🏷

Classifications

Harrison's Part

Mechanistic Nosology

👪

Inheritance

1

HLA-linked polygenic susceptibility HP:0010982

PF is a complex autoimmune trait, not Mendelian. Susceptibility is linked to HLA-DRB1 class II alleles sharing a common peptide-binding-groove sequence; familial clustering occurs in endemic foci.

polygenic inheritance

Show evidence (1 reference)

PMID:9027963 SUPPORT Human Clinical

"particular HLA alleles confer increased risk for the disease"

States the HLA-linked genetic susceptibility underlying the polygenic inheritance.

⚙

Pathophysiology

7

HLA-DRB1-Restricted Susceptibility

Permissive HLA-DRB1 class II alleles (DRB1*0102, *0404, *1402, *1406 across endemic populations) share the amino-acid sequence LLEQRRAA at positions 67-74 of the third hypervariable region, which presents Dsg1 peptides to CD4+ T cells and sets genetic risk.

HLA-DRB1 hgnc:4948

MHC class II peptide antigen binding GO:0042605

Downstream

Anti-Desmoglein 1 IgG Autoantibody Production Presentation of Dsg1 peptides on the permissive allele licenses the autoreactive T-cell help that drives anti-Dsg1 antibody production.

Show evidence (1 reference)

PMID:9027963 SUPPORT Human Clinical

"All these alleles involved in predisposition to the disease in different populations shared the same amino acid sequence at position 67-74 on the third hypervariable region of the DRB1 gene: LLEQRRAA"

Identifies the shared HLA-DRB1 epitope conferring susceptibility.

Anti-Desmoglein 1 IgG Autoantibody Production

Loss of B-cell tolerance to Dsg1 produces circulating IgG autoantibodies. In endemic fogo selvagem the response precedes clinical disease and is initially IgG1; a Dsg1-reactive Th2 response provides the CD4+ help.

B cell CL:0000236

immunoglobulin production GO:0002377 ↑ INCREASED

Animal models

Naturally occurring canine and feline pemphigus foliaceus Dog partially recapitulates Spontaneous IgG-mediated anti-keratinocyte-surface autoimmunity with a PF phenotype.

Downstream

IgG4 Subclass Switch and Epitope Maturation The preclinical antibody response matures toward pathogenic IgG4 as clinical disease appears.

Show evidence (1 reference)

PMID:10882765 SUPPORT Human Clinical

"the onset of the disease is preceded by a sustained antibody response"

Anti-Dsg1 antibodies are present and rising before clinical fogo selvagem.

IgG4 Subclass Switch and Epitope Maturation

Pathogenic autoantibodies are predominantly IgG4 and recognize conformational epitopes in the N-terminal EC1-EC2 adhesive domains of Dsg1. Active disease is marked by a large excess of IgG4 over IgG1 and convergence onto these pathogenic epitopes.

Downstream

Loss of Desmoglein 1 Adhesion IgG4 directed at the EC1 adhesive interface directly blocks Dsg1 trans-adhesion.

Show evidence (2 references)

PMID:12535205 SUPPORT Human Clinical

"patients have similar levels of IgG1 but a mean 19.3-fold higher IgG4 response"

Quantifies the IgG4 dominance that characterizes active disease.

PMID:29307589 SUPPORT In Vitro

"IgG4 from 95% of FS donor sera (19/20) recognized a 16-residue peptide"

Maps the pathogenic IgG4 response to a defined EC1 epitope.

Loss of Desmoglein 1 Adhesion

Autoantibody binding to Dsg1 blocks its adhesive trans-interaction with desmocollin 1, disabling the desmosomal cadherin without any host mutation. Fab fragments alone abolish native Dsg1-Dsc1 binding, showing steric blockade is sufficient.

keratinocyte CL:0000312

DSG1 hgnc:3048

cell-cell adhesion GO:0098609 ↓ DECREASED

Downstream

p38 MAPK Signaling and Desmosome Disassembly Antibody binding triggers intracellular signaling that actively disassembles desmosomes.

Desmoglein Compensation and Mucosal Sparing Whether Dsg1 loss produces a lesion depends on whether Dsg3 is co-expressed to compensate, so the adhesion defect feeds the compensation gate.

Show evidence (1 reference)

PMID:29307589 SUPPORT In Vitro

"native binding interactions between Dsg1 and desmocollin 1 (Dsc1), which underlie desmosome structure, were abolished by Fab fragments of FS IgG4"

Monovalent Fab abolishes Dsg1-Dsc1 adhesion, establishing direct steric blockade.

p38 MAPK Signaling and Desmosome Disassembly

Anti-Dsg1 binding activates p38 MAPK signaling in keratinocytes, promoting desmosome disassembly and Dsg1 depletion in addition to direct steric blockade.

keratinocyte CL:0000312

desmosome disassembly GO:0035921 ↑ INCREASED

Downstream

Superficial Acantholysis and Blister Formation Combined adhesion loss and desmosome disassembly detach superficial keratinocytes.

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"The binding of pathogenic IgG to dsg-1 triggers the phosphorylation of p38 mitogen-activated protein kinase (MAPK) which is thought to induce apoptosis of the affected keratinocyte"

Describes the p38 MAPK signaling response to antibody binding.

Superficial Acantholysis and Blister Formation

Loss of Dsg1-mediated adhesion in the granular layer detaches keratinocytes from one another (acantholysis), producing subcorneal blisters that rupture easily into scaly, crusted erosions.

keratinocyte CL:0000312

stratum granulosum of epidermis UBERON:0002069

Animal models

Passive-transfer neonatal mouse model Mouse recapitulates Passive transfer of patient IgG produces PF-identical lesions.

Downstream

Superficial crusted erosions

Flaccid blisters

Granular-layer acantholysis Histopathologic readout of the acantholysis at the granular layer.

Scaling skin Ruptured superficial blisters leave the scaly surface.

Exfoliative erythroderma The generalized, confluent form of the superficial erosive disease.

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"the loss of intercellular connections between keratinocytes (acantholysis) and the formation of subcorneal blisters within the epidermis"

States the acantholysis-to-subcorneal-blister step in the granular layer.

Desmoglein Compensation and Mucosal Sparing

In mucosa and deep epidermis, Dsg3 is co-expressed with Dsg1 and compensates when Dsg1 is disabled, so anti-Dsg1 alone (as in PF) causes no lesions there. In the superficial epidermis, where Dsg1 is expressed without Dsg3, anti-Dsg1 is sufficient to blister. This explains the superficial, non-mucosal topography that distinguishes PF from pemphigus vulgaris.

Downstream

Superficial Acantholysis and Blister Formation Where Dsg3 does not compensate (superficial epidermis), the adhesion loss proceeds to acantholysis; this gates the site at which blisters form.

Show evidence (2 references)

PMID:10021453 SUPPORT Model Organism

"In areas (such as superficial epidermis of normal mice) where Dsg1 without Dsg3 is expressed, anti-Dsg1 antibodies alone can cause blisters."

Desmoglein compensation theory explaining the superficial-only topography.

PMID:10021453 SUPPORT Model Organism

"either Dsg1 or Dsg3 alone is sufficient to maintain keratinocyte adhesion"

Co-expression of Dsg3 protects mucosa and deep epidermis in PF.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

5

Immune 1

Exfoliative erythroderma HP:0001019

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"In its most severe form, PF can produce an exfoliative erythroderma characterized by generalized erythema and diffuse scaling of the cutaneous surface"

Erythroderma as the severe presentation.

Integument 4

Superficial crusted erosions VERY_FREQUENT Skin erosion HP:0200041

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"fragile, superficial blisters and bullae of the cutaneous surface that easily rupture to yield erosive lesions"

Describes the superficial erosions that are the clinical hallmark.

Flaccid blisters VERY_FREQUENT Abnormal blistering of the skin HP:0008066

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"fragile, superficial blisters and bullae of the cutaneous surface that easily rupture to yield erosive lesions"

Superficial flaccid blisters preceding the erosions.

Scaling skin HP:0040189

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"generalized erythema and diffuse scaling of the cutaneous surface"

Diffuse scaling is part of the cutaneous picture, marked in severe disease.

Granular-layer acantholysis HP:0100792

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"the loss of intercellular connections between keratinocytes (acantholysis) and the formation of subcorneal blisters within the epidermis"

Acantholysis at the subcorneal level is the histopathologic finding.

🧬

Genetic Associations

1

HLA-DRB1 (Class II alleles DRB1*0102, *0404, *1402 and *1406 confer risk across endemic populations, sharing the LLEQRRAA sequence at positions 67-74 of the DRB1 third hypervariable region.)

Gene: HLA-DRB1 hgnc:4948 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:9027963 SUPPORT Human Clinical

"particular HLA alleles confer increased risk for the disease"

HLA-DRB1 alleles are the established susceptibility loci.

💊

Medical Actions

3

Rituximab

Action: Pharmacotherapy NCIT:C15986

Agent: rituximab NCIT:C1702

Platform: Monoclonal antibody

Anti-CD20 B-cell-depleting monoclonal antibody, first-line for moderate-to-severe pemphigus in European and international guidelines. The RITUX 3 trial (newly diagnosed PV and PF) showed rituximab plus short-term prednisone far exceeded prednisone alone; a PF-specific meta-analysis found a pooled 75% complete remission rate.

