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

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

1. Genetic susceptibility. A permissive HLA-DRB1 class II allele presents Dsg1 peptides to CD4+ T cells. (Association is demonstrated; the mechanism is inferred.)
2. Environmental trigger. Insect-borne, drug or other exposure precedes disease. (Exposure is epidemiologic; the antigenic link is not demonstrated.)
3. 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.)
4. 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.)
5. 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).
6. Loss of desmosomal adhesion. The signalling includes p38 MAPK, Src/EGFR, ERK and calcium, and Dsg1 internalization (Berkowitz et al.; Getsios and Green; Waschke).
7. Acantholysis in the granular or subcorneal layer produces superficial blisters that rupture into erosions and crusts.
8. 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).
9. 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.

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