Acquired Epidermolysis Bullosa

Autoimmune MONDO:0018747 Pathograph 38 Show in embeddings browser Autoimmune Disease Skin Disease

Epidermolysis bullosa acquisita (EBA) is an acquired autoimmune subepidermal blistering disease with antibodies against type VII collagen (COL7), the principal anchoring-fibril protein. IgG predominates, but IgA-only and mixed IgG/IgA disease occur; NC1 is the major, not exclusive, antigenic domain. Mechanobullous and inflammatory presentations can coexist or change over time. Complement, neutrophil Fc-receptor signaling, reactive oxygen species and proteases contribute to inflammatory tissue injury, with causal dissection mainly from mouse and human ex vivo models. Direct antibody interference with anchoring-fibril adhesion is a proposed explanation for mechanobullous disease. Diagnosis integrates clinical findings with tissue immunofluorescence and COL7-specific testing; dermal-floor binding alone is not specific, and negative serum assays do not exclude EBA. Mucosal scarring may threaten swallowing, vision or the airway. EBA is distinct from inherited dystrophic epidermolysis bullosa.

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◆

Subtypes

Mechanobullous (classical, non-inflammatory)

Classical presentation with trauma-prone skin fragility, tense blisters, scarring and milia, often with nail abnormalities. Mucosal lesions can occur. Approximately one-third of 83 patients summarized across three older clinical studies had this presentation; this is not a population estimate. Direct anchoring-fibril interference remains a proposed mechanism.

Show evidence (2 references)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The classical form of EBA is characterized by skin fragility, the appearance of vesicles, tense blisters, erosions on non-inflamed skin, and healing with scars and milia formation"

Defines the classical clinical pattern.

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Inflammatory phenotypes: 66% Classical (mechanobullous) phenotype: 33%"

Table 1 summarizes 83 patients from three studies; the subtype proportions are series-specific.

Inflammatory EBA

Inflammatory presentations may resemble bullous pemphigoid, linear IgA disease, mucous membrane pemphigoid or Brunsting-Perry pemphigoid. Approximately two-thirds of patients in older reported series had inflammatory disease. Mucosa-predominant EBA is a minority presentation (5-10% in the cited review), distinct from the broader group with any mucosal involvement. Mixed presentations and transitions between subtypes occur.

Show evidence (2 references)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The inflammatory type of disease appears in two-thirds of reported patients. A mixed type with features of all subtypes has also been reported"

Describes the reported, non-population subtype distribution and overlap.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Although almost half of all patients with EBA have mucosal lesions, only 5–10% have predominant mucosal affection"

Separates predominant mucosal disease from any mucosal involvement.

◈

Mechanistic Hypotheses

Direct anti-COL7 interference with anchoring-fibril adhesion

direct_adhesion_interference ALTERNATIVE Mechanobullous

Evidence balance 1 support

Proposed explanation for mechanobullous fragility, not an experimentally established exclusive subtype mechanism.

Pathograph links

Autoantibody Binding to Type VII Collagen at the Dermal-Epidermal Junction -> Proposed Direct Impairment of Anchoring-Fibril Adhesion INDIRECT UNKNOWN INTERMEDIATES Interference with COL7-mediated adhesion is a proposed additional effect of binding.

Proposed Direct Impairment of Anchoring-Fibril Adhesion -> Skin fragility INDIRECT UNKNOWN INTERMEDIATES Proposed adhesion impairment could explain trauma susceptibility.

Show evidence (1 reference)

PMID:23956869 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"This may explain the pathogenesis of noninflammatory, mechanobullous EBA; however, this assumption needs to be experimentally confirmed."

Direct interference with anchoring-fibril interactions is an unconfirmed explanatory hypothesis.

⚙

Pathophysiology

HLA-Associated Susceptibility to COL7 Autoimmunity

Mechanism confidence: Provisional

HLA-DRB1*15:03 is associated with EBA susceptibility. Its contribution to antigen presentation and loss of tolerance remains an inferred mechanism rather than a demonstrated initiating event.

HLA-DRB1 hgnc:4948

MHC class II peptide antigen binding GO:0042605

Downstream

COL7-Reactive CD4 T-Cell Response An associated class II allele may influence COL7-reactive T-cell responses; the intervening events and initiating trigger are unresolved.

Show evidence (1 reference)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"HLA-DRB1*15:03 was found to be associated with EBA"

An HLA association supports susceptibility, without establishing the initiating tolerance defect.

COL7-Reactive CD4 T-Cell Response

Mechanism confidence: Provisional

COL7-reactive T cells are reported in patients. CD4 depletion delays autoantibody induction in immunized mice, supporting T-cell help in the induction phase; this model does not identify the spontaneous human trigger.

CD4-positive, alpha-beta T cell activation GO:0035710 ↑ INCREASED

Animal models

COL7 immunization-induced mouse EBA Mouse partially recapitulates CD4 depletion delays antibody induction and blistering.

Downstream

Anti-Type-VII-Collagen Autoantibody Production CD4 T-cell help contributes to antibody induction in immunization-induced EBA.

Show evidence (2 references)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism

"Depletion of CD4 T cells for two weeks starting one day prior to immunization significantly delayed both autoantibody production and the onset of clinical disease."

Timed depletion establishes a CD4 T-cell contribution in immunization-induced mouse EBA.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In EBA patients, immunodominant regions of COL7 are recognized by autoreactive T cells"

Human observations support COL7-specific T-cell autoreactivity.

Anti-Type-VII-Collagen Autoantibody Production

Mechanism confidence: Established

Autoreactive B cells and plasma cells generate anti-COL7 antibodies. IgG is most common, with IgA-only or combined responses also observed. NC1 is the predominant target, with rarer NC2 or collagenous-domain reactivity; epitope specificity alone does not define clinical subtype.

B cell CL:0000236 plasma cell CL:0000786

immunoglobulin production GO:0002377 ↑ INCREASED

Animal models

COL7 immunization-induced mouse EBA Mouse partially recapitulates The model generates anti-COL7 antibodies rather than supplying them by passive transfer.

Downstream

Autoantibody Binding to Type VII Collagen at the Dermal-Epidermal Junction Circulating anti-COL7 antibodies bind their antigen in the anchoring-fibril zone.

Show evidence (2 references)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In addition to IgG, IgA anti-COL7 autoantibodies are observed either as the only Ig class or in combination with IgG autoantibodies"

The clinical autoantibody repertoire includes IgA-only and mixed IgG/IgA disease.

PMID:25689103 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"No correlation was detected between antibody specificity and clinical phenotype."

The 69-serum epitope study did not establish an epitope-defined clinical subtype.

FcRn-Mediated Persistence of Anti-COL7 IgG

Mechanism confidence: Provisional

FcRn protects IgG from catabolism, sustaining circulating pathogenic IgG. FcRn disruption accelerates clearance in experimental antibody-mediated disease; this mechanism concerns IgG and does not explain IgA-only EBA.

Downstream

Autoantibody Binding to Type VII Collagen at the Dermal-Epidermal Junction Longer IgG persistence increases availability for tissue binding; deposition and injury also require other factors.

Show evidence (1 reference)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Other

"In line, blockade of the FcRn leads to an enhanced clearance of all IgG, including autoantibodies."

Supports the antibody-persistence mechanism.

Autoantibody Binding to Type VII Collagen at the Dermal-Epidermal Junction

Mechanism confidence: Established

Anti-COL7 antibodies deposit at the anchoring-fibril zone of the dermal-epidermal junction. In human cryosection experiments, IgG binding alone does not produce tissue separation; neutrophil-dependent effector activity is additionally required.

Direct anti-COL7 interference with anchoring-fibril adhesion

COL7A1 hgnc:2214

Anchoring-fibril collagen structural activity GO:0005201

epidermal-dermal junction UBERON:0008877

Downstream

Complement Activation at the Dermal-Epidermal Junction Tissue-bound IgG immune complexes initiate complement-dependent effector responses.

Immune-Complex-Induced Neutrophil Activation Tissue-bound immune complexes engage Fc receptors on recruited neutrophils.

Proposed Direct Impairment of Anchoring-Fibril Adhesion Interference with COL7-mediated adhesion is a proposed additional effect of binding.

Show evidence (1 reference)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS In Vitro

"This led to a linear IgG deposition along the dermal-epidermal junction. Sole antibody binding did not however induce a separation of the epidermis from the dermis."

Separates antigen binding from tissue injury in the human ex vivo system.

Complement Activation at the Dermal-Epidermal Junction

Mechanism confidence: Established

Complement activation contributes to IgG-mediated inflammatory injury. Factor B deficiency markedly attenuates antibody-transfer EBA; classical-pathway deficiency has a smaller early effect and lectin-pathway deficiency did not protect in that experiment.

complement activation GO:0006956 ↑ INCREASED

epidermal-dermal junction UBERON:0008877

Animal models

Anti-type-VII-collagen IgG passive-transfer mouse Mouse partially recapitulates Factor B deficiency attenuates anti-COL7-induced blistering.

Downstream

Neutrophil Recruitment to the Skin Alternative-pathway activity supports recruitment, as shown by granulocyte rescue in factor B-deficient mice.

Show evidence (1 reference)

PMID:17475881 SUPPORT DIRECT PRIMARY RESULT Model Organism

"factor B-deficient mice developed a delayed and significantly less severe blistering disease compared with factor B-sufficient mice."

Factor B deficiency attenuates the passive-transfer phenotype; this does not establish an exclusive pathway in all human EBA.

Neutrophil Recruitment to the Skin

Mechanism confidence: Established

Neutrophils accumulate at affected skin sites. CD18-dependent extravasation and complement-mediated recruitment are required in passive-transfer mouse experiments; cytokines also regulate this process.

neutrophil CL:0000775

neutrophil migration GO:1990266 ↑ INCREASED

epidermal-dermal junction UBERON:0008877

Downstream

Immune-Complex-Induced Neutrophil Activation Recruitment brings neutrophils into contact with tissue-bound immune complexes.

Pruritus Inflammatory skin injury is associated with itch; the sensory mediators are not resolved in the cited EBA sources.

Show evidence (2 references)

PMID:17380558 SUPPORT DIRECT PRIMARY RESULT Model Organism

"recruitment of granulocytes into the skin was required for tissue injury, as demonstrated by the resistance to experimental blistering of wild-type mice depleted of neutrophils and of CD18-deficient mice."

Neutrophil depletion and CD18 deficiency protect in passive-transfer EBA.

PMID:17475881 SUPPORT DIRECT PRIMARY RESULT Model Organism

"A significantly lower neutrophilic infiltration was observed in factor B-deficient mice compared with controls and local reconstitution with granulocytes restored the blistering disease in factor B-deficient mice."

Granulocyte rescue connects alternative-pathway activity to recruitment in this model.

Immune-Complex-Induced Neutrophil Activation

Mechanism confidence: Established

Tissue-bound immune complexes activate neutrophils through Fc receptors and intracellular kinase pathways. Activating Fc gamma RIV is required in the cited mouse model, whereas inhibitory Fc gamma RIIB is protective; those receptor-specific results should not be relabeled as human EBA findings.

neutrophil CL:0000775

neutrophil activation GO:0042119 ↑ INCREASED

Downstream

Neutrophil NADPH-Oxidase-Dependent Reactive Oxygen Species Production Immune-complex activation elicits the neutrophil oxidative burst.

Neutrophil Protease Release Neutrophil activation also elicits degranulation and protease release.

Show evidence (2 references)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Other

"After their extravasation into the skin, neutrophils bind to the Fc fragments of the tissue-bound anti-COL7 antibodies."

Places Fc-mediated activation after recruitment.

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism

"Mice lacking the common, signal-transducing γ-chain of all activating FcgR were completely protected from EBA induction by antibody transfer."

Shows dependence on activating Fc-receptor signaling in mice.

Neutrophil NADPH-Oxidase-Dependent Reactive Oxygen Species Production

Mechanism confidence: Established

Activated neutrophils generate tissue-damaging reactive oxygen species through NADPH oxidase. Ncf1-deficient mice and human ex vivo NADPH-oxidase-deficient granulocytes demonstrate dependence of experimental blistering on this effector.

neutrophil CL:0000775

respiratory burst GO:0045730 ↑ INCREASED

epidermal-dermal junction UBERON:0008877

Experimental models

Human skin cryosection and neutrophil separation assay OTHER Manipulating granulocyte NADPH oxidase changes tissue separation.

Animal models

Anti-type-VII-collagen IgG passive-transfer mouse Mouse partially recapitulates Ncf1-deficient animals resist blister induction.

Downstream

Subepidermal Blister Formation NADPH-oxidase-dependent injury contributes to dermal-epidermal separation; the complete substrate-level sequence is unresolved.

Show evidence (2 references)

PMID:17380558 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Neutrophil cytosolic factor 1-deficient mice lacking functional NADPH oxidase were resistant to skin blistering by the passive transfer of antibodies against type VII collagen."

Ncf1 loss demonstrates a requirement for the oxidative burst in this model.

PMID:17380558 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Pharmacological inhibition or deficiency of human NADPH oxidase abolished dermal-epidermal separation caused by autoantibodies and granulocytes ex vivo."

The human ex vivo experiment links NADPH oxidase to tissue separation, without measuring clinical treatment efficacy.

Neutrophil Protease Release

Mechanism confidence: Established

Protease release provides an effector arm distinct from the oxidative burst. Experimental work implicates gelatinase B and elastase in dermal-epidermal separation.

neutrophil CL:0000775

neutrophil degranulation GO:0043312 ↑ INCREASED

epidermal-dermal junction UBERON:0008877

Downstream

Subepidermal Blister Formation Proteolytic injury to junctional structures contributes to tissue separation.

Show evidence (1 reference)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS In Vitro

"In addition to ROS, gelatinase B and elastase have been identified as crucial mediators of dermal-epidermal separation in EBA"

The review identifies proteases as a separate effector arm of experimental tissue separation.

IFN-Gamma-Dependent Amplification of Cutaneous Inflammation

Mechanism confidence: Provisional

IFN-gamma contributes to inflammatory amplification in antibody-transfer mouse EBA. Prophylactic blockade reduced clinical lesions and neutrophil infiltration with lower epidermal and serum CXCL1; it did not establish a single linear cytokine pathway or human treatment benefit.

Animal models

IFN-gamma blockade in passive-transfer mouse EBA Mouse perturbs Neutralization reduces disease expression in the model.

Downstream

Neutrophil Recruitment to the Skin Reduced neutrophil infiltration after IFN-gamma blockade supports a recruitment-promoting effect; mediation by CXCL1 remains incompletely resolved.

Show evidence (2 references)

PMID:38799441 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The reduced clinical disease in mice treated with the highest dose of the IFN-γ antibody was accompanied with a reduced dermal leukocyte infiltration"

IFN-gamma blockade begun before antibody transfer reduced inflammation in mice.

PMID:38799441 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Serum concentrations of CXCL1 were significantly reduced in mice treated with IFN-γ antibody"

A mechanistic correlate of blockade, rather than proof that CXCL1 fully mediates the effect.

Proposed Direct Impairment of Anchoring-Fibril Adhesion

Mechanism confidence: Hypothetical

Anti-COL7 binding might interfere directly with anchoring-fibril interactions and weaken adhesion in mechanobullous EBA. This remains a hypothesis; it is not established by the clinical absence of overt inflammation.

Direct anti-COL7 interference with anchoring-fibril adhesion

epidermal-dermal junction UBERON:0008877

Downstream

Skin fragility Proposed adhesion impairment could explain trauma susceptibility.

Show evidence (1 reference)

PMID:23956869 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"This may explain the pathogenesis of noninflammatory, mechanobullous EBA; however, this assumption needs to be experimentally confirmed."

Direct interference with anchoring-fibril interactions is an unconfirmed explanatory hypothesis.

Subepidermal Blister Formation

Mechanism confidence: Established

Loss of dermal-epidermal cohesion produces subepidermal blisters. Repeated injury and healing can produce scars, milia, pigment changes, nail damage or mucosal stenosis; mucosal involvement is not restricted to one clinical subtype.

epidermal-dermal junction UBERON:0008877

Experimental models

Human skin cryosection and neutrophil separation assay OTHER The assay measures dermal-epidermal separation after antibody and neutrophil exposure.