Mechanism Target:

INHIBITS Anti-Desmoglein 1 IgG Autoantibody Production — B-cell depletion reduces anti-Dsg1 autoantibody production.

Show evidence (2 references)

PMID:42390708 SUPPORT Human Clinical

"The pooled complete remission (CR) rate was 75.0% (95% confidence interval (CI) 64.0-83.0; I2 = 35.5%)"

PF-specific meta-analysis of rituximab efficacy.

PMID:28342637 SUPPORT Human Clinical

"At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone"

RITUX 3 randomized trial (enrolling PV and PF) establishing first-line rituximab benefit.

Systemic corticosteroids

Action: Pharmacotherapy NCIT:C15986

Agent: prednisone CHEBI:8382

Platform: Small molecule

Oral prednisone (about 0.5-1 mg/kg/day, then tapered) is the mainstay for inducing control, used with a steroid-sparing agent or rituximab.

Mechanism Target:

INHIBITS Superficial Acantholysis and Blister Formation — Immunosuppression reduces autoantibody-driven blistering.

Show evidence (1 reference)

PMID:28342637 SUPPORT BACKGROUND Human Clinical

"High doses of corticosteroids are considered the standard treatment for pemphigus."

Corticosteroids are the standard induction therapy (stated in the RCT's background).

Dapsone

Action: Pharmacotherapy NCIT:C15986

Agent: dapsone CHEBI:4325

Platform: Small molecule

Useful in milder PF, sometimes as a steroid-sparing agent; PF can respond dramatically to dapsone.

Mechanism Target:

INHIBITS Superficial Acantholysis and Blister Formation — Anti-inflammatory/steroid-sparing control of milder disease.

Show evidence (1 reference)

PMID:23248372 SUPPORT Human Clinical

"he was started on dapsone, to which he responded dramatically in four weeks"

Case of PF responding to dapsone.

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Environmental Factors

2

Arthropod (sand fly) salivary antigen exposure

No ECTO exposure_term is bound: ECTO was searched for a sand fly / arthropod salivary-antigen exposure class (l~sand fly, l~insect bite, l~arthropod) and no term matching salivary-antigen exposure was found. The concept is a proposed molecular-mimicry trigger rather than a chemical or organism exposure with an existing ECTO class. The entry and its mechanism link carry their own literature evidence.

In endemic fogo selvagem, epidemiology implicates hematophagous insect bites. Anti-Dsg1 autoantibodies cross-react with the sand fly salivary protein LJM11, and immunizing mice with LJM11 generates anti-Dsg1 antibodies, supporting molecular mimicry as the trigger in genetically susceptible people.

Show evidence (1 reference)

PMID:10882765 SUPPORT Human Clinical

"the production of antibodies against desmoglein 1 is initiated by exposure to an unknown environmental agent"

Supports an environmental trigger for endemic PF.

Mechanism Target:

TRIGGERS Anti-Desmoglein 1 IgG Autoantibody Production — Salivary antigen exposure elicits antibodies that cross-react with Dsg1.

Show evidence (2 references)

PMID:22798673 SUPPORT In Vitro

"Anti-Dsg1 monoclonal autoantibodies derived from FS patients also cross-react with LJM11."

Patient-derived anti-Dsg1 monoclonals cross-react with the sand fly salivary antigen in vitro.

PMID:22798673 SUPPORT Model Organism

"Mice immunized with LJM11 generate anti-Dsg1 Abs."

Immunizing mice with the salivary antigen raises anti-Dsg1 antibodies, the in-vivo half of the mimicry argument.

Drug exposure (thiol and other trigger drugs)

Bound to the generic ECTO:0000509 (exposure to drug) with a penicillamine-specific preferred_term: ECTO was searched (l~penicillamine, l~thiol, and the exposure-to-drug subtree) and has no penicillamine-specific exposure class. The first guessed id (ECTO:9000561) proved to be exposure to propachlor and was rejected.

Drugs can trigger PF, most classically the thiol drug penicillamine; a pharmacovigilance analysis confirmed elevated pemphigus reporting for several trigger drugs.

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most commonly implicated drug is penicillamine"

Penicillamine is the classic drug trigger.

Mechanism Target:

TRIGGERS Anti-Desmoglein 1 IgG Autoantibody Production — Thiol and other trigger drugs can precipitate anti-Dsg1 autoimmunity.

Show evidence (1 reference)

PMID:39906745 SUPPORT Human Clinical

"the odds of reporting the adverse event pemphigus were significantly elevated among individuals exposed to 11/36 previously reported trigger drugs"

Population-level confirmation of drug triggers of pemphigus.

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Diagnosis

3

Direct immunofluorescence of perilesional skin

DIF of perilesional skin shows intercellular IgG (with or without C3) in a chicken-wire pattern; it is the diagnostic gold standard.

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"PF shows a DIF pattern characterized by fluorescent staining around keratinocytes, which is known as the intercellular space (ICS) staining pattern"

Describes the intercellular (chicken-wire) DIF staining pattern that confirms PF.

Nikolsky sign

Lateral pressure on perilesional skin shears the epidermis; a common, highly specific bedside sign in pemphigus.

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"A common clinical finding in PF is a positive Nikolsky's sign"

Nikolsky sign is a characteristic bedside finding in PF.

Anti-desmoglein 1 ELISA

Serum anti-Dsg1 IgG is detected by ELISA; antibody levels rise with disease onset, and pure PF is anti-Dsg3 negative.

Show evidence (2 references)

PMID:10882765 SUPPORT Human Clinical

"We used an enzyme-linked immunosorbent assay to detect antibodies against desmoglein 1 in serum samples from 60 patients with endemic pemphigus foliaceus"

Anti-Dsg1 ELISA is the serologic test used in PF patients.

PMID:10882765 SUPPORT Human Clinical

"the onset of disease was associated with a marked increase in antibody values"

Anti-Dsg1 antibody levels track the transition to clinical disease.

📈

Progression

2

Onset (sporadic PF)

Age: 40-60 years

The non-endemic (sporadic) form typically presents in mid-to-late adulthood.

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"The average age of non-endemic PF symptom onset ranges from 40 to 60 years of age"

Age-of-onset range for sporadic PF.

Onset (endemic fogo selvagem)

Age: second to third decade

Endemic PF affects more children and young adults than the sporadic form.

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"symptoms usually begin during the second or third decade of life"

Earlier age of onset for endemic fogo selvagem.

📊

Prevalence

2

Tunisia

Annual Incidence 0.67 per 100,000 per year 1–9 per 1,000,000 per year

6.7 new cases per million per year, among the highest reported incidences of the sporadic/endemic form outside Brazil. Incidence is female-predominant (~4:1).

Show evidence (2 references)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"the incidence of PF in Tunisia has been found to be as high as 6.7 new cases per million per year"

Gives the Tunisian incidence figure for the normalized rate.

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"female-to-male ratio of incidence rates to be approximately 4 to 1"

Female predominance of PF incidence in the endemic Tunisian setting.

Limao Verde, Mato Grosso do Sul, Brazil (endemic fogo selvagem focus)

Point Prevalence 3000.0 per 100,000 >1 in 1,000

Approximately 3% of the population in an endemic Brazilian focus, far above the sporadic worldwide rate.

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"there is a region located in the state of Maso Grosso do Sul that has a prevalence equal to approximately 3% of its population"

Endemic-focus prevalence (the review reproduces the source's "Maso Grosso" spelling).

⚖️

Clinical Burden

Moderate

PF is generally milder than pemphigus vulgaris because mucosal involvement is absent and blistering is superficial, but widespread or erythrodermic disease causes barrier failure and secondary infection, and long-term immunosuppression carries its own morbidity. Rituximab now induces high rates of complete remission.

Show evidence (1 reference)

PMID:21605805 SUPPORT REVIEW SYNTHESIS Human Clinical

"In its most severe form, PF can produce an exfoliative erythroderma characterized by generalized erythema and diffuse scaling of the cutaneous surface"

Identifies erythroderma as the severe end of the burden spectrum.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Pemphigus Foliaceus:

Pemphigus vulgaris

Overlapping Features The other major pemphigus, with anti-Dsg3 (with or without anti-Dsg1) autoantibodies.

Distinguishing Features

PV causes mucosal erosions and deep suprabasal blistering; PF spares mucosa and blisters superficially (subcorneal).

Staphylococcal scalded skin syndrome / bullous impetigo

Overlapping Features Superficial blistering from staphylococcal exfoliative toxin.

Distinguishing Features

Toxin-mediated Dsg1 cleavage rather than autoantibody; no intercellular IgG on DIF and an infectious course.

Subcorneal pustular dermatosis

Overlapping Features A neutrophilic subcorneal pustular eruption.

Distinguishing Features

Sterile pustules with negative pemphigus serology and DIF.

IgA pemphigus

Overlapping Features Intraepidermal blistering with IgG-negative, IgA intercellular deposits.

Distinguishing Features

IgA (not IgG) intercellular deposits, often anti-desmocollin, and dapsone responsiveness.

