pemphigus vulgaris. It refers to the basal keratinocytes that remain attached to the basement membrane while the suprabasal cells have lost cohesion and separated. When viewed histologically, these attached basal cells resemble a row of upright tombstones along the base of the blister. This occurs because pemphigus autoantibodies target desmosomes (which provide lateral cell-to-cell adhesion) but not hemidesmosomes (which attach basal cells to the basement membrane). Therefore, the suprabasal cleavage occurs just above the basal layer, leaving it intact and attached."

Scenario 3: "Patient on rituximab develops recurrent infections - how do you manage?"

Model Answer: "Rituximab causes B cell depletion, which can lead to:

1. Immediate Issue: Check FBC (cytopenias?), CRP, cultures, assess severity of infection. Treat infection appropriately.
2. Assess Immunoglobulin Levels: Check serum IgG, IgA, IgM. Rituximab can cause hypogammaglobulinemia, especially with repeated dosing.
3. If Hypogammaglobulinemia: Consider IVIG replacement therapy if IgG less than 4 g/L and recurrent infections
4. Prophylaxis Review: Ensure on appropriate prophylaxis (co-trimoxazole for PCP, consider aciclovir for HSV)
5. Risk-Benefit Assessment: Consider if rituximab maintenance dose can be reduced or interval extended
6. Long-term Strategy: If recurrent infections despite measures, may need to transition to alternative steroid-sparing agent (MMF, azathioprine) The key is balancing disease control with infection risk, which requires individualized decision-making."

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18. Related Conditions Quick Reference

Pemphigus Variants Comparison

Pemphigus vs Other Autoimmune Blistering Diseases

Intraepidermal: Pemphigus variants, Hailey-Hailey, Darier disease

Subepidermal: Bullous pemphigoid, mucous membrane pemphigoid, EBA, dermatitis herpetiformis, linear IgA disease

Key Distinguishing Feature: DIF pattern (intercellular vs linear BMZ)

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19. References

Primary Sources

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2. Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell. 1991;67(5):869-877. doi:10.1016/0092-8674(91)90360-b

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8. Ahmed AR, Yunis EJ, Khatri K, et al. Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris. Proc Natl Acad Sci U S A. 1990;87(19):7658-7662. doi:10.1073/pnas.87.19.7658

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13. Berkowitz P, Hu P, Warren S, Liu Z, Diaz LA, Rubenstein DS. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc Natl Acad Sci U S A. 2006;103(34):12855-12860. doi:10.1073/pnas.0602973103

14. Baum S, Sakka N, Artsi O, Trau H, Barzilai A. Diagnosis and classification of autoimmune blistering diseases. Autoimmun Rev. 2014;13(4-5):482-489. doi:10.1016/j.autrev.2014.01.047

15. Kwon EJ, Yamagami J, Nishikawa T, Amagai M. Anti-desmoglein IgG autoantibodies in patients with pemphigus in remission. J Eur Acad Dermatol Venereol. 2008;22(9):1070-1075. doi:10.1111/j.1468-3083.2008.02738.x

16. Wang HH, Liu CW, Li YC, Huang YC. Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. Acta Derm Venereol. 2015;95(8):928-932. doi:10.2340/00015555-2116

17. Gach JE, Ilchyshyn A. Beneficial effect of intravenous immunoglobulin in a patient with pemphigus vulgaris. Br J Dermatol. 2005;153(3):655-656. doi:10.1111/j.1365-2133.2005.06730.x

18. Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet. 2019;394(10201):882-894. doi:10.1016/S0140-6736(19)31778-7

19. Murrell DF, Dick S, Ahmed AR, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol. 2008;58(6):1043-1046. doi:10.1016/j.jaad.2008.01.012

20. Sebaratnam DF, Hanna AM, Chee SN, et al. Development of a quality of life instrument for autoimmune bullous disease: the Autoimmune Bullous Disease Quality of Life questionnaire. JAMA Dermatol. 2013;149(10):1186-1191. doi:10.1001/jamadermatol.2013.4972

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