Animal models

Human COL7 transgenic mouse antibody-transfer EBA Mouse partially recapitulates Antibodies against human COL7 induce tissue separation in the humanized animal.

Downstream

Subepidermal blistering

Milia Milia form during healing of subepidermal blisters.

Atrophic scarring Blisters in the mechanobullous form heal with atrophic scars.

Oral mucosal blistering Mucosal surfaces (oral and others) blister across EBA, including the mechanobullous form, where oral involvement is common.

Nail dystrophy Repeated blistering of trauma-prone sites damages the nails.

Postinflammatory dyspigmentation Healed blisters leave post-inflammatory hyper- and hypopigmentation.

Esophageal stricture Mucosal esophageal blistering heals with stricture.

Cicatrizing ocular involvement Conjunctival blistering heals with scarring that can impair vision.

Skin fragility Loss of cohesion increases vulnerability to subsequent mechanical injury.

Dysphagia Esophageal injury and scarring can impair swallowing.

Laryngeal stenosis Healing of laryngeal mucosal injury can narrow the airway.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Histopathology of a lesional skin or mucous membrane shows subepidermal or subepithelial cleavage"

Documents the tissue-level split in human disease.

⬡

Pathograph

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

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Phenotypes

Digestive 2

Esophageal stricture HP:0002043

Show evidence (1 reference)

PMID:23956869 SUPPORT REVIEW SYNTHESIS Human Clinical

"Esophageal strictures are another extracutaneous manifestation and severe complication in EBA patients."

Esophageal stricture is a severe extracutaneous complication of EBA.

Dysphagia HP:0002015

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Since this form of EBA may have severe consequences such as dysphagia, weight loss, malnutrition, and asphyxiation due to esophageal stenosis and larynx or trachea scaring"

Documents swallowing morbidity in mucosa-predominant disease.

Head and Neck 2

Oral mucosal blistering Oral mucosal blisters HP:0200097

Show evidence (1 reference)

PMID:23956869 SUPPORT REVIEW SYNTHESIS Human Clinical

"Extracutaneous EBA manifestations include ocular, oral mucosa, esophagus, anal, vaginal, tracheal, and laryngeal lesions"

Documents mucosal involvement, including oral mucosa, in EBA.

Context-specific annotations (1)

Four selected refractory EBA cases reported by Wozniak and colleagues in 2023 4/4

Oral lesions were described in all four case narratives; this selected treatment series is not a population frequency estimate.

Show evidence (5 references)

PMID:37503352 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All four patients had a long clinical history of tense blisters, atrophic scars and milia on traumatized skin areas, affected mucous membranes"

The cohort description establishes mucosal involvement; individual narratives specify oral erosions or ulcers in cases 1-4.

PMID:37503352 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She also occasionally presented erosions in the oral cavity."

Case 1 oral involvement.

PMID:37503352 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Occasionally, she developed erosions in the oral cavity."

Case 2 oral involvement.

+ 2 more references

Cicatrizing ocular involvement Conjunctival cicatrization HP:0500039

Show evidence (2 references)

PMID:23956869 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ocular involvement in EBA predominantly presents with scaring, resembling lesions observed in patients with MMP."

Ocular involvement in EBA is cicatrizing (conjunctival scarring), MMP-like.

PMID:23956869 SUPPORT REVIEW SYNTHESIS Human Clinical

"In severe cases, ocular involvement may lead to blindness."

Severe cicatrizing ocular involvement can progress to blindness.

Integument 7

Subepidermal blistering Abnormal blistering of the skin HP:0008066

Show evidence (2 references)

PMID:36769788 SUPPORT REVIEW SYNTHESIS Human Clinical

"The binding of autoantibodies to type-VII collagen subsequently leads to the detachment of the epidermis and the formation of mucocutaneous blisters"

Autoantibody binding to type VII collagen produces epidermal detachment and mucocutaneous blisters.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"EBA can occur at all ages"

The disease is not restricted to adult onset.

Skin fragility Fragile skin HP:0001030

Show evidence (1 reference)

PMID:23956869 SUPPORT REVIEW SYNTHESIS Human Clinical

"is characterized by skin fragility, tense blisters, scaring, and milia formation preferably localized to trauma-prone sites and the extensor skin surface"

Describes the mechanobullous phenotype of skin fragility, blisters, scarring and milia at trauma-prone sites.

Milia HP:0001056

Show evidence (2 references)

PMID:23956869 SUPPORT REVIEW SYNTHESIS Human Clinical

"is characterized by skin fragility, tense blisters, scaring, and milia formation preferably localized to trauma-prone sites and the extensor skin surface"

Milia formation is characteristic of the mechanobullous variant.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Erosions heal with atrophic scars and milia cysts"

The BP-like inflammatory presentation can also heal with these features.

Atrophic scarring Atrophic scars HP:0001075

Show evidence (2 references)

PMID:23956869 SUPPORT REVIEW SYNTHESIS Human Clinical

"is characterized by skin fragility, tense blisters, scaring, and milia formation preferably localized to trauma-prone sites and the extensor skin surface"

Healing with scarring is characteristic of the mechanobullous variant.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Erosions heal with atrophic scars and milia cysts"

The BP-like inflammatory presentation can also heal with these features.

Nail dystrophy HP:0008404

Show evidence (1 reference)

PMID:23956869 SUPPORT REVIEW SYNTHESIS Human Clinical

"In these patients, nail dystrophy and postinflammatory hyper- and hypopigmentation are also frequently observed."

Nail dystrophy is frequently observed in mechanobullous EBA.

Postinflammatory dyspigmentation Abnormality of skin pigmentation HP:0001000

Coarse binding: variable spectrum

Show evidence (1 reference)

PMID:23956869 SUPPORT REVIEW SYNTHESIS Human Clinical

"In these patients, nail dystrophy and postinflammatory hyper- and hypopigmentation are also frequently observed."

Post-inflammatory hyper- and hypopigmentation (both directions, hence the spectrum binding) is frequently observed in mechanobullous EBA.

Pruritus HP:0000989

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In this variant, pruritus is commonly present."

The paragraph describes BP-like inflammatory EBA.

Respiratory 1

Laryngeal stenosis HP:0001602

Show evidence (1 reference)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Symblepharon was also noted in all the patients, as well as pharyngeal and laryngeal strictures."

The detailed assessment of four selected patients describes laryngeal strictures; it is not an incidence estimate.

🧬

Genetic Associations

HLA-DRB1 (The HLA-DRB1*15:03 allele is associated with susceptibility to acquired EBA. Association does not establish penetrance, a Mendelian inheritance pattern or a sufficient cause of tolerance loss.)

Gene: HLA-DRB1 hgnc:4948 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"HLA-DRB1*15:03 was found to be associated with EBA"

An HLA association supports susceptibility, without establishing the initiating tolerance defect.

💊

Medical Actions

Systemic corticosteroids

Action: Systemic Corticosteroid Therapy NCIT:C122080

Agent: corticosteroid CHEBI:50858

Platform: Small molecule

Commonly used systemic treatment, often combined with a steroid-sparing agent. Responses are variable, particularly in mechanobullous disease; prolonged exposure carries substantial morbidity. The cited first-choice designation reflects expert practice rather than a comparative EBA trial.

Show evidence (1 reference)

PMID:36769788 SUPPORT REVIEW SYNTHESIS Human Clinical

"systemic corticosteroid therapy is accepted as a first choice in EBA treatment"

The 2023 review describes common first-choice practice; it is not randomized comparative evidence.

Colchicine

Action: Pharmacotherapy NCIT:C15986

Agent: colchicine CHEBI:23359

Platform: Small molecule

Used alone or as a corticosteroid-sparing adjunct on the basis of clinical reports and expert practice. Gastrointestinal adverse effects can limit use; response is not assured.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Colchicine is used as an adjuvant in first-line combination therapy to allow steroid tapering or as a monotherapy"

Describes reported clinical use without establishing comparative efficacy.

Dapsone

Action: Pharmacotherapy NCIT:C15986

Agent: dapsone CHEBI:4325

Platform: Small molecule

Common corticosteroid-sparing adjunct, with anti-neutrophil activity. Response and tolerability vary; reported toxicities include hemolysis, methemoglobinemia, agranulocytosis and neuropathy.

Show evidence (2 references)

PMID:36769788 SUPPORT REVIEW SYNTHESIS Human Clinical

"dapsone is usually used as an adjuvant therapy to systemic corticosteroids"

Dapsone is a corticosteroid-sparing adjuvant in EBA.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Adverse effects of dapsone therapy are hemolysis, methemoglobinemia, agranulocytosis, and peripheral neuropathy"

Documents clinically relevant limitations of dapsone therapy.

Cyclosporine

Action: Pharmacotherapy NCIT:C15986

Agent: cyclosporine CHEBI:4031

Platform: Small molecule

Calcineurin inhibitor used in refractory EBA, supported by small uncontrolled clinical reports. Long-term renal toxicity and hypertension constrain treatment; the evidence does not establish comparative effectiveness.

Show evidence (2 references)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In all patients, the use of cyclosporine was reported to have improved EBA."

The review summarizes only 11 reported patients, with selection and publication bias possible.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"When using CSA mainly as adjuvant therapy, renal dysfunction was noted if used long-term or in doses higher than 5 mg/kg/day"

Documents the renal toxicity limitation.

Rituximab

Action: Pharmacotherapy NCIT:C15986

Agent: rituximab NCIT:C1702

Platform: Monoclonal antibody

Anti-CD20 B-cell depletion is used for refractory EBA; mature antibody-secreting plasma cells are not directly depleted. A 2024 review of 31 reports included 68 patients: clinical response occurred in 63/68 and remission in 45/61 with that outcome reported. Relapse occurred in 15/38 with durability data, with mean follow-up of 23 months. Adverse events were reported in 11/39 with safety data, including two fatal pneumonias. These selected, heterogeneous, frequently combination-treated reports do not establish randomized comparative efficacy or routine safety.

Mechanism Target:

INHIBITS Anti-Type-VII-Collagen Autoantibody Production — CD20-positive B-cell depletion limits precursors of antibody-secreting cells; existing plasma cells are not directly depleted.

Show evidence (4 references)

PMID:39006807 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Clinical response and disease remission was recorded as 92.7 percent (63 patients) and 73.8 percent (45 patients) of the patients, respectively."

The full-text results and Table 1 supply separate denominators: 68 for response and 61 for remission.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC11238708/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Treatment durability was assessed in 17 studies (38 patients); disease relapse rate was measured as 39.5 percent (15 patients) in the mean follow-up of 23.0 months."

The durability denominator differs from the full 68-patient sample.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC11238708/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The severe side effects were pneumonia in two individuals (leading to death in both), and deep vein thrombosis in one."

Balances the reported responses with severe complications; Table 1 reports safety for 39 patients.

+ 1 more reference

Intravenous immunoglobulin

Action: Pharmacotherapy NCIT:C15986

Agent: human immunoglobulin G NCIT:C80829

Platform: Other

High-dose IVIG is used for severe refractory EBA, sometimes with rituximab or other therapies. Uncontrolled series report responses, but improvement need not mean complete or durable remission. In the 2023 four-case report, case 2 improved without complete remission, whereas case 3 had recurrent activity after IVIG and subsequently received rituximab.

Show evidence (2 references)

PMID:36769788 SUPPORT REVIEW SYNTHESIS Human Clinical

"IVIG has been shown effective in severe EBA cases after exhausting most available treatments of EBA"

IVIG is used for severe refractory EBA.

PMID:37503352 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Despite the lack of complete clinical remission, a significant improvement was observed during the follow-up period, lasting 46 months"

Case 2 demonstrates clinically meaningful improvement without complete remission.

Mycophenolate mofetil

Action: Pharmacotherapy NCIT:C15986

Agent: Mycophenolate Mofetil NCIT:C1468

Platform: Small molecule

Steroid-sparing immunosuppressant with variable responses in uncontrolled EBA reports. It did not provide adequate control in cases 2 and 3 of the 2023 biologics series; data from pemphigus trials should not be interpreted as EBA efficacy evidence.

Mechanism Target:

INHIBITS Anti-Type-VII-Collagen Autoantibody Production — Suppression of lymphocyte proliferation aims to reduce the autoimmune response; clinical nonresponse remains possible.

Show evidence (3 references)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"corticosteroid-sparing agents, which include colchicine, diaminodiphenyl sulfone (dapsone), methotrexate (MTX), azathioprine (AZA), cyclosporine (CSA), mycophenolate mofetil (MMF) and cyclophosphamide (CPA) have been used as a treatment option."

Lists reported adjuncts; inclusion is evidence of use, not demonstrated comparative benefit.

PMID:37503352 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Further treatment involved a six-month course of mycophenolate mofetil (3 g/d), which was also unsuccessful."

Case 3 illustrates nonresponse to MMF.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"MMF, as T- and B-cell proliferation suppressor, is shown to be successful in treating EBA"

Provides the proposed pharmacologic action; the cited literature also contains nonresponders.

Methotrexate

Action: Pharmacotherapy NCIT:C15986

Agent: Methotrexate NCIT:C642

Platform: Small molecule

Reported steroid-sparing adjunct in refractory EBA; disease-specific efficacy evidence remains limited and recommendations partly draw on experience in other bullous diseases.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Lists reported adjuncts; inclusion is evidence of use, not demonstrated comparative benefit.

Azathioprine

Action: Pharmacotherapy NCIT:C15986

Agent: Azathioprine NCIT:C290

Platform: Small molecule

Reported steroid-sparing adjunct. Use in EBA does not establish efficacy independently of concomitant treatments.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Lists reported adjuncts; inclusion is evidence of use, not demonstrated comparative benefit.

Cyclophosphamide

Action: Pharmacotherapy NCIT:C15986

Agent: Cyclophosphamide NCIT:C405

Platform: Small molecule

Occasionally used as rescue immunosuppression when other agents fail; evidence is sparse and does not establish a reliable response rate.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Lists reported adjuncts; inclusion is evidence of use, not demonstrated comparative benefit.

Infliximab in EBA associated with Crohn disease

Action: Pharmacotherapy NCIT:C15986

Agent: Infliximab NCIT:C1789

Platform: Monoclonal antibody

Anti-TNF treatment has case-level support in EBA with concomitant Crohn disease. In case 4 of the 2023 series, both diseases improved and mesalazine plus azathioprine were maintained. This does not establish efficacy for isolated EBA or disentangle concurrent treatments.

Show evidence (2 references)

PMID:37503352 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"During the biological therapy, a remission of both diseases was achieved."

Case 4 received infliximab for severe concomitant EBA and Crohn disease.

PMID:37503352 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Treatment with mesalazine and azathioprine is maintained."

Continuing co-treatment limits attribution to infliximab alone.

Ustekinumab in EBA associated with Crohn disease

Action: Pharmacotherapy NCIT:C15986

Agent: Ustekinumab NCIT:C84237

Platform: Monoclonal antibody

A case summarized in the 2023 literature review reported EBA remission with IL-12/23 blockade in a patient with Crohn disease. The EBA response did not track the bowel response; a proposed immune mechanism remains unproven and evidence is anecdotal.

Show evidence (1 reference)

PMID:37503352 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"However, biological therapy with ustekinumab finally led to the total remission of EBA."

The discussion summarizes a separate single-patient report, not one of the four original cases or a comparative trial.

Immunoadsorption

Action: Immunoadsorption Ontology label: Therapeutic Apheresis NCIT:C173286

Platform: Other

Selective antibody removal has been reported, commonly in combination with rituximab, for severe refractory EBA. Small uncontrolled reports and co-treatment prevent attribution of durable benefit to immunoadsorption alone.

Mechanism Target:

INHIBITS Autoantibody Binding to Type VII Collagen at the Dermal-Epidermal Junction — Removal of circulating antibodies reduces the pool available for tissue binding; this is not selective COL7-antigen-specific adsorption.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In several reports, combination therapy with IA and RTX in EBA shows promising potential treatment protocols for those patients"

Documents reported combination use with limited clinical evidence.