🐁

Animal Models

2

Naturally occurring canine and feline pemphigus foliaceus

PF is one of the most common autoimmune skin diseases of dogs and cats, with IgG autoantibodies against the keratinocyte cell surface and pustules, crusts, erosions, scales and alopecia. A naturally occurring companion-animal counterpart of human PF.

Species

Dog

Publication

PMID:39725576

Pathograph links

Anti-Desmoglein 1 IgG Autoantibody Production partially recapitulates fidelity: moderate observes: organism Spontaneous IgG-mediated anti-keratinocyte-surface autoimmunity with a PF phenotype.

Limitations: The dominant autoantigen in canine PF is debated and may differ from Dsg1; pustular/neutrophilic features are more prominent than in most human PF.

Show evidence (1 reference)

PMID:39725576 SUPPORT Model Organism

"the pathophysiology of canine and feline PF appears to involve immune dysregulation and immunoglobulin G autoantibodies that are directed against the keratinocyte cell surface"

Establishes the shared IgG anti-keratinocyte-surface mechanism.

Passive-transfer neonatal mouse model

Purified IgG from PF (fogo selvagem) patients transferred to neonatal mice reproduces the clinical, histologic and immunologic disease, proving the autoantibodies are pathogenic.

Species

Mouse

Genotype

BALB/c neonatal

Publication

PMID:3905977

Pathograph links

Superficial Acantholysis and Blister Formation recapitulates fidelity: high observes: organism Passive transfer of patient IgG produces PF-identical lesions.

Limitations: Neonatal skin and a short observation window; models the effector arm, not the initiation of autoimmunity.

Show evidence (1 reference)

PMID:3905977 SUPPORT Model Organism

"Thirty-four of 46 mice (74%) receiving parenteral IgG fractions from these patients developed cutaneous lesions that were identical to the human disease"

Passive transfer reproduces the disease, establishing antibody pathogenicity.