Extracorporeal photopheresis

Action: Extracorporeal Photopheresis NCIT:C62729

Platform: Other

Reported rescue treatment for persistent EBA; small reports include complete or partial remission and nonresponse. Comparative effectiveness is unknown.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In contrast, one patient had no therapeutic response"

The ECP section describes mixed responses in a small published experience.

Multidisciplinary mucosal assessment and supportive care

Action: Supportive Care NCIT:C15747

Platform: Other

Assessment of ocular, oral, swallowing and airway involvement supports early management of cicatrizing complications. Esophageal strictures may require repeated endoscopic dilation when disease activity persists.

Show evidence (2 references)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients may not be able to swallow foods and thus require endoscopic esophageal dilations, which may have to be repeated several times, if disease activity cannot be controlled"

Supports management of esophageal complications.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Besides that, more aggressive treatment is needed in cases with conjunctival and laryngeal mucosa affected"

Identifies high-risk mucosal sites requiring specialist assessment.

Experimental IFN-gamma blockade

Platform: Monoclonal antibody

A rat anti-murine IFN-gamma antibody given before and during anti-COL7 transfer reduced disease severity in mice. This prophylactic experiment is not a human EBA trial and did not test emapalumab in patients.

Mechanism Target:

INHIBITS IFN-Gamma-Dependent Amplification of Cutaneous Inflammation — Neutralization reduced inflammatory amplification in the mouse protocol.

Show evidence (1 reference)

PMID:38799441 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Murine IFN-γ was blocked by i.p. injection of a monoclonal rat anti- IFN-γ of either 125 µg, 250 µg, or 500 µg every other day starting 1 day prior to EBA induction."

Establishes prophylactic timing and the species-specific experimental reagent.

Experimental FcRn blockade

Action: Pharmacotherapy NCIT:C15986

Platform: Monoclonal antibody

FcRn blockade promotes IgG clearance and has shown benefit in murine EBA. The cited evidence is preclinical, not proof of human EBA efficacy.

Mechanism Target:

INHIBITS FcRn-Mediated Persistence of Anti-COL7 IgG — Experimental inhibition addresses this process; translation to human EBA is unresolved.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism

"Anti-FcRn treatment in experimental murine EBA have demonstrated promising results in a 4-week treatment period."

The source explicitly identifies a murine experiment.

Experimental GM-CSF blockade

Action: Pharmacotherapy NCIT:C15986

Platform: Monoclonal antibody

GM-CSF inhibition has preventive and therapeutic effects in experimental EBA, associated with neutrophil recruitment and activation. Human EBA efficacy is not established by these experiments.

Mechanism Target:

INHIBITS Neutrophil Recruitment to the Skin — Experimental inhibition addresses this process; translation to human EBA is unresolved.

Show evidence (1 reference)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism

"Therapeutic blockade of GM-CSF in mice with already established immunization-induced EBA showed beneficial therapeutic effects"

Supports a treatment effect in immunized mice, not in patients.

Experimental IL-1 receptor blockade with anakinra

Action: Pharmacotherapy NCIT:C15986

Agent: Anakinra NCIT:C38717

Platform: Other

Recombinant IL-1 receptor antagonist anakinra has preclinical anti-inflammatory evidence in EBA models. The cited studies do not establish human EBA treatment efficacy.

Mechanism Target:

INHIBITS Neutrophil Recruitment to the Skin — Experimental inhibition addresses this process; translation to human EBA is unresolved.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism

"by application of an IL-1 receptor blocker, anakinra proinflammatory events in experimental EBA were counteracted"

The evidence concerns experimental EBA.

🔬

Diagnosis

Integrated clinical and immunopathological diagnosis

Clinical morphology alone is insufficient. Histology, perilesional DIF and COL7-specific or antigen-localization tests are combined according to availability. The 2018 international consensus established nine criteria but no single worldwide procedure; its stated limitation was not addressing bullous systemic lupus erythematosus.

Show evidence (1 reference)

PMID:29165796 SUPPORT DIRECT REVIEW SYNTHESIS Other

"This included nine diagnostic criteria, which are summarized in a flow chart. The IBDG was unable to determine one procedure that would be applicable worldwide. A limitation of the study is that differential diagnosis of bullous systemic lupus erythematosus has not been addressed."

Defines both the consensus scope and its limitations.

Direct immunofluorescence and serration analysis

Linear IgG and/or C3, sometimes IgA, at the epithelial basement membrane supports an autoimmune subepithelial blistering disorder but is not EBA-specific. A u-serrated pattern supports COL7-level autoimmunity and can occur in EBA or bullous systemic lupus. Serration may not be interpretable, particularly in mucosal samples.

Show evidence (2 references)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"is pathognomonic for skin-bound autoantibodies against type-VII collagen found in EBA and bullous systemic lupus erythematosus (BSLE)"

The u-serrated pattern identifies COL7-level autoimmunity rather than EBA alone.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Additionally, in mucosal biopsies and the number of skin samples, the serration pattern cannot be identified."

A noninterpretable serration pattern does not exclude EBA.

Salt-split skin indirect immunofluorescence

Dermal-floor binding is compatible with EBA, in contrast to typical epidermal-roof binding in bullous pemphigoid. It is not specific: anti-p200/laminin gamma-1 and anti-laminin-332 pemphigoid also bind the floor, requiring antigen-specific discrimination.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Since this dermal labeling is not specific, patients with anti-p200/laminin ƴ1 pemphigoid and anti-laminin 332 pemphigoid also reveal autoantibodies attached to the blister floor"

Explicitly limits the specificity of floor binding.

Anti-type-VII-collagen serology

COL7 ELISA or immunoblot supports diagnosis in context. In one 14-patient NC1+NC2 ELISA study, 12/14 EBA samples were positive (86% sensitivity); two bullous-pemphigoid controls were positive among 143 controls (98.6% specificity). Titres correlated with activity in this small sample, but larger validation was requested. Negative serum testing does not exclude EBA, and IgG-only assays can miss IgA-only disease.

Show evidence (5 references)

PMID:22913489 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"12 out of the 14 samples were positive in ELISA"

Provides the case denominator and observed positivity, not universal sensitivity.

PMID:22913489 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Among the controls, only two bullous pemphigoid sera tested positive, the specificity being 98·6%."

Shows imperfect specificity.

PMID:22913489 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The correlation between autoantibody titres and disease severity suggests its usefulness as a marker of disease activity in EBA However, this should be confirmed by studies on larger series of patients."

The activity association is preliminary.

+ 2 more references

Specialist antigen-localization tests

In serum-negative or ambiguous cases, specialist tests can localize tissue-bound antibodies to the anchoring-fibril region: immunoelectron microscopy, fluorescence overlay antigen mapping below type IV collagen, or testing on COL7-deficient substrates. Availability is limited, and results require clinical interpretation.

Show evidence (2 references)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Direct transmission electron microscopy (IEM) in EBA patients shows in vivo bound thick immune deposits in the anchoring fibrils (AF) zone below lamina densa (LD)."

Establishes the ultrastructural localization.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"in vivo-bound immune deposits below type-IV collagen by FOAM"

Describes localization in the seronegative diagnostic framework.

📊

Prevalence

Historical general-population incidence estimates summarized in 2013

Annual Incidence 0.02 per 100,000 per year

The normalized value represents one published annual-incidence estimate (0.2 new cases per million); it is not point prevalence. Other estimates summarized in this review range up to 0.5 per million per year.

Show evidence (1 reference)

PMID:23956869 SUPPORT REVIEW SYNTHESIS Human Clinical

"an incidence of 0.2 new cases per million and per year"

Gives the annual incidence used for the normalized rate.

⚖️

Clinical Burden

Moderate

Chronic recurrent blistering can require prolonged treatment and leave permanent scars or nail damage. Burden is variable: refractory skin disease and cicatrizing mucosal disease may be severe, with dysphagia, nutritional impairment, visual loss or airway compromise. The overall category does not describe every patient.

Show evidence (3 references)

PMID:36769788 SUPPORT REVIEW SYNTHESIS Human Clinical

"classical mechanobullous form have been reported to be refractory to systemic corticosteroids, azathioprine, methotrexate, and cyclophosphamide"

Documents the treatment-refractory, chronic course of EBA.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Since this form of EBA may have severe consequences such as dysphagia, weight loss, malnutrition, and asphyxiation due to esophageal stenosis and larynx or trachea scaring"

Documents severe complications of the mucosa-predominant presentation.

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"mucous membranes are involved in 50-65% of patients"

Aggregate mucosal involvement estimate from the review; it is not an oral-specific frequency.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Acquired Epidermolysis Bullosa:

Bullous systemic lupus erythematosus

Overlapping Features COL7 autoimmunity, u-serration and dermal-floor binding overlap with EBA.

Distinguishing Features

Evaluate the systemic lupus clinical and serological context; COL7 positivity alone does not distinguish the disorders.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"type-VII collagen found in EBA and bullous systemic lupus erythematosus (BSLE)"

Documents the shared target-level diagnostic pattern.

Bullous pemphigoid

Overlapping Features Inflammatory EBA may resemble bullous pemphigoid.

Distinguishing Features

Typical BP antibodies bind the epidermal roof of salt-split skin; EBA antibodies bind the floor. Antigen-specific testing is needed in ambiguous cases.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"immune deposits in patients with EBA remains on the dermal floor, while immune deposits in patients with BP remain within the epidermal roof"

Describes the usual split-skin distinction.

Anti-p200 and anti-laminin-332 pemphigoid

Overlapping Features These diseases can share dermal-floor binding with EBA.

Distinguishing Features

Use antigen-specific studies to distinguish p200/laminin gamma-1 or laminin-332 reactivity from COL7 autoimmunity.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"patients with anti-p200/laminin ƴ1 pemphigoid and anti-laminin 332 pemphigoid also reveal autoantibodies attached to the blister floor"

Floor binding cannot establish EBA alone.

Inherited dystrophic epidermolysis bullosa

Overlapping Features The mechanobullous phenotype can resemble inherited dystrophic EB.

Distinguishing Features

EBA is acquired COL7 autoimmunity; inherited dystrophic EB is a genetically determined disorder. Age alone is insufficient because EBA can occur in children.

Show evidence (1 reference)

PMID:32119399 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Classic mechanobullous EBA resembles dystrophic epidermolysis bullosa (EB), with bullae and erosions developing at sites of trauma."

Describes the clinical overlap.

Porphyria cutanea tarda and pseudoporphyria

Overlapping Features Trauma-prone blistering and fragility may mimic mechanobullous EBA.

Distinguishing Features

The immunopathological evidence for COL7 autoimmunity must be interpreted alongside the clinical differential.

Show evidence (1 reference)

PMID:36769788 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"So, in differential diagnosis, porphyria cutanea tarda, and pseudoporphyria must be excluded."

The classical EBA section identifies these mimics.

🧫

Experimental Models

Human skin cryosection and neutrophil separation assay OTHER

Human skin cryosections incubated with patient anti-COL7 IgG and healthy-donor neutrophils model the effector phase. Antibody binding alone did not produce separation. NADPH-oxidase inhibition or deficient granulocytes prevent separation in this assay.

Cell source

Human skin cryosections, EBA-patient antibodies and donor granulocytes

Pathograph links

Neutrophil NADPH-Oxidase-Dependent Reactive Oxygen Species Production partially recapitulates fidelity: moderate observes: cellular Manipulating granulocyte NADPH oxidase changes tissue separation.

Limitations: Ex vivo tissue assay lacks circulation, tolerance induction and chronic healing.

Show evidence (1 reference)

PMID:17380558 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Pharmacological inhibition or deficiency of human NADPH oxidase abolished dermal-epidermal separation caused by autoantibodies and granulocytes ex vivo."

Human ex vivo dependence on NADPH oxidase.

Subepidermal Blister Formation partially recapitulates fidelity: moderate observes: tissue The assay measures dermal-epidermal separation after antibody and neutrophil exposure.

Limitations: Experimental separation is not a measured clinical treatment response.

Show evidence (1 reference)

PMID:17380558 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Pharmacological inhibition or deficiency of human NADPH oxidase abolished dermal-epidermal separation caused by autoantibodies and granulocytes ex vivo."

Human ex vivo dependence on NADPH oxidase.

Show evidence (1 reference)

PMID:17380558 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Pharmacological inhibition or deficiency of human NADPH oxidase abolished dermal-epidermal separation caused by autoantibodies and granulocytes ex vivo."

Human ex vivo dependence on NADPH oxidase.

🐁

Animal Models

Anti-type-VII-collagen IgG passive-transfer mouse

Passive transfer of anti-type VII collagen IgG into mice reproduces subepidermal blistering; gene-knockout strains dissect the complement and neutrophil effector steps.

Species

Mouse

Genotype

Wild-type and complement/NADPH-oxidase-deficient strains injected with anti-COL7 IgG

Publication

PMID:17475881

Pathograph links

Complement Activation at the Dermal-Epidermal Junction partially recapitulates fidelity: moderate observes: tissue Factor B deficiency attenuates anti-COL7-induced blistering.

Limitations: Acute antibody-transfer model bypasses tolerance loss and endogenous antibody induction.

Show evidence (1 reference)

PMID:17475881 SUPPORT DIRECT PRIMARY RESULT Model Organism

"factor B-deficient mice developed a delayed and significantly less severe blistering disease compared with factor B-sufficient mice"

Shows alternative-pathway dependence in this passive-transfer experiment.

Neutrophil NADPH-Oxidase-Dependent Reactive Oxygen Species Production partially recapitulates fidelity: moderate observes: cellular Ncf1-deficient animals resist blister induction.

Limitations: Induced mouse disease does not establish clinical response to oxidase blockade in people.

Show evidence (1 reference)

PMID:17380558 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Neutrophil cytosolic factor 1-deficient mice lacking functional NADPH oxidase were resistant to skin blistering by the passive transfer of antibodies against type VII collagen."

Demonstrates oxidative-burst dependence in mice.

COL7 immunization-induced mouse EBA

Active immunization generates an endogenous antibody response and permits study of induction as well as effector phases. Susceptibility depends on strain, antigen and protocol; immunization is not the spontaneous human initiating event.

Species

Mouse

Genotype

Susceptible inbred strains immunized with recombinant murine COL7 fragments

Pathograph links

COL7-Reactive CD4 T-Cell Response partially recapitulates fidelity: moderate observes: cellular CD4 depletion delays antibody induction and blistering.

Limitations: Artificial antigen/adjuvant immunization and strain-dependent susceptibility.

Show evidence (1 reference)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism

"Depletion of CD4 T cells for two weeks starting one day prior to immunization significantly delayed both autoantibody production and the onset of clinical disease."

Timed depletion establishes an induction-phase contribution.

Anti-Type-VII-Collagen Autoantibody Production partially recapitulates fidelity: moderate observes: cellular The model generates anti-COL7 antibodies rather than supplying them by passive transfer.

Limitations: Does not identify the cause of spontaneous tolerance loss in people.

Show evidence (1 reference)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism

"Depletion of CD4 T cells for two weeks starting one day prior to immunization significantly delayed both autoantibody production and the onset of clinical disease."

Timed depletion establishes an induction-phase contribution.

IFN-gamma blockade in passive-transfer mouse EBA

Randomized, blinded assessments tested rat anti-murine IFN-gamma starting one day before antibody transfer. The highest dose reduced late disease burden and neutrophil infiltration; skin-bound IgG was unchanged and C3 deposition increased. The study does not test treatment initiated after established EBA or human clinical efficacy.

Species

Mouse

Genotype

C57BL/6J mice receiving rabbit anti-murine COL7 IgG

Publication

PMID:38799441

Pathograph links

IFN-Gamma-Dependent Amplification of Cutaneous Inflammation perturbs fidelity: moderate observes: tissue Neutralization reduces disease expression in the model.

Limitations: Prophylactic antibody-transfer protocol; not emapalumab treatment of human EBA.

Show evidence (1 reference)

PMID:38799441 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The impact of IFN-γ inhibition on disease manifestation is significant but, compared to other drugs used in this model, relatively moderate."

The authors characterize the effect as moderate.

Human COL7 transgenic mouse antibody-transfer EBA

Rabbit antibodies against two human NC1 subdomains induced subepidermal blisters. This establishes pathogenic potential across more than one epitope region; it does not map each human clinical subtype to an epitope.

Species

Mouse

Genotype

Murine Col7 null with a human COL7 transgene

Publication

PMID:25689103

Pathograph links

Subepidermal Blister Formation partially recapitulates fidelity: moderate observes: tissue Antibodies against human COL7 induce tissue separation in the humanized animal.

Limitations: Human target protein in a mouse effector environment, with rabbit antibodies rather than spontaneous human autoimmunity.

Show evidence (1 reference)

PMID:25689103 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Antibodies against two of these subdomains were injected into mice carrying null mutations of mouse COL7 and the human COL7 transgene and induced subepidermal blisters."

Rabbit antibodies recognizing human COL7 NC1 subdomains were pathogenic in humanized mice.

{ }

Source YAML

click to show

name: Acquired Epidermolysis Bullosa
creation_date: "2026-10-01T01:15:00Z"
category: Autoimmune
description: >-
  Epidermolysis bullosa acquisita (EBA) is an acquired autoimmune subepidermal blistering disease with antibodies against type VII collagen (COL7), the principal anchoring-fibril protein. IgG predominates, but IgA-only and mixed IgG/IgA disease occur; NC1 is the major, not exclusive, antigenic domain. Mechanobullous and inflammatory presentations can coexist or change over time. Complement, neutrophil Fc-receptor signaling, reactive oxygen species and proteases contribute to inflammatory tissue injury, with causal dissection mainly from mouse and human ex vivo models. Direct antibody interference with anchoring-fibril adhesion is a proposed explanation for mechanobullous disease. Diagnosis integrates clinical findings with tissue immunofluorescence and COL7-specific testing; dermal-floor binding alone is not specific, and negative serum assays do not exclude EBA. Mucosal scarring may threaten swallowing, vision or the airway. EBA is distinct from inherited dystrophic epidermolysis bullosa.
disease_term:
  preferred_term: epidermolysis bullosa acquisita
  term:
    id: MONDO:0018747
    label: acquired epidermolysis bullosa
synonyms:
- epidermolysis bullosa acquisita
- EBA
- EB acquisita
parents:
- Autoimmune Disease
- Skin Disease
notes: >-
  COL7A1 encodes the autoantigen rather than an established Mendelian cause of EBA. HLA-DRB1*15:03 is an associated susceptibility allele. Clinical subtype does not establish a unique pathogenic pathway or antibody epitope. Historical reports link EBA with inflammatory bowel disease, especially Crohn disease, but many predate modern EBA diagnostic criteria; the often-quoted roughly 30% figure is not a reliable contemporary population prevalence. A later record-based analysis discussed in PMID:37503352 did not identify IBD as a risk factor or sequela. Anti-COL7 serum reactivity in IBD or systemic lupus also does not by itself establish EBA.
has_subtypes:
- name: Mechanobullous
  display_name: Mechanobullous (classical, non-inflammatory)
  description: >-
    Classical presentation with trauma-prone skin fragility, tense blisters, scarring and milia, often with nail abnormalities. Mucosal lesions can occur. Approximately one-third of 83 patients summarized across three older clinical studies had this presentation; this is not a population estimate. Direct anchoring-fibril interference remains a proposed mechanism.
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The classical form of EBA is characterized by skin fragility, the appearance of vesicles, tense blisters, erosions on non-inflamed skin, and healing with scars and milia formation
    explanation: Defines the classical clinical pattern.
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'Inflammatory phenotypes: 66% Classical (mechanobullous) phenotype: 33%'
    explanation: Table 1 summarizes 83 patients from three studies; the subtype proportions are series-specific.
- name: Inflammatory
  display_name: Inflammatory EBA
  description: >-
    Inflammatory presentations may resemble bullous pemphigoid, linear IgA disease, mucous membrane pemphigoid or Brunsting-Perry pemphigoid. Approximately two-thirds of patients in older reported series had inflammatory disease. Mucosa-predominant EBA is a minority presentation (5-10% in the cited review), distinct from the broader group with any mucosal involvement. Mixed presentations and transitions between subtypes occur.
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The inflammatory type of disease appears in two-thirds of reported patients. A mixed type with features of all subtypes has also been reported
    explanation: Describes the reported, non-population subtype distribution and overlap.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Although almost half of all patients with EBA have mucosal lesions, only 5–10% have predominant mucosal affection
    explanation: Separates predominant mucosal disease from any mucosal involvement.
prevalence:
- population: Historical general-population incidence estimates summarized in 2013
  measure_type: ANNUAL_INCIDENCE
  rate_per_100000: 0.02
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    The normalized value represents one published annual-incidence estimate (0.2 new cases per million); it is not point prevalence. Other estimates summarized in this review range up to 0.5 per million per year.
  evidence:
  - reference: PMID:23956869
    reference_title: "Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      an incidence of 0.2 new cases per million and per year
    explanation: Gives the annual incidence used for the normalized rate.
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    Chronic recurrent blistering can require prolonged treatment and leave permanent scars or nail damage. Burden is variable: refractory skin disease and cicatrizing mucosal disease may be severe, with dysphagia, nutritional impairment, visual loss or airway compromise. The overall category does not describe every patient.
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      classical mechanobullous form have been reported to be refractory to
      systemic corticosteroids, azathioprine, methotrexate, and cyclophosphamide
    explanation: Documents the treatment-refractory, chronic course of EBA.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Since this form of EBA may have severe consequences such as dysphagia, weight loss, malnutrition, and asphyxiation due to esophageal stenosis and larynx or trachea scaring
    explanation: Documents severe complications of the mucosa-predominant presentation.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: mucous membranes are involved in 50-65% of patients
    explanation: Aggregate mucosal involvement estimate from the review; it is not an oral-specific frequency.
pathophysiology:
- name: HLA-Associated Susceptibility to COL7 Autoimmunity
  description: HLA-DRB1*15:03 is associated with EBA susceptibility. Its contribution to antigen presentation and loss of tolerance remains an inferred mechanism rather than a demonstrated initiating event.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: HLA-DRB1*15:03 was found to be associated with EBA
    explanation: An HLA association supports susceptibility, without establishing the initiating tolerance defect.
  genes:
  - preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  downstream:
  - target: COL7-Reactive CD4 T-Cell Response
    description: An associated class II allele may influence COL7-reactive T-cell responses; the intervening events and initiating trigger are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23956869
      reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: HLA-DRB1*15:03 was found to be associated with EBA
      explanation: An HLA association supports susceptibility, without establishing the initiating tolerance defect.
  molecular_functions:
  - preferred_term: MHC class II peptide antigen binding
    term:
      id: GO:0042605
      label: peptide antigen binding
- name: COL7-Reactive CD4 T-Cell Response
  description: COL7-reactive T cells are reported in patients. CD4 depletion delays autoantibody induction in immunized mice, supporting T-cell help in the induction phase; this model does not identify the spontaneous human trigger.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Depletion of CD4 T cells for two weeks starting one day prior to immunization significantly delayed both autoantibody production and the onset of clinical disease.
    explanation: Timed depletion establishes a CD4 T-cell contribution in immunization-induced mouse EBA.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In EBA patients, immunodominant regions of COL7 are recognized by autoreactive T cells
    explanation: Human observations support COL7-specific T-cell autoreactivity.
  biological_processes:
  - preferred_term: CD4-positive, alpha-beta T cell activation
    term:
      id: GO:0035710
      label: CD4-positive, alpha-beta T cell activation
    modifier: INCREASED
  downstream:
  - target: Anti-Type-VII-Collagen Autoantibody Production
    description: CD4 T-cell help contributes to antibody induction in immunization-induced EBA.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23956869
      reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Depletion of CD4 T cells for two weeks starting one day prior to immunization significantly delayed both autoantibody production and the onset of clinical disease.
      explanation: Timed depletion establishes a CD4 T-cell contribution in immunization-induced mouse EBA.
- name: Anti-Type-VII-Collagen Autoantibody Production
  description: Autoreactive B cells and plasma cells generate anti-COL7 antibodies. IgG is most common, with IgA-only or combined responses also observed. NC1 is the predominant target, with rarer NC2 or collagenous-domain reactivity; epitope specificity alone does not define clinical subtype.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In addition to IgG, IgA anti-COL7 autoantibodies are observed either as the only Ig class or in combination with IgG autoantibodies
    explanation: The clinical autoantibody repertoire includes IgA-only and mixed IgG/IgA disease.
  - reference: PMID:25689103
    reference_title: Autoantibodies to Multiple Epitopes on the Non-Collagenous-1 Domain of Type VII Collagen Induce Blisters.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: No correlation was detected between antibody specificity and clinical phenotype.
    explanation: The 69-serum epitope study did not establish an epitope-defined clinical subtype.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: INCREASED
  downstream:
  - target: Autoantibody Binding to Type VII Collagen at the Dermal-Epidermal Junction
    description: Circulating anti-COL7 antibodies bind their antigen in the anchoring-fibril zone.
    causal_link_type: DIRECT
- name: FcRn-Mediated Persistence of Anti-COL7 IgG
  description: FcRn protects IgG from catabolism, sustaining circulating pathogenic IgG. FcRn disruption accelerates clearance in experimental antibody-mediated disease; this mechanism concerns IgG and does not explain IgA-only EBA.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In line, blockade of the FcRn leads to an enhanced clearance of all IgG, including autoantibodies.
    explanation: Supports the antibody-persistence mechanism.
  downstream:
  - target: Autoantibody Binding to Type VII Collagen at the Dermal-Epidermal Junction
    description: Longer IgG persistence increases availability for tissue binding; deposition and injury also require other factors.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Autoantibody Binding to Type VII Collagen at the Dermal-Epidermal Junction
  description: Anti-COL7 antibodies deposit at the anchoring-fibril zone of the dermal-epidermal junction. In human cryosection experiments, IgG binding alone does not produce tissue separation; neutrophil-dependent effector activity is additionally required.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: This led to a linear IgG deposition along the dermal-epidermal junction. Sole antibody binding did not however induce a separation of the epidermis from the dermis.
    explanation: Separates antigen binding from tissue injury in the human ex vivo system.
  genes:
  - preferred_term: COL7A1
    term:
      id: hgnc:2214
      label: COL7A1
  locations:
  - preferred_term: epidermal-dermal junction
    term:
      id: UBERON:0008877
      label: epidermal-dermal junction
  downstream:
  - target: Complement Activation at the Dermal-Epidermal Junction
    description: Tissue-bound IgG immune complexes initiate complement-dependent effector responses.
    causal_link_type: DIRECT
  - target: Immune-Complex-Induced Neutrophil Activation
    description: Tissue-bound immune complexes engage Fc receptors on recruited neutrophils.
    causal_link_type: DIRECT
  - target: Proposed Direct Impairment of Anchoring-Fibril Adhesion
    description: Interference with COL7-mediated adhesion is a proposed additional effect of binding.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - direct_adhesion_interference
    evidence:
    - reference: PMID:23956869
      reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: This may explain the pathogenesis of noninflammatory, mechanobullous EBA; however, this assumption needs to be experimentally confirmed.
      explanation: Direct interference with anchoring-fibril interactions is an unconfirmed explanatory hypothesis.
  molecular_functions:
  - preferred_term: Anchoring-fibril collagen structural activity
    term:
      id: GO:0005201
      label: extracellular matrix structural constituent
- name: Complement Activation at the Dermal-Epidermal Junction
  description: Complement activation contributes to IgG-mediated inflammatory injury. Factor B deficiency markedly attenuates antibody-transfer EBA; classical-pathway deficiency has a smaller early effect and lectin-pathway deficiency did not protect in that experiment.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:17475881
    reference_title: The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: factor B-deficient mice developed a delayed and significantly less severe blistering disease compared with factor B-sufficient mice.
    explanation: Factor B deficiency attenuates the passive-transfer phenotype; this does not establish an exclusive pathway in all human EBA.
  biological_processes:
  - preferred_term: complement activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: INCREASED
  locations:
  - preferred_term: epidermal-dermal junction
    term:
      id: UBERON:0008877
      label: epidermal-dermal junction
  downstream:
  - target: Neutrophil Recruitment to the Skin
    description: Alternative-pathway activity supports recruitment, as shown by granulocyte rescue in factor B-deficient mice.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17475881
      reference_title: The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: A significantly lower neutrophilic infiltration was observed in factor B-deficient mice compared with controls and local reconstitution with granulocytes restored the blistering disease in factor B-deficient mice.
      explanation: Granulocyte rescue connects alternative-pathway activity to recruitment in this model.
- name: Neutrophil Recruitment to the Skin
  description: Neutrophils accumulate at affected skin sites. CD18-dependent extravasation and complement-mediated recruitment are required in passive-transfer mouse experiments; cytokines also regulate this process.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:17380558
    reference_title: NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: recruitment of granulocytes into the skin was required for tissue injury, as demonstrated by the resistance to experimental blistering of wild-type mice depleted of neutrophils and of CD18-deficient mice.
    explanation: Neutrophil depletion and CD18 deficiency protect in passive-transfer EBA.
  - reference: PMID:17475881
    reference_title: The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A significantly lower neutrophilic infiltration was observed in factor B-deficient mice compared with controls and local reconstitution with granulocytes restored the blistering disease in factor B-deficient mice.
    explanation: Granulocyte rescue connects alternative-pathway activity to recruitment in this model.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil migration
    term:
      id: GO:1990266
      label: neutrophil migration
    modifier: INCREASED
  locations:
  - preferred_term: epidermal-dermal junction
    term:
      id: UBERON:0008877
      label: epidermal-dermal junction
  downstream:
  - target: Immune-Complex-Induced Neutrophil Activation
    description: Recruitment brings neutrophils into contact with tissue-bound immune complexes.
    causal_link_type: DIRECT
  - target: Pruritus
    description: Inflammatory skin injury is associated with itch; the sensory mediators are not resolved in the cited EBA sources.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Immune-Complex-Induced Neutrophil Activation
  description: Tissue-bound immune complexes activate neutrophils through Fc receptors and intracellular kinase pathways. Activating Fc gamma RIV is required in the cited mouse model, whereas inhibitory Fc gamma RIIB is protective; those receptor-specific results should not be relabeled as human EBA findings.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: After their extravasation into the skin, neutrophils bind to the Fc fragments of the tissue-bound anti-COL7 antibodies.
    explanation: Places Fc-mediated activation after recruitment.
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Mice lacking the common, signal-transducing γ-chain of all activating FcgR were completely protected from EBA induction by antibody transfer.
    explanation: Shows dependence on activating Fc-receptor signaling in mice.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil activation
    term:
      id: GO:0042119
      label: neutrophil activation
    modifier: INCREASED
  downstream:
  - target: Neutrophil NADPH-Oxidase-Dependent Reactive Oxygen Species Production
    description: Immune-complex activation elicits the neutrophil oxidative burst.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Neutrophil Protease Release
    description: Neutrophil activation also elicits degranulation and protease release.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Neutrophil NADPH-Oxidase-Dependent Reactive Oxygen Species Production
  description: Activated neutrophils generate tissue-damaging reactive oxygen species through NADPH oxidase. Ncf1-deficient mice and human ex vivo NADPH-oxidase-deficient granulocytes demonstrate dependence of experimental blistering on this effector.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:17380558
    reference_title: NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Neutrophil cytosolic factor 1-deficient mice lacking functional NADPH oxidase were resistant to skin blistering by the passive transfer of antibodies against type VII collagen.
    explanation: Ncf1 loss demonstrates a requirement for the oxidative burst in this model.
  - reference: PMID:17380558
    reference_title: NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Pharmacological inhibition or deficiency of human NADPH oxidase abolished dermal-epidermal separation caused by autoantibodies and granulocytes ex vivo.
    explanation: The human ex vivo experiment links NADPH oxidase to tissue separation, without measuring clinical treatment efficacy.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  locations:
  - preferred_term: epidermal-dermal junction
    term:
      id: UBERON:0008877
      label: epidermal-dermal junction
  biological_processes:
  - preferred_term: respiratory burst
    term:
      id: GO:0045730
      label: respiratory burst
    modifier: INCREASED
  downstream:
  - target: Subepidermal Blister Formation
    description: NADPH-oxidase-dependent injury contributes to dermal-epidermal separation; the complete substrate-level sequence is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17380558
      reference_title: NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Pharmacological inhibition or deficiency of human NADPH oxidase abolished dermal-epidermal separation caused by autoantibodies and granulocytes ex vivo.
      explanation: The human ex vivo experiment links NADPH oxidase to tissue separation, without measuring clinical treatment efficacy.
- name: Neutrophil Protease Release
  description: Protease release provides an effector arm distinct from the oxidative burst. Experimental work implicates gelatinase B and elastase in dermal-epidermal separation.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In addition to ROS, gelatinase B and elastase have been identified as crucial mediators of dermal-epidermal separation in EBA
    explanation: The review identifies proteases as a separate effector arm of experimental tissue separation.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil degranulation
    term:
      id: GO:0043312
      label: neutrophil degranulation
    modifier: INCREASED
  locations:
  - preferred_term: epidermal-dermal junction
    term:
      id: UBERON:0008877
      label: epidermal-dermal junction
  downstream:
  - target: Subepidermal Blister Formation
    description: Proteolytic injury to junctional structures contributes to tissue separation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23956869
      reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: In addition to ROS, gelatinase B and elastase have been identified as crucial mediators of dermal-epidermal separation in EBA
      explanation: The review identifies proteases as a separate effector arm of experimental tissue separation.
- name: IFN-Gamma-Dependent Amplification of Cutaneous Inflammation
  description: IFN-gamma contributes to inflammatory amplification in antibody-transfer mouse EBA. Prophylactic blockade reduced clinical lesions and neutrophil infiltration with lower epidermal and serum CXCL1; it did not establish a single linear cytokine pathway or human treatment benefit.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:38799441
    reference_title: Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The reduced clinical disease in mice treated with the highest dose of the IFN-γ antibody was accompanied with a reduced dermal leukocyte infiltration
    explanation: IFN-gamma blockade begun before antibody transfer reduced inflammation in mice.
  - reference: PMID:38799441
    reference_title: Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Serum concentrations of CXCL1 were significantly reduced in mice treated with IFN-γ antibody
    explanation: A mechanistic correlate of blockade, rather than proof that CXCL1 fully mediates the effect.
  downstream:
  - target: Neutrophil Recruitment to the Skin
    description: Reduced neutrophil infiltration after IFN-gamma blockade supports a recruitment-promoting effect; mediation by CXCL1 remains incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38799441
      reference_title: Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The reduced clinical disease in mice treated with the highest dose of the IFN-γ antibody was accompanied with a reduced dermal leukocyte infiltration
      explanation: IFN-gamma blockade begun before antibody transfer reduced inflammation in mice.
- name: Proposed Direct Impairment of Anchoring-Fibril Adhesion
  description: Anti-COL7 binding might interfere directly with anchoring-fibril interactions and weaken adhesion in mechanobullous EBA. This remains a hypothesis; it is not established by the clinical absence of overt inflammation.
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: This may explain the pathogenesis of noninflammatory, mechanobullous EBA; however, this assumption needs to be experimentally confirmed.
    explanation: Direct interference with anchoring-fibril interactions is an unconfirmed explanatory hypothesis.
  locations:
  - preferred_term: epidermal-dermal junction
    term:
      id: UBERON:0008877
      label: epidermal-dermal junction
  downstream:
  - target: Skin fragility
    description: Proposed adhesion impairment could explain trauma susceptibility.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - direct_adhesion_interference
    evidence:
    - reference: PMID:23956869
      reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: This may explain the pathogenesis of noninflammatory, mechanobullous EBA; however, this assumption needs to be experimentally confirmed.
      explanation: Direct interference with anchoring-fibril interactions is an unconfirmed explanatory hypothesis.
- name: Subepidermal Blister Formation