{ }

Source YAML

click to show

name: Pemphigus Foliaceus
creation_date: "2026-09-29T03:00:00Z"
category: Autoimmune
description: >-
  Pemphigus foliaceus is an autoimmune blistering disease in which IgG
  autoantibodies against desmoglein 1 cause loss of keratinocyte adhesion in
  the superficial epidermis, producing crusted, scaly erosions without mucosal
  involvement.
disease_term:
  preferred_term: pemphigus foliaceus
  term:
    id: MONDO:0019324
    label: pemphigus foliaceus
synonyms:
- PF
notes: >-
  This entry models the sporadic and endemic forms together, since both are
  IgG anti-Dsg1 diseases with the same effector mechanism; the endemic-specific
  epidemiology (arthropod exposure, fogo selvagem) is carried on the
  environmental entry and the fogo-selvagem-derived evidence. Pemphigus
  erythematosus (Senear-Usher) is curated separately (Pemphigus_Erythematosus).
  DSG1 is the autoantigen, not a susceptibility gene; germline DSG1
  loss-of-function causes a distinct keratoderma phenotype and is not modelled
  here. No GeneReviews chapter exists (PF is a complex autoimmune, non-Mendelian
  disease). Age of onset differs sharply by form (see progression): sporadic PF
  onsets at 40-60 years, endemic fogo selvagem earlier, in the second-to-third
  decade — the clearest clinical difference between the two forms this entry lumps.
prevalence:
- population: Tunisia
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.67
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    6.7 new cases per million per year, among the highest reported incidences of
    the sporadic/endemic form outside Brazil. Incidence is female-predominant
    (~4:1).
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the incidence of PF in Tunisia has been found to be as high as 6.7 new
      cases per million per year
    explanation: >-
      Gives the Tunisian incidence figure for the normalized rate.
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      female-to-male ratio of incidence rates to be approximately 4 to 1
    explanation: >-
      Female predominance of PF incidence in the endemic Tunisian setting.
- population: Limao Verde, Mato Grosso do Sul, Brazil (endemic fogo selvagem focus)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 3000.0
  notes: >-
    Approximately 3% of the population in an endemic Brazilian focus, far above
    the sporadic worldwide rate.
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      there is a region located in the state of Maso Grosso do Sul that has a
      prevalence equal to approximately 3% of its population
    explanation: >-
      Endemic-focus prevalence (the review reproduces the source's "Maso Grosso"
      spelling).
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    PF is generally milder than pemphigus vulgaris because mucosal involvement
    is absent and blistering is superficial, but widespread or erythrodermic
    disease causes barrier failure and secondary infection, and long-term
    immunosuppression carries its own morbidity. Rituximab now induces high
    rates of complete remission.
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In its most severe form, PF can produce an exfoliative erythroderma
      characterized by generalized erythema and diffuse scaling of the
      cutaneous surface
    explanation: >-
      Identifies erythroderma as the severe end of the burden spectrum.
inheritance:
- name: HLA-linked polygenic susceptibility
  inheritance_term:
    preferred_term: polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  description: >-
    PF is a complex autoimmune trait, not Mendelian. Susceptibility is linked to
    HLA-DRB1 class II alleles sharing a common peptide-binding-groove sequence;
    familial clustering occurs in endemic foci.
  evidence:
  - reference: PMID:9027963
    reference_title: An epitope in the third hypervariable region of the DRB1 gene is involved in the susceptibility to endemic pemphigus foliaceus (fogo selvagem) in three different Brazilian populations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      particular HLA alleles confer increased risk for the disease
    explanation: >-
      States the HLA-linked genetic susceptibility underlying the polygenic
      inheritance.
progression:
- phase: Onset (sporadic PF)
  age_range: 40-60 years
  notes: The non-endemic (sporadic) form typically presents in mid-to-late adulthood.
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The average age of non-endemic PF symptom onset ranges from 40 to 60 years
      of age
    explanation: >-
      Age-of-onset range for sporadic PF.
- phase: Onset (endemic fogo selvagem)
  age_range: second to third decade
  notes: Endemic PF affects more children and young adults than the sporadic form.
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      symptoms usually begin during the second or third decade of life
    explanation: >-
      Earlier age of onset for endemic fogo selvagem.
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
  - classification_value: IMMUNE_RHEUMATOLOGIC
  mechanistic_category:
  - classification_value: desmosomopathy
    notes: >-
      Acquired autoimmune desmosomopathy: desmosome dysfunction arises from IgG
      autoantibodies against the desmosomal cadherin desmoglein 1, not from a
      germline desmosomal-gene variant. Tagged because the category denotes
      desmosome dysfunction of any etiology.
differential_diagnoses:
- name: Pemphigus vulgaris
  description: The other major pemphigus, with anti-Dsg3 (with or without anti-Dsg1) autoantibodies.
  distinguishing_features:
  - PV causes mucosal erosions and deep suprabasal blistering; PF spares mucosa and blisters superficially (subcorneal).
- name: Staphylococcal scalded skin syndrome / bullous impetigo
  description: Superficial blistering from staphylococcal exfoliative toxin.
  distinguishing_features:
  - Toxin-mediated Dsg1 cleavage rather than autoantibody; no intercellular IgG on DIF and an infectious course.
- name: Subcorneal pustular dermatosis
  description: A neutrophilic subcorneal pustular eruption.
  distinguishing_features:
  - Sterile pustules with negative pemphigus serology and DIF.
- name: IgA pemphigus
  description: Intraepidermal blistering with IgG-negative, IgA intercellular deposits.
  distinguishing_features:
  - IgA (not IgG) intercellular deposits, often anti-desmocollin, and dapsone responsiveness.
pathophysiology:
- name: HLA-DRB1-Restricted Susceptibility
  biological_scale: MOLECULAR
  description: >-
    Permissive HLA-DRB1 class II alleles (DRB1*0102, *0404, *1402, *1406 across
    endemic populations) share the amino-acid sequence LLEQRRAA at positions
    67-74 of the third hypervariable region, which presents Dsg1 peptides to
    CD4+ T cells and sets genetic risk.
  genes:
  - preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  molecular_functions:
  - preferred_term: MHC class II peptide antigen binding
    term:
      id: GO:0042605
      label: peptide antigen binding
  downstream:
  - target: Anti-Desmoglein 1 IgG Autoantibody Production
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Presentation of Dsg1 peptides on the permissive allele licenses the
      autoreactive T-cell help that drives anti-Dsg1 antibody production.
    evidence:
    - reference: PMID:10642599
      reference_title: Desmoglein-1-specific T lymphocytes from patients with endemic pemphigus foliaceus (fogo selvagem).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These Dsg1-reactive FS T cells exhibited a CD4-positive memory T-cell
        phenotype and produced a T helper 2-like cytokine profile.
      explanation: >-
        Dsg1-specific CD4+ Th2 T cells provide the help linking HLA presentation
        to antibody production.
  evidence:
  - reference: PMID:9027963
    reference_title: An epitope in the third hypervariable region of the DRB1 gene is involved in the susceptibility to endemic pemphigus foliaceus (fogo selvagem) in three different Brazilian populations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All these alleles involved in predisposition to the disease in different
      populations shared the same amino acid sequence at position 67-74 on the
      third hypervariable region of the DRB1 gene: LLEQRRAA
    explanation: >-
      Identifies the shared HLA-DRB1 epitope conferring susceptibility.
- name: Anti-Desmoglein 1 IgG Autoantibody Production
  biological_scale: CELLULAR
  description: >-
    Loss of B-cell tolerance to Dsg1 produces circulating IgG autoantibodies. In
    endemic fogo selvagem the response precedes clinical disease and is
    initially IgG1; a Dsg1-reactive Th2 response provides the CD4+ help.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: INCREASED
  downstream:
  - target: IgG4 Subclass Switch and Epitope Maturation
    causal_link_type: DIRECT
    description: >-
      The preclinical antibody response matures toward pathogenic IgG4 as
      clinical disease appears.
    evidence:
    - reference: PMID:12535205
      reference_title: The role of subclass switching in the pathogenesis of endemic pemphigus foliaceus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Acquisition of an IgG4 response is a key step in the development of
        clinical disease.
      explanation: >-
        Links the maturing autoantibody response to disease onset.
  evidence:
  - reference: PMID:10882765
    reference_title: The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. Cooperative Group on Fogo Selvagem Research.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the onset of the disease is preceded by a sustained antibody response
    explanation: >-
      Anti-Dsg1 antibodies are present and rising before clinical fogo selvagem.
- name: IgG4 Subclass Switch and Epitope Maturation
  biological_scale: MOLECULAR
  description: >-
    Pathogenic autoantibodies are predominantly IgG4 and recognize conformational
    epitopes in the N-terminal EC1-EC2 adhesive domains of Dsg1. Active disease
    is marked by a large excess of IgG4 over IgG1 and convergence onto these
    pathogenic epitopes.
  downstream:
  - target: Loss of Desmoglein 1 Adhesion
    causal_link_type: DIRECT
    description: >-
      IgG4 directed at the EC1 adhesive interface directly blocks Dsg1
      trans-adhesion.
    evidence:
    - reference: PMID:19340014
      reference_title: Pathogenic epitopes of autoantibodies in pemphigus reside in the amino-terminal adhesive region of desmogleins which are unmasked by proteolytic processing of prosequence.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        these findings support the idea that at least some pathogenic pemphigus
        autoantibodies induce the loss of cell adhesion by directly binding the
        trans-interaction site of Dsgs
      explanation: >-
        Pathogenic anti-Dsg1 binds the adhesive trans-interaction site.
  evidence:
  - reference: PMID:12535205
    reference_title: The role of subclass switching in the pathogenesis of endemic pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients have similar levels of IgG1 but a mean 19.3-fold higher IgG4
      response
    explanation: >-
      Quantifies the IgG4 dominance that characterizes active disease.
  - reference: PMID:29307589
    reference_title: Pathogenic IgG4 autoantibodies from endemic pemphigus foliaceus recognize a desmoglein-1 conformational epitope.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      IgG4 from 95% of FS donor sera (19/20) recognized a 16-residue peptide
    explanation: >-
      Maps the pathogenic IgG4 response to a defined EC1 epitope.
- name: Loss of Desmoglein 1 Adhesion
  conforms_to: "desmosomal_adhesion_failure#Desmosomal Component Loss or Blockade"
  biological_scale: MOLECULAR
  description: >-
    Autoantibody binding to Dsg1 blocks its adhesive trans-interaction with
    desmocollin 1, disabling the desmosomal cadherin without any host mutation.
    Fab fragments alone abolish native Dsg1-Dsc1 binding, showing steric
    blockade is sufficient.
  genes:
  - preferred_term: DSG1
    term:
      id: hgnc:3048
      label: DSG1
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: cell-cell adhesion
    term:
      id: GO:0098609
      label: cell-cell adhesion
    modifier: DECREASED
  downstream:
  - target: p38 MAPK Signaling and Desmosome Disassembly
    causal_link_type: DIRECT
    description: >-
      Antibody binding triggers intracellular signaling that actively
      disassembles desmosomes.
    evidence:
    - reference: PMID:21605805
      reference_title: Diagnosis and clinical features of pemphigus foliaceus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The binding of pathogenic IgG to dsg-1 triggers the phosphorylation of
        p38 mitogen-activated protein kinase (MAPK)
      explanation: >-
        Connects antibody binding to the p38 signaling step.
  - target: Desmoglein Compensation and Mucosal Sparing
    causal_link_type: DIRECT
    description: >-
      Whether Dsg1 loss produces a lesion depends on whether Dsg3 is co-expressed
      to compensate, so the adhesion defect feeds the compensation gate.
  evidence:
  - reference: PMID:29307589
    reference_title: Pathogenic IgG4 autoantibodies from endemic pemphigus foliaceus recognize a desmoglein-1 conformational epitope.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      native binding interactions between Dsg1 and desmocollin 1 (Dsc1), which
      underlie desmosome structure, were abolished by Fab fragments of FS IgG4
    explanation: >-
      Monovalent Fab abolishes Dsg1-Dsc1 adhesion, establishing direct steric
      blockade.
- name: p38 MAPK Signaling and Desmosome Disassembly
  conforms_to: "desmosomal_adhesion_failure#Loss of Desmosomal Intercellular Adhesion"
  biological_scale: CELLULAR
  description: >-
    Anti-Dsg1 binding activates p38 MAPK signaling in keratinocytes, promoting
    desmosome disassembly and Dsg1 depletion in addition to direct steric
    blockade.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: desmosome disassembly
    term:
      id: GO:0035921
      label: desmosome disassembly
    modifier: INCREASED
  downstream:
  - target: Superficial Acantholysis and Blister Formation
    causal_link_type: DIRECT
    description: >-
      Combined adhesion loss and desmosome disassembly detach superficial
      keratinocytes.
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The binding of pathogenic IgG to dsg-1 triggers the phosphorylation of
      p38 mitogen-activated protein kinase (MAPK) which is thought to induce
      apoptosis of the affected keratinocyte
    explanation: >-
      Describes the p38 MAPK signaling response to antibody binding.
- name: Superficial Acantholysis and Blister Formation
  conforms_to: "desmosomal_adhesion_failure#Acantholysis and Mechanical Failure of Desmosome-Dependent Tissues"
  biological_scale: TISSUE
  description: >-
    Loss of Dsg1-mediated adhesion in the granular layer detaches keratinocytes
    from one another (acantholysis), producing subcorneal blisters that rupture
    easily into scaly, crusted erosions.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: stratum granulosum of epidermis
    term:
      id: UBERON:0002069
      label: stratum granulosum of epidermis
  downstream:
  - target: Superficial crusted erosions
    causal_link_type: DIRECT
  - target: Flaccid blisters
    causal_link_type: DIRECT
  - target: Granular-layer acantholysis
    causal_link_type: DIRECT
    description: Histopathologic readout of the acantholysis at the granular layer.
  - target: Scaling skin
    causal_link_type: DIRECT
    description: Ruptured superficial blisters leave the scaly surface.
  - target: Exfoliative erythroderma
    causal_link_type: DIRECT
    description: The generalized, confluent form of the superficial erosive disease.
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the loss of intercellular connections between keratinocytes (acantholysis)
      and the formation of subcorneal blisters within the epidermis
    explanation: >-
      States the acantholysis-to-subcorneal-blister step in the granular layer.
- name: Desmoglein Compensation and Mucosal Sparing
  biological_scale: TISSUE
  description: >-
    In mucosa and deep epidermis, Dsg3 is co-expressed with Dsg1 and compensates
    when Dsg1 is disabled, so anti-Dsg1 alone (as in PF) causes no lesions there.
    In the superficial epidermis, where Dsg1 is expressed without Dsg3,
    anti-Dsg1 is sufficient to blister. This explains the superficial, non-mucosal
    topography that distinguishes PF from pemphigus vulgaris.
  downstream:
  - target: Superficial Acantholysis and Blister Formation
    causal_link_type: DIRECT
    description: >-
      Where Dsg3 does not compensate (superficial epidermis), the adhesion loss
      proceeds to acantholysis; this gates the site at which blisters form.
  evidence:
  - reference: PMID:10021453
    reference_title: Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In areas (such as superficial epidermis of normal mice) where Dsg1 without
      Dsg3 is expressed, anti-Dsg1 antibodies alone can cause blisters.
    explanation: >-
      Desmoglein compensation theory explaining the superficial-only topography.
  - reference: PMID:10021453
    reference_title: Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      either Dsg1 or Dsg3 alone is sufficient to maintain keratinocyte adhesion
    explanation: >-
      Co-expression of Dsg3 protects mucosa and deep epidermis in PF.
phenotypes:
- category: Cutaneous
  name: Superficial crusted erosions
  description: >-
    Scaly, crusted erosions in a seborrheic distribution (scalp, face, upper
    trunk); the clinical hallmark of PF.
  phenotype_term:
    preferred_term: superficial crusted skin erosion
    term:
      id: HP:0200041
      label: Skin erosion
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      fragile, superficial blisters and bullae of the cutaneous surface that
      easily rupture to yield erosive lesions
    explanation: >-
      Describes the superficial erosions that are the clinical hallmark.
- category: Cutaneous
  name: Flaccid blisters
  description: >-
    Fragile, superficial (subcorneal) flaccid blisters that rupture easily.
  phenotype_term:
    preferred_term: superficial flaccid blisters
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      fragile, superficial blisters and bullae of the cutaneous surface that
      easily rupture to yield erosive lesions
    explanation: >-
      Superficial flaccid blisters preceding the erosions.
- category: Cutaneous
  name: Scaling skin
  description: >-
    Diffuse scaling, most marked in seborrheic areas.
  phenotype_term:
    preferred_term: scaling skin
    term:
      id: HP:0040189
      label: Scaling skin
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      generalized erythema and diffuse scaling of the cutaneous surface
    explanation: >-
      Diffuse scaling is part of the cutaneous picture, marked in severe disease.
- category: Cutaneous
  name: Exfoliative erythroderma
  description: >-
    In its most severe form PF generalizes to an exfoliative erythroderma with
    generalized erythema and diffuse scaling.
  phenotype_term:
    preferred_term: exfoliative erythroderma
    term:
      id: HP:0001019
      label: Erythroderma
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In its most severe form, PF can produce an exfoliative erythroderma
      characterized by generalized erythema and diffuse scaling of the
      cutaneous surface
    explanation: >-
      Erythroderma as the severe presentation.
- category: Histopathologic
  name: Granular-layer acantholysis
  description: >-
    Histology shows acantholysis with cleavage within the granular/subcorneal
    layer of the epidermis.
  phenotype_term:
    preferred_term: subcorneal acantholysis
    term:
      id: HP:0100792
      label: Acantholysis
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the loss of intercellular connections between keratinocytes (acantholysis)
      and the formation of subcorneal blisters within the epidermis
    explanation: >-
      Acantholysis at the subcorneal level is the histopathologic finding.
genetic:
- name: HLA-DRB1
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  relationship_type: SUSCEPTIBILITY
  association: >-
    Class II alleles DRB1*0102, *0404, *1402 and *1406 confer risk across
    endemic populations, sharing the LLEQRRAA sequence at positions 67-74 of the
    DRB1 third hypervariable region.
  evidence:
  - reference: PMID:9027963
    reference_title: An epitope in the third hypervariable region of the DRB1 gene is involved in the susceptibility to endemic pemphigus foliaceus (fogo selvagem) in three different Brazilian populations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      particular HLA alleles confer increased risk for the disease
    explanation: >-
      HLA-DRB1 alleles are the established susceptibility loci.
environmental:
- name: Arthropod (sand fly) salivary antigen exposure
  description: >-
    In endemic fogo selvagem, epidemiology implicates hematophagous insect
    bites. Anti-Dsg1 autoantibodies cross-react with the sand fly salivary
    protein LJM11, and immunizing mice with LJM11 generates anti-Dsg1 antibodies,
    supporting molecular mimicry as the trigger in genetically susceptible people.
  effect: Proposed environmental trigger of endemic PF via molecular mimicry
  influences_mechanisms:
  - target: Anti-Desmoglein 1 IgG Autoantibody Production
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Salivary antigen exposure elicits antibodies that cross-react with Dsg1.
    evidence:
    - reference: PMID:22798673
      reference_title: 'Cutting Edge: Brazilian pemphigus foliaceus anti-desmoglein 1 autoantibodies cross-react with sand fly salivary LJM11 antigen.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Anti-Dsg1 monoclonal autoantibodies derived from FS patients also
        cross-react with LJM11.
      explanation: >-
        Patient-derived anti-Dsg1 monoclonals cross-react with the sand fly
        salivary antigen in vitro.
    - reference: PMID:22798673
      reference_title: 'Cutting Edge: Brazilian pemphigus foliaceus anti-desmoglein 1 autoantibodies cross-react with sand fly salivary LJM11 antigen.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mice immunized with LJM11 generate anti-Dsg1 Abs.
      explanation: >-
        Immunizing mice with the salivary antigen raises anti-Dsg1 antibodies,
        the in-vivo half of the mimicry argument.
  notes: >-
    No ECTO exposure_term is bound: ECTO was searched for a sand fly / arthropod
    salivary-antigen exposure class (l~sand fly, l~insect bite, l~arthropod) and
    no term matching salivary-antigen exposure was found. The concept is a
    proposed molecular-mimicry trigger rather than a chemical or organism
    exposure with an existing ECTO class. The entry and its mechanism link carry
    their own literature evidence.
  evidence:
  - reference: PMID:10882765
    reference_title: The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. Cooperative Group on Fogo Selvagem Research.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the production of antibodies against desmoglein 1 is initiated by exposure
      to an unknown environmental agent
    explanation: >-
      Supports an environmental trigger for endemic PF.
- name: Drug exposure (thiol and other trigger drugs)
  description: >-
    Drugs can trigger PF, most classically the thiol drug penicillamine; a
    pharmacovigilance analysis confirmed elevated pemphigus reporting for several
    trigger drugs.
  effect: Recognized environmental trigger of drug-induced PF
  exposure_term:
    preferred_term: exposure to penicillamine
    term:
      id: ECTO:0000509
      label: exposure to drug
  chemicals:
  - penicillamine
  notes: >-
    Bound to the generic ECTO:0000509 (exposure to drug) with a
    penicillamine-specific preferred_term: ECTO was searched (l~penicillamine,
    l~thiol, and the exposure-to-drug subtree) and has no penicillamine-specific
    exposure class. The first guessed id (ECTO:9000561) proved to be exposure to
    propachlor and was rejected.
  influences_mechanisms:
  - target: Anti-Desmoglein 1 IgG Autoantibody Production
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Thiol and other trigger drugs can precipitate anti-Dsg1 autoimmunity.
    evidence:
    - reference: PMID:39906745
      reference_title: A comprehensive, population level evaluation of previously reported drug triggers of pemphigus highlights immunomodulatory capacity as a common characteristic.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the odds of reporting the adverse event pemphigus were significantly
        elevated among individuals exposed to 11/36 previously reported trigger
        drugs
      explanation: >-
        Population-level confirmation of drug triggers of pemphigus.
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most commonly implicated drug is penicillamine
    explanation: >-
      Penicillamine is the classic drug trigger.
treatments:
- name: Rituximab
  description: >-
    Anti-CD20 B-cell-depleting monoclonal antibody, first-line for
    moderate-to-severe pemphigus in European and international guidelines. The
    RITUX 3 trial (newly diagnosed PV and PF) showed rituximab plus short-term
    prednisone far exceeded prednisone alone; a PF-specific meta-analysis found a
    pooled 75% complete remission rate.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Anti-Desmoglein 1 IgG Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      B-cell depletion reduces anti-Dsg1 autoantibody production.
  evidence:
  - reference: PMID:42390708
    reference_title: 'Efficacy and Safety of Rituximab in Pemphigus Foliaceus: A Systematic Review and Meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled complete remission (CR) rate was 75.0% (95% confidence interval
      (CI) 64.0-83.0; I2 = 35.5%)
    explanation: >-
      PF-specific meta-analysis of rituximab efficacy.
  - reference: PMID:28342637
    reference_title: 'First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term
      prednisone were in complete remission off-therapy versus 15 (34%) of 44
      assigned to prednisone alone
    explanation: >-
      RITUX 3 randomized trial (enrolling PV and PF) establishing first-line
      rituximab benefit.
- name: Systemic corticosteroids
  description: >-
    Oral prednisone (about 0.5-1 mg/kg/day, then tapered) is the mainstay for
    inducing control, used with a steroid-sparing agent or rituximab.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  target_mechanisms:
  - target: Superficial Acantholysis and Blister Formation
    treatment_effect: INHIBITS
    description: >-
      Immunosuppression reduces autoantibody-driven blistering.
  evidence:
  - reference: PMID:28342637
    reference_title: 'First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      High doses of corticosteroids are considered the standard treatment for
      pemphigus.
    explanation: >-
      Corticosteroids are the standard induction therapy (stated in the RCT's
      background).
- name: Dapsone
  description: >-
    Useful in milder PF, sometimes as a steroid-sparing agent; PF can respond
    dramatically to dapsone.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dapsone
      term:
        id: CHEBI:4325
        label: dapsone
  target_mechanisms:
  - target: Superficial Acantholysis and Blister Formation
    treatment_effect: INHIBITS
    description: >-
      Anti-inflammatory/steroid-sparing control of milder disease.
  evidence:
  - reference: PMID:23248372
    reference_title: Pemphigus foliaceus masquerading as IgA pemphigus and responding to dapsone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he was started on dapsone, to which he responded dramatically in four
      weeks
    explanation: >-
      Case of PF responding to dapsone.
diagnosis:
- name: Direct immunofluorescence of perilesional skin
  description: >-
    DIF of perilesional skin shows intercellular IgG (with or without C3) in a
    chicken-wire pattern; it is the diagnostic gold standard.
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      PF shows a DIF pattern characterized by fluorescent staining around
      keratinocytes, which is known as the intercellular space (ICS) staining
      pattern
    explanation: >-
      Describes the intercellular (chicken-wire) DIF staining pattern that
      confirms PF.
- name: Nikolsky sign
  description: >-
    Lateral pressure on perilesional skin shears the epidermis; a common,
    highly specific bedside sign in pemphigus.
  evidence:
  - reference: PMID:21605805
    reference_title: Diagnosis and clinical features of pemphigus foliaceus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      A common clinical finding in PF is a positive Nikolsky's sign
    explanation: >-
      Nikolsky sign is a characteristic bedside finding in PF.
- name: Anti-desmoglein 1 ELISA
  description: >-
    Serum anti-Dsg1 IgG is detected by ELISA; antibody levels rise with disease
    onset, and pure PF is anti-Dsg3 negative.
  evidence:
  - reference: PMID:10882765
    reference_title: The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. Cooperative Group on Fogo Selvagem Research.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We used an enzyme-linked immunosorbent assay to detect antibodies against
      desmoglein 1 in serum samples from 60 patients with endemic pemphigus
      foliaceus
    explanation: >-
      Anti-Dsg1 ELISA is the serologic test used in PF patients.
  - reference: PMID:10882765
    reference_title: The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. Cooperative Group on Fogo Selvagem Research.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the onset of disease was associated with a marked increase in antibody
      values
    explanation: >-
      Anti-Dsg1 antibody levels track the transition to clinical disease.
animal_models:
- name: Naturally occurring canine and feline pemphigus foliaceus
  species: Dog
  description: >-
    PF is one of the most common autoimmune skin diseases of dogs and cats, with
    IgG autoantibodies against the keratinocyte cell surface and pustules,
    crusts, erosions, scales and alopecia. A naturally occurring companion-animal
    counterpart of human PF.
  publication: PMID:39725576
  modeled_mechanisms:
  - target: Anti-Desmoglein 1 IgG Autoantibody Production
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Spontaneous IgG-mediated anti-keratinocyte-surface autoimmunity with a PF
      phenotype.
    limitations: >-
      The dominant autoantigen in canine PF is debated and may differ from Dsg1;
      pustular/neutrophilic features are more prominent than in most human PF.
    evidence:
    - reference: PMID:39725576
      reference_title: Canine and Feline Pemphigus Foliaceus-an Update on Pathogenesis and Treatment.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the pathophysiology of canine and feline PF appears to involve immune
        dysregulation and immunoglobulin G autoantibodies that are directed
        against the keratinocyte cell surface
      explanation: >-
        Establishes the shared IgG anti-keratinocyte-surface mechanism.
- name: Passive-transfer neonatal mouse model
  species: Mouse
  genotype: BALB/c neonatal
  description: >-
    Purified IgG from PF (fogo selvagem) patients transferred to neonatal mice
    reproduces the clinical, histologic and immunologic disease, proving the
    autoantibodies are pathogenic.
  publication: PMID:3905977
  modeled_mechanisms:
  - target: Superficial Acantholysis and Blister Formation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Passive transfer of patient IgG produces PF-identical lesions.
    limitations: >-
      Neonatal skin and a short observation window; models the effector arm, not
      the initiation of autoimmunity.
    evidence:
    - reference: PMID:3905977
      reference_title: Brazilian pemphigus foliaceus autoantibodies are pathogenic to BALB/c mice by passive transfer.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thirty-four of 46 mice (74%) receiving parenteral IgG fractions from
        these patients developed cutaneous lesions that were identical to the
        human disease
      explanation: >-
        Passive transfer reproduces the disease, establishing antibody
        pathogenicity.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Pemphigus_Foliaceus · 2026-09-29T03:12:08Z · View source