  description: Loss of dermal-epidermal cohesion produces subepidermal blisters. Repeated injury and healing can produce scars, milia, pigment changes, nail damage or mucosal stenosis; mucosal involvement is not restricted to one clinical subtype.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Histopathology of a lesional skin or mucous membrane shows subepidermal or subepithelial cleavage
    explanation: Documents the tissue-level split in human disease.
  locations:
  - preferred_term: epidermal-dermal junction
    term:
      id: UBERON:0008877
      label: epidermal-dermal junction
  downstream:
  - target: Subepidermal blistering
    causal_link_type: DIRECT
  - target: Milia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Milia form during healing of subepidermal blisters.
    intermediate_mechanisms:
    - Repeated tissue injury and healing
  - target: Atrophic scarring
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Blisters in the mechanobullous form heal with atrophic scars.
    intermediate_mechanisms:
    - Repeated tissue injury and healing
  - target: Oral mucosal blistering
    causal_link_type: DIRECT
    description: >-
      Mucosal surfaces (oral and others) blister across EBA, including the
      mechanobullous form, where oral involvement is common.
  - target: Nail dystrophy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Repeated blistering of trauma-prone sites damages the nails.
    intermediate_mechanisms:
    - Repeated tissue injury and healing
  - target: Postinflammatory dyspigmentation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Healed blisters leave post-inflammatory hyper- and hypopigmentation.
    intermediate_mechanisms:
    - Repeated tissue injury and healing
  - target: Esophageal stricture
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Mucosal esophageal blistering heals with stricture.
    intermediate_mechanisms:
    - Repeated tissue injury and healing
  - target: Cicatrizing ocular involvement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Conjunctival blistering heals with scarring that can impair vision.
    intermediate_mechanisms:
    - Repeated tissue injury and healing
  - target: Skin fragility
    description: Loss of cohesion increases vulnerability to subsequent mechanical injury.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Dysphagia
    description: Esophageal injury and scarring can impair swallowing.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Esophageal scarring and stenosis
  - target: Laryngeal stenosis
    description: Healing of laryngeal mucosal injury can narrow the airway.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Laryngeal scarring
phenotypes:
- category: Cutaneous
  name: Subepidermal blistering
  description: >-
    Tense subepidermal blisters; trauma-induced in the mechanobullous form and widespread/inflammatory in the inflammatory variants. Onset is often in adulthood, but children can also be affected.
  phenotype_term:
    preferred_term: subepidermal blistering
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The binding of autoantibodies to type-VII collagen subsequently leads to
      the detachment of the epidermis and the formation of mucocutaneous blisters
    explanation: >-
      Autoantibody binding to type VII collagen produces epidermal detachment and
      mucocutaneous blisters.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: EBA can occur at all ages
    explanation: The disease is not restricted to adult onset.
- category: Cutaneous
  name: Skin fragility
  subtype: Mechanobullous
  description: >-
    Trauma-prone skin fragility is characteristic of mechanobullous EBA; direct anchoring-fibril interference is one proposed explanation.
  phenotype_term:
    preferred_term: skin fragility
    term:
      id: HP:0001030
      label: Fragile skin
  evidence:
  - reference: PMID:23956869
    reference_title: "Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      is characterized by skin fragility, tense blisters, scaring, and milia
      formation preferably localized to trauma-prone sites and the extensor skin
      surface
    explanation: >-
      Describes the mechanobullous phenotype of skin fragility, blisters,
      scarring and milia at trauma-prone sites.
- category: Cutaneous
  name: Milia
  description: >-
    Small keratin cysts that form during healing of subepidermal blisters, characteristic of the mechanobullous variant. Scars and milia can also accompany inflammatory BP-like EBA.
  phenotype_term:
    preferred_term: milia
    term:
      id: HP:0001056
      label: Milia
  evidence:
  - reference: PMID:23956869
    reference_title: "Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      is characterized by skin fragility, tense blisters, scaring, and milia
      formation preferably localized to trauma-prone sites and the extensor skin
      surface
    explanation: >-
      Milia formation is characteristic of the mechanobullous variant.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Erosions heal with atrophic scars and milia cysts
    explanation: The BP-like inflammatory presentation can also heal with these features.
- category: Cutaneous
  name: Atrophic scarring
  description: >-
    Blisters in the mechanobullous form heal with scarring. Scars and milia can also accompany inflammatory BP-like EBA.
  phenotype_term:
    preferred_term: atrophic scars
    term:
      id: HP:0001075
      label: Atrophic scars
  evidence:
  - reference: PMID:23956869
    reference_title: "Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      is characterized by skin fragility, tense blisters, scaring, and milia
      formation preferably localized to trauma-prone sites and the extensor skin
      surface
    explanation: >-
      Healing with scarring is characteristic of the mechanobullous variant.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Erosions heal with atrophic scars and milia cysts
    explanation: The BP-like inflammatory presentation can also heal with these features.
- category: Mucosal
  name: Oral mucosal blistering
  description: >-
    Oral blisters and erosions occur across EBA presentations. The review estimate of 50-65% concerns involvement of any mucosal site and cannot be assigned specifically to oral disease.
  phenotype_term:
    preferred_term: oral mucosal blisters
    term:
      id: HP:0200097
      label: Oral mucosal blisters
  evidence:
  - reference: PMID:23956869
    reference_title: "Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Extracutaneous EBA manifestations include ocular, oral mucosa, esophagus,
      anal, vaginal, tracheal, and laryngeal lesions
    explanation: >-
      Documents mucosal involvement, including oral mucosa, in EBA.
  phenotype_contexts:
  - population: Four selected refractory EBA cases reported by Wozniak and colleagues in 2023
    frequency: 4/4
    notes: Oral lesions were described in all four case narratives; this selected treatment series is not a population frequency estimate.
    evidence:
    - reference: PMID:37503352
      reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: All four patients had a long clinical history of tense blisters, atrophic scars and milia on traumatized skin areas, affected mucous membranes
      explanation: The cohort description establishes mucosal involvement; individual narratives specify oral erosions or ulcers in cases 1-4.
    - reference: PMID:37503352
      reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: She also occasionally presented erosions in the oral cavity.
      explanation: Case 1 oral involvement.
    - reference: PMID:37503352
      reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Occasionally, she developed erosions in the oral cavity.
      explanation: Case 2 oral involvement.
    - reference: PMID:37503352
      reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In periods of skin exacerbations, the patient also developed oral erosions.
      explanation: Case 3 oral involvement.
    - reference: PMID:37503352
      reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Ulcers were also present in the oral cavity and esophagus.
      explanation: Case 4 oral involvement.
- category: Cutaneous
  name: Nail dystrophy
  subtype: Mechanobullous
  description: >-
    Nail dystrophy is frequently observed in the mechanobullous variant,
    following repeated blistering of trauma-prone sites.
  phenotype_term:
    preferred_term: nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:23956869
    reference_title: "Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In these patients, nail dystrophy and postinflammatory hyper- and
      hypopigmentation are also frequently observed.
    explanation: Nail dystrophy is frequently observed in mechanobullous EBA.
- category: Cutaneous
  name: Postinflammatory dyspigmentation
  subtype: Mechanobullous
  description: >-
    Healed blisters in the mechanobullous variant leave post-inflammatory
    hyper- and hypopigmentation.
  phenotype_term:
    preferred_term: postinflammatory hyper- and hypopigmentation
    term:
      id: HP:0001000
      label: Abnormality of skin pigmentation
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:23956869
    reference_title: "Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In these patients, nail dystrophy and postinflammatory hyper- and
      hypopigmentation are also frequently observed.
    explanation: >-
      Post-inflammatory hyper- and hypopigmentation (both directions, hence the
      spectrum binding) is frequently observed in mechanobullous EBA.
- category: Mucosal
  name: Esophageal stricture
  description: >-
    Esophageal mucosal involvement heals with strictures that can cause
    dysphagia and require repeated dilation; a severe extracutaneous complication.
  phenotype_term:
    preferred_term: esophageal stricture
    term:
      id: HP:0002043
      label: Esophageal stricture
  evidence:
  - reference: PMID:23956869
    reference_title: "Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Esophageal strictures are another extracutaneous manifestation and severe
      complication in EBA patients.
    explanation: Esophageal stricture is a severe extracutaneous complication of EBA.
- category: Ocular
  name: Cicatrizing ocular involvement
  subtype: Inflammatory
  description: >-
    Ocular involvement presents with cicatrizing (conjunctival scarring) lesions
    resembling mucous membrane pemphigoid; in severe cases it can lead to
    blindness.
  phenotype_term:
    preferred_term: conjunctival cicatrization
    term:
      id: HP:0500039
      label: Conjunctival cicatrization
  evidence:
  - reference: PMID:23956869
    reference_title: "Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Ocular involvement in EBA predominantly presents with scaring, resembling
      lesions observed in patients with MMP.
    explanation: >-
      Ocular involvement in EBA is cicatrizing (conjunctival scarring), MMP-like.
  - reference: PMID:23956869
    reference_title: "Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In severe cases, ocular involvement may lead to blindness.
    explanation: Severe cicatrizing ocular involvement can progress to blindness.
- name: Pruritus
  category: Cutaneous
  description: Itch accompanies the inflammatory, particularly BP-like, presentation.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In this variant, pruritus is commonly present.
    explanation: The paragraph describes BP-like inflammatory EBA.
- name: Dysphagia
  category: Mucosal
  description: Swallowing difficulty can complicate severe mucosal EBA and esophageal scarring.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Since this form of EBA may have severe consequences such as dysphagia, weight loss, malnutrition, and asphyxiation due to esophageal stenosis and larynx or trachea scaring
    explanation: Documents swallowing morbidity in mucosa-predominant disease.
- name: Laryngeal stenosis
  category: Mucosal
  description: Laryngeal mucosal scarring can narrow the airway and cause respiratory compromise.
  phenotype_term:
    preferred_term: Laryngeal stenosis
    term:
      id: HP:0001602
      label: Laryngeal stenosis
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Symblepharon was also noted in all the patients, as well as pharyngeal and laryngeal strictures.
    explanation: The detailed assessment of four selected patients describes laryngeal strictures; it is not an incidence estimate.
genetic:
- name: HLA-DRB1
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  relationship_type: SUSCEPTIBILITY
  association: >-
    The HLA-DRB1*15:03 allele is associated with susceptibility to acquired EBA. Association does not establish penetrance, a Mendelian inheritance pattern or a sufficient cause of tolerance loss.
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: HLA-DRB1*15:03 was found to be associated with EBA
    explanation: An HLA association supports susceptibility, without establishing the initiating tolerance defect.
treatments:
- name: Systemic corticosteroids
  description: >-
    Commonly used systemic treatment, often combined with a steroid-sparing agent. Responses are variable, particularly in mechanobullous disease; prolonged exposure carries substantial morbidity. The cited first-choice designation reflects expert practice rather than a comparative EBA trial.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Systemic Corticosteroid Therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      systemic corticosteroid therapy is accepted as a first choice in EBA
      treatment
    explanation: The 2023 review describes common first-choice practice; it is not randomized comparative evidence.
- name: Colchicine
  description: >-
    Used alone or as a corticosteroid-sparing adjunct on the basis of clinical reports and expert practice. Gastrointestinal adverse effects can limit use; response is not assured.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: colchicine
      term:
        id: CHEBI:23359
        label: colchicine
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Colchicine is used as an adjuvant in first-line combination therapy to allow steroid tapering or as a monotherapy
    explanation: Describes reported clinical use without establishing comparative efficacy.
- name: Dapsone
  description: >-
    Common corticosteroid-sparing adjunct, with anti-neutrophil activity. Response and tolerability vary; reported toxicities include hemolysis, methemoglobinemia, agranulocytosis and neuropathy.
  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
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      dapsone is usually used as an adjuvant therapy to systemic corticosteroids
    explanation: Dapsone is a corticosteroid-sparing adjuvant in EBA.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Adverse effects of dapsone therapy are hemolysis, methemoglobinemia, agranulocytosis, and peripheral neuropathy
    explanation: Documents clinically relevant limitations of dapsone therapy.
- name: Cyclosporine
  description: >-
    Calcineurin inhibitor used in refractory EBA, supported by small uncontrolled clinical reports. Long-term renal toxicity and hypertension constrain treatment; the evidence does not establish comparative effectiveness.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cyclosporine
      term:
        id: CHEBI:4031
        label: cyclosporin A
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In all patients, the use of cyclosporine was reported to have improved EBA.
    explanation: The review summarizes only 11 reported patients, with selection and publication bias possible.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: When using CSA mainly as adjuvant therapy, renal dysfunction was noted if used long-term or in doses higher than 5 mg/kg/day
    explanation: Documents the renal toxicity limitation.
- name: Rituximab
  description: >-
    Anti-CD20 B-cell depletion is used for refractory EBA; mature antibody-secreting plasma cells are not directly depleted. A 2024 review of 31 reports included 68 patients: clinical response occurred in 63/68 and remission in 45/61 with that outcome reported. Relapse occurred in 15/38 with durability data, with mean follow-up of 23 months. Adverse events were reported in 11/39 with safety data, including two fatal pneumonias. These selected, heterogeneous, frequently combination-treated reports do not establish randomized comparative efficacy or routine safety.
  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
  evidence:
  - reference: PMID:39006807
    reference_title: 'Rituximab in the Treatment of Epidermolysis Bullosa Acquisita: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Clinical response and disease remission was recorded as 92.7 percent (63 patients) and 73.8 percent (45 patients) of the patients, respectively.
    explanation: 'The full-text results and Table 1 supply separate denominators: 68 for response and 61 for remission.'
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC11238708/
    reference_title: 'Rituximab in the Treatment of Epidermolysis Bullosa Acquisita: A Systematic Review - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Treatment durability was assessed in 17 studies (38 patients); disease relapse rate was measured as 39.5 percent (15 patients) in the mean follow-up of 23.0 months.
    explanation: The durability denominator differs from the full 68-patient sample.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC11238708/
    reference_title: 'Rituximab in the Treatment of Epidermolysis Bullosa Acquisita: A Systematic Review - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The severe side effects were pneumonia in two individuals (leading to death in both), and deep vein thrombosis in one.
    explanation: Balances the reported responses with severe complications; Table 1 reports safety for 39 patients.
  - reference: PMID:37503352
    reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The patient has been in clinical remission for 2 years taking methylprednisone at a maintenance dose of 4 mg/d
    explanation: Case 3 improved after rituximab following transient IVIG benefit, with continuing maintenance treatment.
  target_mechanisms:
  - target: Anti-Type-VII-Collagen Autoantibody Production
    treatment_effect: INHIBITS
    description: CD20-positive B-cell depletion limits precursors of antibody-secreting cells; existing plasma cells are not directly depleted.
- name: Intravenous immunoglobulin
  description: >-
    High-dose IVIG is used for severe refractory EBA, sometimes with rituximab or other therapies. Uncontrolled series report responses, but improvement need not mean complete or durable remission. In the 2023 four-case report, case 2 improved without complete remission, whereas case 3 had recurrent activity after IVIG and subsequently received rituximab.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: human immunoglobulin G
      term:
        id: NCIT:C80829
        label: Human Immunoglobulin G
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      IVIG has been shown effective in severe EBA cases after exhausting most
      available treatments of EBA
    explanation: IVIG is used for severe refractory EBA.
  - reference: PMID:37503352
    reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Despite the lack of complete clinical remission, a significant improvement was observed during the follow-up period, lasting 46 months
    explanation: Case 2 demonstrates clinically meaningful improvement without complete remission.
- name: Mycophenolate mofetil
  description: Steroid-sparing immunosuppressant with variable responses in uncontrolled EBA reports. It did not provide adequate control in cases 2 and 3 of the 2023 biologics series; data from pemphigus trials should not be interpreted as EBA efficacy evidence.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Mycophenolate Mofetil
      term:
        id: NCIT:C1468
        label: Mycophenolate Mofetil
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: corticosteroid-sparing agents, which include colchicine, diaminodiphenyl sulfone (dapsone), methotrexate (MTX), azathioprine (AZA), cyclosporine (CSA), mycophenolate mofetil (MMF) and cyclophosphamide (CPA) have been used as a treatment option.
    explanation: Lists reported adjuncts; inclusion is evidence of use, not demonstrated comparative benefit.
  - reference: PMID:37503352
    reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Further treatment involved a six-month course of mycophenolate mofetil (3 g/d), which was also unsuccessful.
    explanation: Case 3 illustrates nonresponse to MMF.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: MMF, as T- and B-cell proliferation suppressor, is shown to be successful in treating EBA
    explanation: Provides the proposed pharmacologic action; the cited literature also contains nonresponders.
  target_mechanisms:
  - target: Anti-Type-VII-Collagen Autoantibody Production
    treatment_effect: INHIBITS
    description: Suppression of lymphocyte proliferation aims to reduce the autoimmune response; clinical nonresponse remains possible.
- name: Methotrexate
  description: Reported steroid-sparing adjunct in refractory EBA; disease-specific efficacy evidence remains limited and recommendations partly draw on experience in other bullous diseases.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Methotrexate
      term:
        id: NCIT:C642
        label: Methotrexate
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: corticosteroid-sparing agents, which include colchicine, diaminodiphenyl sulfone (dapsone), methotrexate (MTX), azathioprine (AZA), cyclosporine (CSA), mycophenolate mofetil (MMF) and cyclophosphamide (CPA) have been used as a treatment option.
    explanation: Lists reported adjuncts; inclusion is evidence of use, not demonstrated comparative benefit.
- name: Azathioprine
  description: Reported steroid-sparing adjunct. Use in EBA does not establish efficacy independently of concomitant treatments.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Azathioprine
      term:
        id: NCIT:C290
        label: Azathioprine
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: corticosteroid-sparing agents, which include colchicine, diaminodiphenyl sulfone (dapsone), methotrexate (MTX), azathioprine (AZA), cyclosporine (CSA), mycophenolate mofetil (MMF) and cyclophosphamide (CPA) have been used as a treatment option.
    explanation: Lists reported adjuncts; inclusion is evidence of use, not demonstrated comparative benefit.
- name: Cyclophosphamide
  description: Occasionally used as rescue immunosuppression when other agents fail; evidence is sparse and does not establish a reliable response rate.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Cyclophosphamide
      term:
        id: NCIT:C405
        label: Cyclophosphamide
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: corticosteroid-sparing agents, which include colchicine, diaminodiphenyl sulfone (dapsone), methotrexate (MTX), azathioprine (AZA), cyclosporine (CSA), mycophenolate mofetil (MMF) and cyclophosphamide (CPA) have been used as a treatment option.
    explanation: Lists reported adjuncts; inclusion is evidence of use, not demonstrated comparative benefit.
- name: Infliximab in EBA associated with Crohn disease
  description: Anti-TNF treatment has case-level support in EBA with concomitant Crohn disease. In case 4 of the 2023 series, both diseases improved and mesalazine plus azathioprine were maintained. This does not establish efficacy for isolated EBA or disentangle concurrent treatments.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Infliximab
      term:
        id: NCIT:C1789
        label: Infliximab
  evidence:
  - reference: PMID:37503352
    reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: During the biological therapy, a remission of both diseases was achieved.
    explanation: Case 4 received infliximab for severe concomitant EBA and Crohn disease.
  - reference: PMID:37503352
    reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Treatment with mesalazine and azathioprine is maintained.
    explanation: Continuing co-treatment limits attribution to infliximab alone.
- name: Ustekinumab in EBA associated with Crohn disease
  description: A case summarized in the 2023 literature review reported EBA remission with IL-12/23 blockade in a patient with Crohn disease. The EBA response did not track the bowel response; a proposed immune mechanism remains unproven and evidence is anecdotal.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Ustekinumab
      term:
        id: NCIT:C84237
        label: Ustekinumab
  evidence:
  - reference: PMID:37503352
    reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: However, biological therapy with ustekinumab finally led to the total remission of EBA.
    explanation: The discussion summarizes a separate single-patient report, not one of the four original cases or a comparative trial.
- name: Immunoadsorption
  description: Selective antibody removal has been reported, commonly in combination with rituximab, for severe refractory EBA. Small uncontrolled reports and co-treatment prevent attribution of durable benefit to immunoadsorption alone.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In several reports, combination therapy with IA and RTX in EBA shows promising potential treatment protocols for those patients
    explanation: Documents reported combination use with limited clinical evidence.
  treatment_term:
    preferred_term: Immunoadsorption
    term:
      id: NCIT:C173286
      label: Therapeutic Apheresis
  target_mechanisms:
  - target: Autoantibody Binding to Type VII Collagen at the Dermal-Epidermal Junction
    treatment_effect: INHIBITS
    description: Removal of circulating antibodies reduces the pool available for tissue binding; this is not selective COL7-antigen-specific adsorption.
- name: Extracorporeal photopheresis
  description: Reported rescue treatment for persistent EBA; small reports include complete or partial remission and nonresponse. Comparative effectiveness is unknown.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Extracorporeal Photopheresis
    term:
      id: NCIT:C62729
      label: Extracorporeal Photopheresis
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In contrast, one patient had no therapeutic response
    explanation: The ECP section describes mixed responses in a small published experience.
- name: Multidisciplinary mucosal assessment and supportive care
  description: Assessment of ocular, oral, swallowing and airway involvement supports early management of cicatrizing complications. Esophageal strictures may require repeated endoscopic dilation when disease activity persists.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Patients may not be able to swallow foods and thus require endoscopic esophageal dilations, which may have to be repeated several times, if disease activity cannot be controlled
    explanation: Supports management of esophageal complications.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Besides that, more aggressive treatment is needed in cases with conjunctival and laryngeal mucosa affected
    explanation: Identifies high-risk mucosal sites requiring specialist assessment.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Experimental IFN-gamma blockade
  description: A rat anti-murine IFN-gamma antibody given before and during anti-COL7 transfer reduced disease severity in mice. This prophylactic experiment is not a human EBA trial and did not test emapalumab in patients.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  context: 'PRECLINICAL: antibody-transfer mouse EBA'
  target_mechanisms:
  - target: IFN-Gamma-Dependent Amplification of Cutaneous Inflammation
    treatment_effect: INHIBITS
    description: Neutralization reduced inflammatory amplification in the mouse protocol.
  evidence:
  - reference: PMID:38799441
    reference_title: Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Murine IFN-γ was blocked by i.p. injection of a monoclonal rat anti- IFN-γ of either 125 µg, 250 µg, or 500 µg every other day starting 1 day prior to EBA induction.
    explanation: Establishes prophylactic timing and the species-specific experimental reagent.
- name: Experimental FcRn blockade
  description: FcRn blockade promotes IgG clearance and has shown benefit in murine EBA. The cited evidence is preclinical, not proof of human EBA efficacy.
  context: 'PRECLINICAL: mouse EBA'
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: FcRn-Mediated Persistence of Anti-COL7 IgG
    treatment_effect: INHIBITS
    description: Experimental inhibition addresses this process; translation to human EBA is unresolved.
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Anti-FcRn treatment in experimental murine EBA have demonstrated promising results in a 4-week treatment period.
    explanation: The source explicitly identifies a murine experiment.
- name: Experimental GM-CSF blockade
  description: GM-CSF inhibition has preventive and therapeutic effects in experimental EBA, associated with neutrophil recruitment and activation. Human EBA efficacy is not established by these experiments.
  context: 'PRECLINICAL: mouse EBA'
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Neutrophil Recruitment to the Skin
    treatment_effect: INHIBITS
    description: Experimental inhibition addresses this process; translation to human EBA is unresolved.
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Therapeutic blockade of GM-CSF in mice with already established immunization-induced EBA showed beneficial therapeutic effects
    explanation: Supports a treatment effect in immunized mice, not in patients.
- name: Experimental IL-1 receptor blockade with anakinra
  description: Recombinant IL-1 receptor antagonist anakinra has preclinical anti-inflammatory evidence in EBA models. The cited studies do not establish human EBA treatment efficacy.
  context: 'PRECLINICAL: mouse EBA'
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
  target_mechanisms:
  - target: Neutrophil Recruitment to the Skin
    treatment_effect: INHIBITS
    description: Experimental inhibition addresses this process; translation to human EBA is unresolved.
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: by application of an IL-1 receptor blocker, anakinra proinflammatory events in experimental EBA were counteracted
    explanation: The evidence concerns experimental EBA.
diagnosis:
- name: Integrated clinical and immunopathological diagnosis
  description: Clinical morphology alone is insufficient. Histology, perilesional DIF and COL7-specific or antigen-localization tests are combined according to availability. The 2018 international consensus established nine criteria but no single worldwide procedure; its stated limitation was not addressing bullous systemic lupus erythematosus.
  evidence:
  - reference: PMID:29165796
    reference_title: 'International Bullous Diseases Group: consensus on diagnostic criteria for epidermolysis bullosa acquisita.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: This included nine diagnostic criteria, which are summarized in a flow chart. The IBDG was unable to determine one procedure that would be applicable worldwide. A limitation of the study is that differential diagnosis of bullous systemic lupus erythematosus has not been addressed.
    explanation: Defines both the consensus scope and its limitations.
- name: Direct immunofluorescence and serration analysis
  description: Linear IgG and/or C3, sometimes IgA, at the epithelial basement membrane supports an autoimmune subepithelial blistering disorder but is not EBA-specific. A u-serrated pattern supports COL7-level autoimmunity and can occur in EBA or bullous systemic lupus. Serration may not be interpretable, particularly in mucosal samples.
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: is pathognomonic for skin-bound autoantibodies against type-VII collagen found in EBA and bullous systemic lupus erythematosus (BSLE)
    explanation: The u-serrated pattern identifies COL7-level autoimmunity rather than EBA alone.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Additionally, in mucosal biopsies and the number of skin samples, the serration pattern cannot be identified.
    explanation: A noninterpretable serration pattern does not exclude EBA.
- name: Salt-split skin indirect immunofluorescence
  description: 'Dermal-floor binding is compatible with EBA, in contrast to typical epidermal-roof binding in bullous pemphigoid. It is not specific: anti-p200/laminin gamma-1 and anti-laminin-332 pemphigoid also bind the floor, requiring antigen-specific discrimination.'
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Since this dermal labeling is not specific, patients with anti-p200/laminin ƴ1 pemphigoid and anti-laminin 332 pemphigoid also reveal autoantibodies attached to the blister floor
    explanation: Explicitly limits the specificity of floor binding.
- name: Anti-type-VII-collagen serology
  description: COL7 ELISA or immunoblot supports diagnosis in context. In one 14-patient NC1+NC2 ELISA study, 12/14 EBA samples were positive (86% sensitivity); two bullous-pemphigoid controls were positive among 143 controls (98.6% specificity). Titres correlated with activity in this small sample, but larger validation was requested. Negative serum testing does not exclude EBA, and IgG-only assays can miss IgA-only disease.
  evidence:
  - reference: PMID:22913489
    reference_title: 'Diagnosis and disease severity assessment of epidermolysis bullosa acquisita by ELISA for anti-type VII collagen autoantibodies: an Italian multicentre study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 12 out of the 14 samples were positive in ELISA
    explanation: Provides the case denominator and observed positivity, not universal sensitivity.
  - reference: PMID:22913489
    reference_title: 'Diagnosis and disease severity assessment of epidermolysis bullosa acquisita by ELISA for anti-type VII collagen autoantibodies: an Italian multicentre study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Among the controls, only two bullous pemphigoid sera tested positive, the specificity being 98·6%.
    explanation: Shows imperfect specificity.
  - reference: PMID:22913489
    reference_title: 'Diagnosis and disease severity assessment of epidermolysis bullosa acquisita by ELISA for anti-type VII collagen autoantibodies: an Italian multicentre study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The correlation between autoantibody titres and disease severity suggests its usefulness as a marker of disease activity in EBA However, this should be confirmed by studies on larger series of patients.
    explanation: The activity association is preliminary.
  - reference: PMID:37503352
    reference_title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The other two patients tested negative in serum studies using IIF on salt-split skin, ELISA and BIOCHIP  # codespell:ignore iif
    explanation: Cases 1 and 2 illustrate serum-negative disease.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: a group of EBA patients with only positive IgA autoantibodies may not be picked up on IB IgG assay
    explanation: The limitation is assay-isotype dependent.
- name: Specialist antigen-localization tests
  description: 'In serum-negative or ambiguous cases, specialist tests can localize tissue-bound antibodies to the anchoring-fibril region: immunoelectron microscopy, fluorescence overlay antigen mapping below type IV collagen, or testing on COL7-deficient substrates. Availability is limited, and results require clinical interpretation.'
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Direct transmission electron microscopy (IEM) in EBA patients shows in vivo bound thick immune deposits in the anchoring fibrils (AF) zone below lamina densa (LD).
    explanation: Establishes the ultrastructural localization.
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: in vivo-bound immune deposits below type-IV collagen by FOAM
    explanation: Describes localization in the seronegative diagnostic framework.
animal_models:
- name: Anti-type-VII-collagen IgG passive-transfer mouse
  species: Mouse
  genotype: Wild-type and complement/NADPH-oxidase-deficient strains injected with anti-COL7 IgG
  publication: PMID:17475881
  description: >-
    Passive transfer of anti-type VII collagen IgG into mice reproduces
    subepidermal blistering; gene-knockout strains dissect the complement and
    neutrophil effector steps.
  modeled_mechanisms:
  - target: Complement Activation at the Dermal-Epidermal Junction
    description: Factor B deficiency attenuates anti-COL7-induced blistering.
    evidence:
    - reference: PMID:17475881
      reference_title: The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: factor B-deficient mice developed a delayed and significantly less severe blistering disease compared with factor B-sufficient mice
      explanation: Shows alternative-pathway dependence in this passive-transfer experiment.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: TISSUE
    limitations: Acute antibody-transfer model bypasses tolerance loss and endogenous antibody induction.
    fidelity: MODERATE
  - target: Neutrophil NADPH-Oxidase-Dependent Reactive Oxygen Species Production
    description: Ncf1-deficient animals resist blister induction.
    evidence:
    - reference: PMID:17380558
      reference_title: NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Neutrophil cytosolic factor 1-deficient mice lacking functional NADPH oxidase were resistant to skin blistering by the passive transfer of antibodies against type VII collagen.
      explanation: Demonstrates oxidative-burst dependence in mice.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Induced mouse disease does not establish clinical response to oxidase blockade in people.
    fidelity: MODERATE
- name: COL7 immunization-induced mouse EBA
  species: Mouse
  genotype: Susceptible inbred strains immunized with recombinant murine COL7 fragments
  description: Active immunization generates an endogenous antibody response and permits study of induction as well as effector phases. Susceptibility depends on strain, antigen and protocol; immunization is not the spontaneous human initiating event.
  modeled_mechanisms:
  - target: COL7-Reactive CD4 T-Cell Response
    description: CD4 depletion delays antibody induction and blistering.
    evidence:
    - reference: PMID:23956869
      reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Depletion of CD4 T cells for two weeks starting one day prior to immunization significantly delayed both autoantibody production and the onset of clinical disease.
      explanation: Timed depletion establishes an induction-phase contribution.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Artificial antigen/adjuvant immunization and strain-dependent susceptibility.
    fidelity: MODERATE
  - target: Anti-Type-VII-Collagen Autoantibody Production
    description: The model generates anti-COL7 antibodies rather than supplying them by passive transfer.
    evidence:
    - reference: PMID:23956869
      reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Depletion of CD4 T cells for two weeks starting one day prior to immunization significantly delayed both autoantibody production and the onset of clinical disease.
      explanation: Timed depletion establishes an induction-phase contribution.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Does not identify the cause of spontaneous tolerance loss in people.
    fidelity: MODERATE
- name: IFN-gamma blockade in passive-transfer mouse EBA
  species: Mouse
  genotype: C57BL/6J mice receiving rabbit anti-murine COL7 IgG
  publication: PMID:38799441
  description: Randomized, blinded assessments tested rat anti-murine IFN-gamma starting one day before antibody transfer. The highest dose reduced late disease burden and neutrophil infiltration; skin-bound IgG was unchanged and C3 deposition increased. The study does not test treatment initiated after established EBA or human clinical efficacy.
  modeled_mechanisms:
  - target: IFN-Gamma-Dependent Amplification of Cutaneous Inflammation
    description: Neutralization reduces disease expression in the model.
    evidence:
    - reference: PMID:38799441
      reference_title: Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The impact of IFN-γ inhibition on disease manifestation is significant but, compared to other drugs used in this model, relatively moderate.
      explanation: The authors characterize the effect as moderate.
    relationship: PERTURBS
    model_scale: TISSUE
    limitations: Prophylactic antibody-transfer protocol; not emapalumab treatment of human EBA.
    fidelity: MODERATE
- name: Human COL7 transgenic mouse antibody-transfer EBA
  species: Mouse
  genotype: Murine Col7 null with a human COL7 transgene
  publication: PMID:25689103
  description: Rabbit antibodies against two human NC1 subdomains induced subepidermal blisters. This establishes pathogenic potential across more than one epitope region; it does not map each human clinical subtype to an epitope.
  modeled_mechanisms:
  - target: Subepidermal Blister Formation
    description: Antibodies against human COL7 induce tissue separation in the humanized animal.
    evidence:
    - reference: PMID:25689103
      reference_title: Autoantibodies to Multiple Epitopes on the Non-Collagenous-1 Domain of Type VII Collagen Induce Blisters.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Antibodies against two of these subdomains were injected into mice carrying null mutations of mouse COL7 and the human COL7 transgene and induced subepidermal blisters.
      explanation: Rabbit antibodies recognizing human COL7 NC1 subdomains were pathogenic in humanized mice.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: TISSUE
    limitations: Human target protein in a mouse effector environment, with rabbit antibodies rather than spontaneous human autoimmunity.
    fidelity: MODERATE
mechanistic_hypotheses:
- hypothesis_group_id: direct_adhesion_interference
  hypothesis_label: Direct anti-COL7 interference with anchoring-fibril adhesion
  status: ALTERNATIVE
  description: Proposed explanation for mechanobullous fragility, not an experimentally established exclusive subtype mechanism.
  applies_to_subtypes:
  - Mechanobullous
  evidence:
  - reference: PMID:23956869
    reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: This may explain the pathogenesis of noninflammatory, mechanobullous EBA; however, this assumption needs to be experimentally confirmed.
    explanation: Direct interference with anchoring-fibril interactions is an unconfirmed explanatory hypothesis.
differential_diagnoses:
- name: Bullous systemic lupus erythematosus
  description: COL7 autoimmunity, u-serration and dermal-floor binding overlap with EBA.
  distinguishing_features:
  - Evaluate the systemic lupus clinical and serological context; COL7 positivity alone does not distinguish the disorders.
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: type-VII collagen found in EBA and bullous systemic lupus erythematosus (BSLE)
    explanation: Documents the shared target-level diagnostic pattern.
- name: Bullous pemphigoid
  description: Inflammatory EBA may resemble bullous pemphigoid.
  distinguishing_features:
  - Typical BP antibodies bind the epidermal roof of salt-split skin; EBA antibodies bind the floor. Antigen-specific testing is needed in ambiguous cases.
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: immune deposits in patients with EBA remains on the dermal floor, while immune deposits in patients with BP remain within the epidermal roof
    explanation: Describes the usual split-skin distinction.
- name: Anti-p200 and anti-laminin-332 pemphigoid
  description: These diseases can share dermal-floor binding with EBA.
  distinguishing_features:
  - Use antigen-specific studies to distinguish p200/laminin gamma-1 or laminin-332 reactivity from COL7 autoimmunity.
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: patients with anti-p200/laminin ƴ1 pemphigoid and anti-laminin 332 pemphigoid also reveal autoantibodies attached to the blister floor
    explanation: Floor binding cannot establish EBA alone.
- name: Inherited dystrophic epidermolysis bullosa
  description: The mechanobullous phenotype can resemble inherited dystrophic EB.
  distinguishing_features:
  - EBA is acquired COL7 autoimmunity; inherited dystrophic EB is a genetically determined disorder. Age alone is insufficient because EBA can occur in children.
  evidence:
  - reference: PMID:32119399
    reference_title: Epidermolysis Bullosa Acquisita.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Classic mechanobullous EBA resembles dystrophic epidermolysis bullosa (EB), with bullae and erosions developing at sites of trauma.
    explanation: Describes the clinical overlap.
- name: Porphyria cutanea tarda and pseudoporphyria
  description: Trauma-prone blistering and fragility may mimic mechanobullous EBA.
  distinguishing_features:
  - The immunopathological evidence for COL7 autoimmunity must be interpreted alongside the clinical differential.
  evidence:
  - reference: PMID:36769788
    reference_title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: So, in differential diagnosis, porphyria cutanea tarda, and pseudoporphyria must be excluded.
    explanation: The classical EBA section identifies these mimics.
experimental_models:
- name: Human skin cryosection and neutrophil separation assay
  experimental_model_type: OTHER
  description: Human skin cryosections incubated with patient anti-COL7 IgG and healthy-donor neutrophils model the effector phase. Antibody binding alone did not produce separation. NADPH-oxidase inhibition or deficient granulocytes prevent separation in this assay.
  cell_source: Human skin cryosections, EBA-patient antibodies and donor granulocytes
  modeled_mechanisms:
  - target: Neutrophil NADPH-Oxidase-Dependent Reactive Oxygen Species Production
    description: Manipulating granulocyte NADPH oxidase changes tissue separation.
    evidence:
    - reference: PMID:17380558
      reference_title: NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Pharmacological inhibition or deficiency of human NADPH oxidase abolished dermal-epidermal separation caused by autoantibodies and granulocytes ex vivo.
      explanation: Human ex vivo dependence on NADPH oxidase.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Ex vivo tissue assay lacks circulation, tolerance induction and chronic healing.
    fidelity: MODERATE
  - target: Subepidermal Blister Formation
    description: The assay measures dermal-epidermal separation after antibody and neutrophil exposure.
    evidence:
    - reference: PMID:17380558
      reference_title: NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Pharmacological inhibition or deficiency of human NADPH oxidase abolished dermal-epidermal separation caused by autoantibodies and granulocytes ex vivo.
      explanation: Human ex vivo dependence on NADPH oxidase.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: TISSUE
    limitations: Experimental separation is not a measured clinical treatment response.
    fidelity: MODERATE
  evidence:
  - reference: PMID:17380558
    reference_title: NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Pharmacological inhibition or deficiency of human NADPH oxidase abolished dermal-epidermal separation caused by autoantibodies and granulocytes ex vivo.
    explanation: Human ex vivo dependence on NADPH oxidase.
references:
- reference: PMID:17380558
  title: NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage.
- reference: PMID:17475881
  title: The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita.
- reference: PMID:22913489
  title: 'Diagnosis and disease severity assessment of epidermolysis bullosa acquisita by ELISA for anti-type VII collagen autoantibodies: an Italian multicentre study.'
- reference: PMID:23956869
  title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
  findings:
  - statement: The full review separates induction, antibody persistence and effector mechanisms; active immunization and passive transfer answer different questions.
  - statement: HSP90 inhibition prevented and ameliorated experimental EBA without reducing plasma-cell numbers, while T-cell proliferation was inhibited. This is preclinical evidence rather than a clinical EBA treatment recommendation.
    evidence:
    - reference: PMID:23956869
      reference_title: Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Unexpectedly, total plasma cell numbers, COL7-specific plasma cells, and germinal center B cells were unaffected by HSP90 blockade.
      explanation: Avoids mislabeling HSP90 inhibition as demonstrated plasma-cell depletion.
- reference: PMID:25689103
  title: Autoantibodies to Multiple Epitopes on the Non-Collagenous-1 Domain of Type VII Collagen Induce Blisters.
- reference: PMID:29165796
  title: 'International Bullous Diseases Group: consensus on diagnostic criteria for epidermolysis bullosa acquisita.'
- reference: PMID:32119399
  title: Epidermolysis Bullosa Acquisita.
  tags:
  - StatPearls
- reference: PMID:36769788
  title: Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.
- reference: PMID:37503352
  title: 'Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.'
- reference: PMID:38799441
  title: Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.
  findings:
  - statement: Prophylactic IFN-gamma blockade reduced mouse lesions despite unchanged tissue IgG and increased C3 deposition; complement deposition alone is not a monotonic readout of disease severity.
    evidence:
    - reference: PMID:38799441
      reference_title: Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Tissue- bound IgG in the skin and circulating total mouse IgG were also identical among the groups. However, C3 deposits along the dermal epidermal junction were significantly increased in the two highest treated groups compared to that in isotype antibody- treated mice.
      explanation: The full results qualify a simple interpretation of complement staining.
- reference: PMID:39006807
  title: 'Rituximab in the Treatment of Epidermolysis Bullosa Acquisita: A Systematic Review.'
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC11238708/
  title: 'Rituximab in the Treatment of Epidermolysis Bullosa Acquisita: A Systematic Review - PMC'