New entry for pemphigus foliaceus (MONDO:0019324), an IgG anti-desmoglein-1 autoimmune blistering disease. Deep research: claude_code (research/Pemphigus_Foliaceus-deep-research-claude_code.md; the report gave no PMIDs by design, so all references were found via PubMed search). Pathophysiology built as a causal chain (HLA-DRB1 susceptibility -> anti-Dsg1 IgG -> IgG4 maturation -> loss of Dsg1 adhesion -> p38 signaling -> superficial acantholysis), conforming to the desmosomal_adhesion_failure module, plus a desmoglein-compensation node explaining mucosal sparing. Key PMIDs: 21605805 (clinical review), 10021453 (Mahoney compensation), 10882765/12535205 (fogo selvagem anti-Dsg1, IgG4 switch), 22798673 (LJM11 sand fly mimicry), 9027963 (HLA-DRB1), 19340014/29307589 (pathogenic EC1 epitope), 3905977 (passive-transfer mouse), 39725576 (canine/feline PF), 28342637 (RITUX 3), 42390708 (PF rituximab meta-analysis), 39906745 (drug triggers). Endemic sand-fly exposure left with a review_notes ECTO waiver; penicillamine bound to generic ECTO:0000509 with a specific preferred_term after ECTO:9000561 was found to be a wrong (guessed) id. No GeneReviews chapter (non-Mendelian). Validated: just validate (schema/terms/35 snippets), check-entity-refs, check-causal-targets, check-duplicate-keys.

Claude Code ▸

Pemphigus Foliaceus (MONDO:0019324): Disease Characteristics Research Report

claude-haiku-4-5-20251001, claude-sonnet-5-5 2026-09-29T02:58:29.930288

Pemphigus Foliaceus (MONDO:0019324): Disease Characteristics Research Report

Evidence and citation status - I could not run live PubMed, OMIM or ClinicalTrials.gov queries in this session. The PubMed lookup was blocked, so nothing below was verified against a live source. - The content comes from my knowledge of the literature. Citations are given as author, journal and year, and I have deliberately given no PMIDs. A PMID recalled from memory can be wrong, and the KB treats a fabricated identifier as worse than a missing one. - Before curation, resolve each citation with just fetch-reference PMID:… and copy snippets from the cache. Do not use snippets from this report. - Every ontology CURIE below is a lead only. Look each one up with runoak or the term caches before binding it. CURIEs I'm less sure of are written as a label with "(look up)". - Trial and approval statements from 2023 onward are the least certain. They are marked "verify".

1. Disease Information

Overview. Pemphigus foliaceus (PF) is an organ-specific autoimmune blistering disease. Pathogenic IgG, mainly of the IgG4 subclass, targets desmoglein 1 (Dsg1), the desmosomal cadherin of the upper epidermis. - The antibodies cause loss of keratinocyte–keratinocyte adhesion (acantholysis) in the superficial epidermis, at the granular or subcorneal layer. - Lesions are fragile superficial blisters that break easily. They leave scaly, crusted, erythematous erosions on the seborrheic areas (scalp, face, upper trunk), usually without mucosal involvement.

Identifiers - MONDO: MONDO:0019324 (given in the template; confirm the label). - Other codes: ICD-10 L10.2, ICD-11 EB40.1 (look up), MeSH "Pemphigus" (PF is a MeSH descriptor or supplementary concept; look up), Orphanet (check whether PF has its own entry; look up), OMIM (none; PF is not a Mendelian disease).

Synonyms and variants - Superficial pemphigus. - Endemic PF: fogo selvagem ("wild fire") in Brazil, and the El Bagre (Colombia) and Tunisian foci. - Pemphigus erythematosus (Senear–Usher syndrome): PF with lupus-like features. - Pemphigus herpetiformis: an eosinophilic or neutrophilic variant. - Drug-induced PF. - Paraneoplastic PF: rare and debated. - Neonatal pemphigus: transplacental IgG transfer.

Data provenance. This is aggregated disease-level knowledge from cohort studies, registries, reviews and consensus guidelines. It is not EHR-derived.

2. Etiology

Causal factors. PF is multifactorial: HLA-linked genetic susceptibility plus a loss of B-cell tolerance to Dsg1, usually after an environmental trigger. - In endemic FS the leading hypothesis is an arthropod-borne exposure. Hematophagous black flies (Simulium nigrimanum) were epidemiologically implicated (Eaton et al., Brazil field studies, 1998; Diaz et al.). Causation is not proven. - The hypothesis is that insect salivary antigens, or a virus or parasite, break tolerance through molecular mimicry or epitope spreading.

Genetic risk factors - HLA-DRB1 class II alleles. FS is associated with DRB10102, 0404, 1402 and 1406, with a shared epitope in the peptide-binding groove (Petzl-Erler and Diaz groups, Brazil, 1990s–2000s). PV alleles overlap only partly. - Non-HLA loci in pemphigus generally include ST18 (Sarig et al., PV in Jewish and Egyptian cohorts). Whether this applies to PF is unclear. - Familial clustering exists in endemic areas. - No single causal gene or Mendelian variant is known. There is no OMIM gene entry.

Environmental and other risk factors - Rural residence near rivers in endemic areas, and young age at exposure. - Drug triggers, mostly thiol drugs (penicillamine, captopril) and some non-thiol drugs. - UV light and possibly other triggers exacerbate the disease. - A large fraction of healthy people in endemic foci carry anti-Dsg1 IgG, mostly IgG1 (Warren et al., Lancet 2003). This supports an environmental exposure that most people tolerate.

Protective factors. None is well established. - Non-permissive HLA-DRB1 alleles are relatively protective by inference. - The IgG4-to-IgG1 pattern seems to distinguish exposed-but-healthy people from those who develop disease.

Gene–environment interaction. The HLA-DRB1 risk genotype plus the endemic exposure yields anti-Dsg1 IgG1, which class-switches to IgG4 as disease appears. Only a subset of exposed carriers develop clinical disease.