📚

References & Deep Research

References

PMID:17380558

NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage.

No top-level findings curated for this source.

PMID:17475881

The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita.

No top-level findings curated for this source.

PMID:22913489

Diagnosis and disease severity assessment of epidermolysis bullosa acquisita by ELISA for anti-type VII collagen autoantibodies: an Italian multicentre study.

No top-level findings curated for this source.

PMID:23956869

Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita.

2 findings

The full review separates induction, antibody persistence and effector mechanisms; active immunization and passive transfer answer different questions.

HSP90 inhibition prevented and ameliorated experimental EBA without reducing plasma-cell numbers, while T-cell proliferation was inhibited. This is preclinical evidence rather than a clinical EBA treatment recommendation.

Show evidence (1 reference)

PMID:23956869 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism

"Unexpectedly, total plasma cell numbers, COL7-specific plasma cells, and germinal center B cells were unaffected by HSP90 blockade."

Avoids mislabeling HSP90 inhibition as demonstrated plasma-cell depletion.

PMID:25689103

Autoantibodies to Multiple Epitopes on the Non-Collagenous-1 Domain of Type VII Collagen Induce Blisters.

No top-level findings curated for this source.

PMID:29165796

International Bullous Diseases Group: consensus on diagnostic criteria for epidermolysis bullosa acquisita.

No top-level findings curated for this source.

PMID:32119399

Epidermolysis Bullosa Acquisita.

No top-level findings curated for this source.

PMID:36769788

Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.

No top-level findings curated for this source.

PMID:37503352

Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.

No top-level findings curated for this source.

PMID:38799441

Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.

1 finding

Prophylactic IFN-gamma blockade reduced mouse lesions despite unchanged tissue IgG and increased C3 deposition; complement deposition alone is not a monotonic readout of disease severity.

Show evidence (1 reference)

PMID:38799441 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Tissue- bound IgG in the skin and circulating total mouse IgG were also identical among the groups. However, C3 deposits along the dermal epidermal junction were significantly increased in the two highest treated groups compared to that in isotype antibody- treated mice."

The full results qualify a simple interpretation of complement staining.

PMID:39006807

Rituximab in the Treatment of Epidermolysis Bullosa Acquisita: A Systematic Review.

No top-level findings curated for this source.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC11238708/

Rituximab in the Treatment of Epidermolysis Bullosa Acquisita: A Systematic Review - PMC

No top-level findings curated for this source.