3. Phenotypes

Feature	Approximate frequency	HPO suggestion (look up)
Superficial flaccid blisters that rupture, leaving erosions	Very frequent	Abnormal blistering of the skin (I believe HP:0008066)
Scaly, crusted, erythematous plaques in seborrheic distribution	Very frequent	Erythema; Skin erosion; Scaling skin
Positive Nikolsky sign	Frequent	Nikolsky sign (look up)
Pruritus	Frequent	Pruritus (I believe HP:0000989)
Burning or pain	Common	Skin pain (look up)
Mucosal sparing	Typical (mucosal involvement is rare)	Not an HPO term; record as a negative feature
Exfoliative erythroderma	Uncommon, severe	Exfoliative erythroderma (look up)
Secondary bacterial infection	Occasional	Recurrent cutaneous infections (look up)
Fever and malaise	Rare, in severe flares	Fever

Onset and course - Onset is usually in adults. Sporadic PF is typically diagnosed between age 40 and 60. - Endemic FS often begins in children and young adults. - The course is chronic and relapsing, occasionally with spontaneous remission (better documented in FS). - PF is generally less severe than PV, and some patients remain localized for years. - Sporadic PF and PV can evolve into each other. This is thought to reflect epitope spreading, and mucosal disease appears with anti-Dsg3.

Quality of life. Disease-specific instruments include ABQOL and TABQOL, DLQI and Skindex. QoL is impaired by pruritus, pain, disfigurement, crusting and odor, and by corticosteroid side effects. QoL tends to track disease activity (PDAI and ABSIS). I'm not aware of validated per-phenotype QoL data.

4. Genetic and Molecular Information

Autoantigen gene: DSG1 (desmoglein 1). HGNC ID probably hgnc:3048 (the KB uses lowercase hgnc:; verify by lookup). The protein is a ~160 kDa calcium-dependent desmosomal cadherin with five extracellular cadherin domains (EC1–EC5), highest in the upper epidermis.
Not a Mendelian disease. There are no pathogenic variants in the ACMG/AMP sense.
Allele frequency and founder data. No variant-level data. The HLA-DRB1 associations vary by population.
Related germline DSG1 disease. Loss-of-function DSG1 variants cause striate palmoplantar keratoderma and SAM syndrome. This is a distinct mechanism (loss of Dsg1 expression, not antibody blockade), but it confirms Dsg1's role in epidermal integrity.
Modifier genes: unknown.
Epigenetic, chromosomal and structural data: not established for PF.

5. Environmental Information

Exposures. Endemic vectors (black flies), rural and riverine living, and possibly viral or parasitic infections. Drug exposure is the best-established trigger: penicillamine, captopril and other thiol drugs, plus non-thiol drugs such as rifampin and some NSAIDs (Brenner et al. reviews).
Physical triggers. UV light exacerbates pemphigus, and radiation therapy has been reported as a trigger.
Lifestyle. Smoking appears associated with a lower risk of PV in some studies. This is not established for PF, and it is not a recommendation.
Infectious agents. No pathogen has been proven to be causal. Staphylococcus aureus exfoliative toxin A cleaves Dsg1 and causes staphylococcal scalded skin syndrome and bullous impetigo (Amagai et al., Nat Med 2000). This is a phenocopy, not the cause of PF, and it is a key mechanistic proof that Dsg1 loss alone yields superficial blistering.

6. Mechanism / Pathophysiology

Causal chain

Genetic susceptibility. A permissive HLA-DRB1 class II allele presents Dsg1 peptides to CD4+ T cells. (Association is demonstrated; the mechanism is inferred.)
Environmental trigger. Insect-borne, drug or other exposure precedes disease. (Exposure is epidemiologic; the antigenic link is not demonstrated.)
Breakdown of tolerance. Dsg1-reactive T cells and B cells escape tolerance and produce anti-Dsg1 IgG, often IgG1 or IgM at first. The preclinical phase appears in serum before disease. (Demonstrated in FS.)
Epitope spreading and class switch. The response moves from non-pathogenic epitopes in the C-terminal extracellular domains (EC3–EC5) to pathogenic epitopes in the N-terminal EC1–EC2 domains, and to IgG4. (Demonstrated by Li et al. and Warren et al.; Sekiguchi et al., Immunity 2001, mapped the pathogenic epitopes.)
Pathogenic IgG4 binds Dsg1 on keratinocytes in the upper epidermis. This leads to Dsg1 disruption by two routes: steric interference with trans-adhesion, and signalling and endocytic depletion of Dsg1 (the relative weight of the two is debated).
Loss of desmosomal adhesion. The signalling includes p38 MAPK, Src/EGFR, ERK and calcium, and Dsg1 internalization (Berkowitz et al.; Getsios and Green; Waschke).
Acantholysis in the granular or subcorneal layer produces superficial blisters that rupture into erosions and crusts.
Desmoglein compensation explains the topography. In the mucosa and deep epidermis, Dsg3 is abundant and compensates for Dsg1 loss. So in PF, with only anti-Dsg1, the mucosa and lower epidermis are spared. In PV with anti-Dsg3, mucosal and deep lesions occur (Mahoney et al., J Clin Invest 1999).
Chronic inflammation with neutrophils and eosinophils, pruritus and secondary infection follow. (Inferred and observational.)

Details by category

Molecular pathways: p38 MAPK, Src, EGFR, ERK, calcium and PKC signalling downstream of antibody binding. Apoptosis is a secondary event, not the primary lesion (a debated point).
Cellular processes: acantholysis, keratinocyte detachment, desmosome disassembly.
Protein dysfunction: Dsg1 loses its adhesive function. Pathogenic antibodies map to EC1–EC2 (adhesive interface); non-pathogenic ones bind elsewhere.
Immune system: T-cell-dependent B-cell autoimmunity (Th2 and Tfh bias), and IgG4 that is non-complement-fixing. Blistering does not need complement or inflammation, as shown by Fab-fragment passive transfer (Rock, Labib and Diaz, J Clin Invest 1990). Rituximab response argues for a central role of B cells.
Metabolic and biochemical: no specific abnormalities beyond steroid effects.
Omics and advanced technologies: I know of no robust PF-specific single-cell, spatial or CRISPR dataset. Bulk transcriptomic work exists mainly for PV, and FS serology is well studied. Treat this section as a gap in the report and search GEO before assuming none exists.

Suggested ontology terms (look up)

GO: cell–cell adhesion via plasma-membrane adhesion molecules (I believe GO:0098609); homophilic cell adhesion via plasma membrane adhesion molecules (I believe GO:0007156); adaptive immune response (I believe GO:0002250); desmosome organization (look up).
CL: keratinocyte (I believe CL:0000312), B cell (I believe CL:0000236), plasma cell, CD4+ alpha-beta T cell, T follicular helper cell (look up).
GO CC: desmosome (look up).

7. Anatomical Structures Affected

Primary: skin epidermis, upper layers (granular layer and stratum corneum junction). UBERON epidermis (I believe UBERON:0001003) and the more specific layers (look up).
Distribution: seborrheic areas (scalp, face, presternal and interscapular trunk), often bilateral and symmetric. It can generalize to erythroderma.
Secondary: mucous membranes are typically spared. Secondary involvement is the skin surface and barrier (infection, fluid loss), and drug toxicity in other organs.
Cells and subcellular: keratinocytes; the desmosome (Dsg1, plus desmocollin 1 in the same complex); plasma-membrane cadherin domains.

8. Temporal Development

Onset: adult in sporadic PF, childhood to young adult in endemic FS. Pemphigus onset in childhood is uncommon. Presentation is insidious to subacute.
Progression: chronic and relapsing–remitting, with flares. Patients may stay localized.
Duration: usually chronic. Remission off therapy is possible: treatment-induced (especially after rituximab) or, in some FS patients, spontaneous.
Critical windows: the preclinical period with anti-Dsg1 seropositivity precedes disease in FS. Early treatment reduces cumulative steroid exposure. Pregnancy carries neonatal transfer risk.

9. Inheritance and Population

Inheritance: not Mendelian. It is a complex autoimmune trait with HLA association. Do not record it as monogenic.
Prevalence and incidence
Sporadic pemphigus overall: about 0.1–1 per 100,000 per year, with wide geographic variation. PF is usually much rarer than PV in Europe and North America, and more common in parts of Tunisia, Brazil and Colombia.
Endemic FS has historically been reported in up to a few percent of residents in some isolated Brazilian foci, such as Amerindian settlements. Verify the exact figures.
Use measure_type and rate_denominator per the KB conventions, and treat the numbers as leads until sourced.
Sex ratio: about equal in FS. Sporadic PF may show a modest female predominance, and Tunisian PF is female-predominant.
Geography: Brazil (Central-West and Southeast, Goiás, Mato Grosso do Sul, Paraná), El Bagre in Colombia, Tunisia and parts of North Africa, and sporadic worldwide.