Deep Research

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 (2)

Review EBA full-text evidence, diagnostic specificity and mechanisms · 2026-10-02T19:36:31Z · View source

Scope: substantive review of an acquired autoimmune disorder with CREATE and EDIT history but no REVIEW event. Infectious and environmental diseases/poisonings remain excluded from the campaign. Fresh worktree and main were both 093f725c2404daf223b730d6c901167470314dea; fetch confirmed no rebase delta. No open disease/history PR overlap at selection. Source consumption: read the complete cached scientific text and all tables of PMID:23956869 (2013 review), PMID:36769788 (2023 review), PMID:37503352 (four cases, including Table 1 and each case narrative), and PMID:38799441 (2024 mouse IFN-gamma study, including methods, results, discussion and tables). Read all original cached abstracts PMID:17380558, 17475881, 22913489 and 25689103, plus PMID:2031664 as diagnostic background. Read the new consensus PMID:29165796 and StatPearls PMID:32119399 abstracts. Read PMID:39006807 abstract, then recovered its full PMC article through just fetch-reference url:https://pmc.ncbi.nlm.nih.gov/articles/PMC11238708/ and read the scientific narrative and aggregate Table 1. The detailed individual-study Table 2 and supplements of the rituximab review were not exhaustively audited. No hand-edited cache files. Access limitations: PMID:25689103 remained abstract-only after refetch; the 2018 consensus publisher route returned 403. The PMC rituximab reader URL and StatPearls reader URL returned CAPTCHA pages; these unused caches were stashed. The canonical rituximab PMC URL succeeded. The StatPearls Bookshelf PDF route returned 404; only its verified abstract supports the inherited-EB differential. Do not equate these access attempts with proof that full text is unavailable everywhere. Research cross-check: read the substantive narrative and citation appendix of Acquired_Epidermolysis_Bullosa-deep-research-claude_code, including reference and term validation. The report relied heavily on the 2023 review and left several primary-paper links as titles only. Disease identity is acquired anti-COL7 autoimmunity, not inherited COL7A1 deficiency. No phase II-or-later EBA trial identifier was surfaced by that report. Trial identifiers discussed in the 2013 review concern pemphigus or rheumatoid arthritis and were not imported as EBA trials. Completeness assessment: (1) Phenotypes adequate after adding pruritus, dysphagia and laryngeal stenosis, removing adult-only onset and unsupported global frequency assignments, and preserving oral involvement as 4/4 in the explicitly selected refractory case series. The 50-65% estimate concerns all mucosal sites and is retained only in that scope. (2) Clinical subtypes adequate: classical/inflammatory presentations can overlap or transition; the historical 83-patient series is not a population estimate. (3) Mechanisms adequate after separating T-cell help, autoantibody production, FcRn persistence, binding, complement, recruitment, neutrophil activation, ROS and protease arms, and tissue separation. Added IFN-gamma mouse amplification; direct adhesion interference is explicitly hypothetical with a hypothesis group. (4) Care adequate: conventional adjuncts, variable IVIG/rituximab responses, case-level infliximab/ustekinumab, immunoadsorption/ECP, specialist mucosal care, and preclinical FcRn/GM-CSF/anakinra/IFN-gamma entries are distinguished. No invented clinical trial or established human efficacy for mouse interventions. (5) Genetics adequate for an acquired disease: HLA susceptibility allele, no fabricated Mendelian penetrance or causal COL7A1 variant. (6) Diagnostics adequate after fixing u-serration/BSLE and floor-binding overlap, documenting seronegative/IgA-only assay limitations, and adding consensus and specialist localization. (7) Central references adequate: cached full text and research leads actively used, with publication titles checked for identifier/topic alignment. (8) Overall consumption adequate; source errors and unsupported extrapolations were not adopted. Specific interpretation safeguards: antibodies recognizing different NC1 epitopes did not correlate with clinical subtype in the 69-serum primary study; mouse Fc gamma RIV is not relabeled as a human receptor result. Passive transfer bypasses induction, and the IFN-gamma antibody started one day before induction, so that experiment is not treatment of established disease. Higher C3 staining despite improved mouse lesions is retained in publication findings. In the four-case paper, the overview implies nail involvement in all four while case 2 says nails were unaffected; no 4/4 nail frequency was curated. Some table and narrative follow-up intervals differ; the specific treatment descriptions quote the individual narratives and do not pool these times. The 2023 review's absolute statement that off-treatment remission is impossible conflicts with its own IVIG series and was not adopted. Its erroneous salt concentration and FOAM dye example were also not copied. The historical IBD association predates modern EBA criteria, not modern IBD criteria; the later contrary record-based finding is explicitly attributed to the 2023 discussion rather than presented as a newly audited primary cohort. Ontology: OAK local SQLite searches and definitions confirmed new HP, GO and NCIT terms; configured term validation passed. Immunoadsorption is represented by Therapeutic Apheresis with the specific preferred term. Granulocyte oxidase deficiency is an experimental perturbation, not patient EBA inheritance. Process narration moved out of disease notes into this record. Validation: authoritative batched schema/ontology/reference validation passes with 114 snippets, zero skipped/unavailable snippets, 126 titles and zero issues. All23 repository QA gates pass after restoring the retained HLA/COL7 molecular-function annotations during node separation (22 initial passes plus a successful targeted rerun of the gene-activity gate). Snippet grading, hypothesis links, history validation, Bookshelf baseline and page rendering pass. The GeneReviews snapshot reports no chapter; StatPearls is tagged and actively cited.

Create: Acquired Epidermolysis Bullosa (EBA) · 2026-10-01T01:53:03Z · View source

Created the EBA entry (MONDO:0018747), the acquired autoimmune subepidermal blistering disease completing the autoimmune-blistering set with Pemphigus_Foliaceus (desmosomal) and Dermatitis_Herpetiformis (IgA/TG3). Deep research: claude_code provider (report thin, 1 web search), so evidence was sourced independently from PubMed. Causal chain: HLA-DRB1*15:03 susceptibility -> anti-type-VII-collagen IgG response (NC1 domain) -> autoantibody binding at the dermal-epidermal junction (COL7A1 autoantigen, grounded GO:0005201), branching to skin fragility (direct anchoring-fibril impairment, mechanobullous) and to complement + neutrophil recruitment -> neutrophil NADPH-oxidase ROS/protease-mediated dermal-epidermal separation -> subepidermal blister -> phenotypes (blistering, skin fragility, milia, atrophic scars, oral mucosal blisters). has_subtypes Mechanobullous/Inflammatory with subtype FKs. Treatments: corticosteroids, colchicine, dapsone, rituximab, IVIG. Diagnosis: DIF u-serrated, salt-split dermal-floor, anti-COL7 ELISA. Animal model: anti-COL7 passive-transfer mouse (complement + NADPH-oxidase effector steps). Key PMIDs 23956869 (Ludwig review), 36769788 (Perkovic treatment review), 25689103, 22913489, 17475881, 17380558. Validation: validate-disorders clean, 29/29 snippets verified, terms/entity-refs/causal-targets/enum/duplicate-key/coarse-phenotype gates pass, 5/5 phenotypes connected, both pathograph genes grounded. No GeneReviews chapter (complex autoimmune, not Mendelian).

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-sonnet-5-5 7 citations 2026-10-01T01:26:02.236298

1. Disease Information

Overview. EBA is a rare, chronic, acquired autoimmune subepidermal blistering disease. IgG autoantibodies (occasionally IgA) target type VII collagen (COL7A1 product). Type VII collagen is the main component of the anchoring fibrils that tether the epidermal basement membrane to the papillary dermis. Antibody binding causes dermal-epidermal separation below the lamina densa.
Identifiers.
MONDO:0018747, as in the existing KB entry.
ICD-10: L12.3 (acquired epidermolysis bullosa).
MeSH: Epidermolysis Bullosa Acquisita.
Orphanet and OMIM codes were not checked. Look them up with just fetch-reference ORPHA:<code>.
Synonyms. EBA; acquired epidermolysis bullosa; anti-type VII collagen disease.
Data level. The sources are aggregated, disease-level literature (reviews and case series). No EHR-derived data were used.

2. Etiology

Primary cause. Loss of tolerance to the NC1 (non-collagenous 1) and other domains of type VII collagen, producing pathogenic autoantibodies.
Genetic risk.
HLA-DR2 association; the Perković 2023 review (PMID:36769788) notes that "people of African descent carry the HLA-DRB1 risk allele." The specific allele (reported elsewhere as HLA-DRB1*15:03) is not verified here.
No Mendelian cause. This is not the inherited dystrophic EB caused by COL7A1 variants.
Associations (risk contexts).
Inflammatory bowel disease, especially Crohn's disease. The review mentions the correlation, but the frequency was not verified.
Lymphoma. Perković 2023 reports an association "in 8% of patients."
Drug-associated cases, for example after a DPP-4 inhibitor (case report PMC12812923, not read).
Protective factors and gene-environment interactions. None established. No data found.

3. Phenotypes

Phenotype frequencies were not extracted from the sources I could read. Mark each frequency as "unspecified" in the KB unless it is curated from a primary source.

Phenotype	Notes	Suggested HPO (verify first)
Subepidermal blistering	Core feature	HP:0008066 Abnormal blistering of the skin (already in the KB entry)
Skin fragility (mechanobullous form)	Trauma-prone sites (extensor surfaces, hands, feet)	to be looked up
Scarring, milia, nail dystrophy	Healing of mechanobullous lesions	to be looked up
Inflammatory bullae, pruritus	Widespread, in traumatic and non-traumatic areas	to be looked up
Mucosal erosions	Oral, ocular, esophageal	to be looked up

Clinical types. Two main types are distinguished: mechanobullous and inflammatory (search-result summary of the literature).
Onset. Mostly adult, but not quantified here.
Course. Chronic.
Quality of life. No data retrieved.

4. Genetic/Molecular Information

Autoantigen. COL7A1 (HGNC ID not looked up; use lowercase hgnc: and resolve it with runoak).
Pathogenic variants. None. The disease is autoimmune.
Modifier genes. HLA class II, as above.
Epigenetic and chromosomal findings. Not available.

5. Environmental Information

Drug triggers. Case reports exist, for example DPP-4 inhibitors (unverified beyond the title).
Lifestyle and infectious agents. None established.
Mechanical trauma. It determines where lesions form in the mechanobullous type.

6. Mechanism / Pathophysiology

Causal chain (steps marked inferred are not demonstrated in the sources I read):

Genetic susceptibility, including HLA class II (HLA-DR2), plus unknown triggers, leads to loss of tolerance to type VII collagen (the trigger is inferred).
Autoreactive B and T cells produce IgG anti-COL7 autoantibodies, mainly against the NC1 domain.
The autoantibodies bind COL7 in the anchoring fibrils at the dermal-epidermal junction.
Binding has two consequences. It can directly impair COL7 function and its interaction with other basement membrane components. It can also recruit complement and Fcγ-receptor-bearing cells.
In the inflammatory pathway, neutrophils and other myeloid cells are activated and release proteases and reactive oxygen species. In experimental EBA this involves IFN-γ (PMC11116581, title only).
The result is damage to the lamina densa and sublamina densa and dermal-epidermal separation.
Clinically, this produces tense subepidermal blisters, with scarring and milia when healing follows trauma.
Branching. The mechanobullous type is driven by skin fragility. The inflammatory type is driven by immune-cell infiltration.
Suggested terms.
GO: adaptive immune response; complement activation; neutrophil activation involved in immune response.
CL: B cell (CL:0000236), neutrophil (CL:0000775), plasma cell (CL:0000786).

7. Anatomical Structures Affected

Primary. Skin, at the dermal-epidermal junction (the sublamina densa, where anchoring fibrils lie).
Secondary. Oral, ocular and esophageal mucosa.
Suggested UBERON (verify before binding): skin of body, basement membrane of epithelium, epidermis, dermis.
Subcellular. Extracellular matrix and anchoring fibrils.
Lateralization. Typically bilateral and symmetric at trauma-prone sites.

8. Temporal Development

Onset. Adult.
Pattern. Chronic, with relapses.
Remission. Perković 2023 states that "complete remission off-treatment in EBA is impossible since maintenance therapy is needed." Treat this as a review-level claim, not an absolute.

9. Inheritance and Population

Incidence. Perković 2023 gives "between 0.08 and 0.5 per million," with Germany the highest at 2.8 per million. A search-result summary states an incidence of 0.2 new cases per million per year.
Inheritance. Not inherited (acquired). The HLA association is a susceptibility factor only.
Population. HLA-DRB1 risk allele in people of African descent.
Sex ratio and age distribution. Not verified.

10. Diagnostics

Direct immunofluorescence (DIF). Linear IgG, and sometimes C3, deposits along the basement membrane zone.
Salt-split skin immunofluorescence. The deposits localize to the dermal (floor) side, and a u-serrated pattern is a key differentiating feature.
ELISA. Detects serum anti-COL7 (NC1) autoantibodies.
Combined criteria. Perković 2023: "Positive DIF test, and ELISA showing patients' serum autoantibodies targeting Col7" constitute ideal diagnostic criteria.
Histology. Subepidermal split. Infiltrate type was not verified.
Differential diagnosis.
Bullous pemphigoid.
Mucous membrane pemphigoid.
Dystrophic EB.
Bullous SLE.
Porphyria cutanea tarda.
The KB already has entries for several of these.
Genetic testing and screening. Not applicable.

11. Outcome/Prognosis

Chronic course that needs maintenance therapy (Perković 2023).
Complications: scarring, mucosal strictures, and risk related to immunosuppression. Specific figures were not retrieved.
Survival and mortality data were not found. This is a gap.

12. Treatment

All details are from Perković 2023 (PMID:36769788) unless stated.

First line (search-result summary). Systemic corticosteroids with dapsone. Colchicine and dapsone are listed as steroid-sparing agents.
Rituximab. "Complete disease remission was achieved in 10 cases using the lymphoma protocol."
IVIG. "After 16 to 31 IVIG infusion therapies...clinical remission was observed."
Emerging.
Anti-FcRn therapy.
Anakinra (anti-IL-1).
Anti-GM-CSF antibodies.
Biologic case series: PMC10371012, title only.
Suggested NCIT terms (look up each CURIE first): Pharmacotherapy (NCIT:C15986, listed in CLAUDE.md), with therapeutic_agent for dapsone, colchicine, rituximab and immunoglobulin; therapeutic_modality MONOCLONAL_ANTIBODY for rituximab and anti-FcRn agents.
Not covered. Clinical trials (NCT IDs), pharmacogenomics and adverse-event data were not retrieved. Run just fetch-reference on any NCT ID before citing it.

13. Prevention

No primary prevention is known. Secondary and tertiary prevention rely on early diagnosis and trauma avoidance in the mechanobullous type. This is an inference and was not sourced.

14. Other Species / Natural Disease

No naturally occurring animal disease was found in the sources read. OMIA was not queried.

15. Model Organisms

Mouse. The experimental EBA models are:
Passive transfer of anti-COL7 antibodies.
Active immunization with COL7 fragments.
Recapitulation. Subepidermal blistering with neutrophilic involvement. IFN-γ inhibition impairs induction of experimental EBA (title-level only: PMC11116581).
Limitations and resources. Not retrieved. In the KB these models belong in animal_models: with modeled_mechanisms.

Gaps for curation follow-up

Fetch and cache PMID:36769788 and PMID:23956869 with just fetch-reference, then curate exact snippets.
Phenotype frequencies, mortality and survival, HLA allele-level data and drug-trigger evidence are unsourced.
Resolve the ontology IDs (COL7A1 HGNC, HP, UBERON, NCIT) by lookup before binding.
Add a history/ record for any KB edit.

Sources: - Perković et al. 2023, EBA Current and Emerging Treatments (PMC9917799) - Kim et al., EBA review (PMC3727188) - PubMed 23956869 - StatPearls EBA (NBK554512) - Experimental EBA, IFN-γ (PMC11116581) - Biologic treatment case series (PMC10371012) - DPP-4 inhibitor case report (PMC12812923)

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	7
Resolved	7
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	3
Quoted claims found in source	3
Quoted claims not found in source	0
References weighed for topical relevance	7
On topic	7
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	6
Resolved	6
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	0
Terms whose name is worth a second look	1

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

CL:0000236 (1 mention) - the report calls it "CL: B cell"; CL calls it B cell

Every term resolved, and every label the report gave matched.

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Medical Actions

Diagnosis

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Clinical Burden

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

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

Gaps for curation follow-up

Reference Validation

Term Validation

Terms whose name is worth a second look