10. Diagnostics

Clinical exam: superficial erosions and crusts in a seborrheic pattern, Nikolsky sign, and absence of mucosal disease.
Histopathology: lesional biopsy from an intact fresh blister or edge shows subcorneal or granular-layer acantholysis. Inflammation is neutrophilic or eosinophilic. A Tzanck smear shows acantholytic cells.
Direct immunofluorescence (DIF): perilesional skin shows intercellular IgG, with or without C3, in a chicken-wire pattern. In PF it may be strongest in the upper epidermis. DIF is the gold standard for confirmation.
Indirect immunofluorescence (IIF): serum on monkey or guinea pig esophagus or on salt-split skin. Guinea pig esophagus is often more sensitive for anti-Dsg1.
ELISA or BIOCHIP: anti-Dsg1 IgG is positive and anti-Dsg3 negative in pure PF (commercial assays such as MBL and Euroimmun). Titers correlate with disease activity.
Differential diagnosis: PV, pemphigus erythematosus, IgA pemphigus, subcorneal pustular dermatosis, staphylococcal scalded skin syndrome, bullous impetigo, seborrheic dermatitis, discoid or subacute cutaneous lupus, bullous pemphigoid, Hailey–Hailey and Darier disease, and drug eruptions.
Genetic testing: not indicated.
Severity scoring: PDAI (Rosenbach et al. 2009), ABSIS, and the international consensus definitions of disease activity (Murrell et al., J Am Acad Dermatol 2008).
Guidelines: Murrell et al. (J Am Acad Dermatol 2020, international panel); Joly et al. (EADV, J Eur Acad Dermatol Venereol 2020); Hertl et al. (EDF/EADV, 2015); Venning et al. (BAD, Br J Dermatol 2012).
Screening: none. Anti-Dsg1 surveillance in endemic areas is a research tool.

11. Outcome / Prognosis

Mortality: untreated pemphigus (mostly PV) was often fatal before corticosteroids. PF is milder overall. Current mortality is modest and largely from treatment complications (infection, cardiovascular disease, steroid toxicity). I did not verify specific survival percentages, so pull them from cohort studies (French, Brazilian, Israeli and Tunisian) before citing.
Complications: secondary infection, dehydration and heat loss in erythroderma, steroid adverse effects (osteoporosis, diabetes, infection), and neonatal pemphigus in offspring of affected mothers.
Prognostic factors: extent of disease at onset, response to first-line treatment, persistence of anti-Dsg1 titers, and age and comorbidity.
Recovery: many patients reach remission on minimal or no therapy, especially with rituximab. Relapse is common when titers rise.
Comorbidities: other autoimmune disease (thyroid, RA, lupus, myasthenia gravis with thymoma), and diabetes and osteoporosis from steroids.

12. Treatment

Pharmacotherapy (NCIT:C15986 for the generic action; agents via therapeutic_agent) - Localized or mild PF: high-potency topical corticosteroids, sometimes with dapsone. - Systemic corticosteroids: prednisone or prednisolone, about 0.5–1 mg/kg/day, then tapered. CHEBI class: corticosteroid (CHEBI:50858, per the KB notes). - Steroid-sparing immunosuppressants: azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, and dapsone (useful in milder PF). - Rituximab (anti-CD20 monoclonal antibody; therapeutic_modality: MONOCLONAL_ANTIBODY). The Ritux 3 randomized trial (Joly et al., Lancet 2017) enrolled newly diagnosed PV and PF. Rituximab plus short-term prednisone produced complete remission off therapy in far more patients at 24 months than prednisone alone (I recall about 89% vs 34%; verify). Rituximab is now first-line in international guidelines. The US FDA approval (2018) is for moderate to severe PV, not PF, and PF use is off-label there. Verify. - Adjuncts: IVIG, plasmapheresis or immunoadsorption for refractory disease. - Supportive care: wound care, antiseptics, antibacterial treatment for secondary infection, and patient education. - Prophylaxis during immunosuppression: PJP prophylaxis, calcium and vitamin D with bone protection, gastric protection, and hepatitis B screening before rituximab.

Experimental and emerging (verify all status before curation) - Anti-FcRn (efgartigimod): a phase 3 trial (ADDRESS) in PV and PF was reported as missing its primary endpoint, as I recall. Check the status and publication. - BTK inhibitor (rilzabrutinib): the phase 3 PEGASUS trial in pemphigus did not meet its primary endpoint, as I recall (verify). - DSG3 CAAR-T cells: preclinical work is from Ellebrecht et al. (Science 2016), and early clinical work is in PV. There are no PF-specific data. - For NCT identifiers, search ClinicalTrials.gov directly with just fetch-reference NCT…. I am not providing NCT numbers from memory. - The PEMPHIX trial (rituximab vs mycophenolate, Werth et al., N Engl J Med 2021) was PV-only. Do not cite it for PF.

Pharmacogenomics. None established.

Treatment strategy. Mild localized: topical steroid ± dapsone. Moderate to severe: rituximab plus a short prednisone taper. Relapse: repeat rituximab or add an immunosuppressant.

Suggested NCIT terms (look up): Pharmacotherapy (NCIT:C15986); Corticosteroid Therapy and Immunosuppressive Therapy (look up); Rituximab (drug term, look up); Plasmapheresis and Intravenous Immunoglobulin (look up).

13. Prevention

Primary: no established prevention. In endemic areas, vector control and reducing insect exposure are proposed. Avoid known trigger drugs where alternatives exist.
Secondary: early recognition and early treatment of localized disease.
Tertiary: prevent relapse with the lowest effective steroid dose and rituximab maintenance. Manage the steroid complications listed above.
Immunization: inactivated vaccines are advised. Live vaccines are contraindicated during high-dose immunosuppression or rituximab. Ideally vaccinate before rituximab, since B-cell depletion blunts responses. Verify against current guidelines.
Counseling: pregnancy counseling for the risk of neonatal pemphigus, which is usually transient. Sun protection.

14. Other Species / Natural Disease

Dogs: PF is the most common autoimmune skin disease in dogs (NCBITaxon:9615 for Canis lupus familiaris, verify). Predisposed breeds include Akita, Chow Chow, Dachshund, Bearded Collie, Doberman Pinscher, Newfoundland and Finnish Spitz.
The major autoantigen is desmocollin-1 (Bizikova et al. and Olivry's group, Vet Dermatol, 2010s), not DSG1. Other targets have been proposed.
Lesions are pustules, crusts and footpad hyperkeratosis on the nose, ears and face.
Cats and horses: PF is also seen in cats (the most common feline autoimmune skin disease) and horses. Check OMIA for confirmation.
Cross-species comparison. Superficial acantholysis is conserved, but the antigen differs in dogs (desmocollin-1 vs human DSG1). Treatment is similar: glucocorticoids ± azathioprine or chlorambucil.
Zoonosis: none. Breed ontology (VBO) terms: look up.

15. Model Organisms

Passive-transfer mouse models (main model). Injecting IgG or Fab from FS or PF patients into neonatal BALB/c mice reproduces superficial blistering (Roscoe et al., 1985; Rock et al., J Clin Invest 1990). It shows that the antibody alone is sufficient, and that Fab fragments are enough, so complement is not required. Limits: the disease is transient and needs no adaptive immune response of the host.
Recombinant human monoclonals. Antibodies from PF patients, or mAbs against Dsg1 EC1/EC2, are pathogenic in neonatal mice and skin explants (Ishii and Amagai group; Sekiguchi et al. 2001).
Toxin model. Exfoliative toxin A injection in neonatal mice cleaves Dsg1 and gives PF-like superficial blistering (Amagai et al., Nat Med 2000).
Genetic models. Loss of Dsg1 in mouse (Dsg1 cluster deletion, from work around Green, Koch and colleagues) gives a barrier defect and blistering phenotype. These do not model the autoimmune phase. I would check the exact model citation before recording it.
Active-disease and immunization models. Adoptive transfer of splenocytes into Rag2-null mice works well in PV (Dsg3 model). A comparable robust chronic model for PF is not established. This is the main limitation.
In vitro and ex vivo. Human keratinocytes (HaCaT, primary NHEK) with dispase-based dissociation assays, human skin explants, and organotypic cultures. Signalling (p38, Src, EGFR) is studied in these systems.
Cellosaurus and MGI identifiers were not pulled. Search them before recording.

Curation Cautions

PF vs PV. Do not merge them. They are separate entries by antigen (Dsg1 vs Dsg3) and by topography. The desmoglein compensation theory is the reason.
Endemic FS vs sporadic PF. Curate FS as a subtype of PF, since it shares the antigen but differs in trigger and epidemiology.
Evidence sources. Rituximab and consensus statements are HUMAN_CLINICAL. Passive transfer in neonatal mice is MODEL_ORGANISM, and keratinocyte assays are IN_VITRO. Do not let the mouse work carry the human phenotypes alone.
Mechanism nodes. Pathogenic vs non-pathogenic anti-Dsg1 epitope shifts should be separate nodes. The exact split between steric and signalling mechanisms is unresolved and belongs in a knowledge-gap discussion. The Dsg1 depletion role of p38 was contested in some models.
Genes. Confirm hgnc:3048 for DSG1 and check it against the entry text before binding.
Gaps. Omics profiling, per-phenotype QoL, PF-specific survival numbers, and PF-specific trial results were not established here.

Reference Validation

No PMID or DOI references were found in this report.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	12
Resolved	12
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0019324 (2 mentions) - the report calls it "given in the template; confirm the label"; MONDO calls it pemphigus foliaceus

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Pemphigus Foliaceus (MONDO:0019324): Disease Characteristics Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic and Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain

Details by category

Suggested ontology terms (look up)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Curation Cautions

Reference Validation

Term Validation

Terms the report names something else