Updated Protocol for Diagnosis and Treatment of Epidermolysis Bullosa Acquisita and Simplex
Critical Distinction: These are Fundamentally Different Diseases
Epidermolysis Bullosa Simplex (EBS) and Epidermolysis Bullosa Acquisita (EBA) require completely different diagnostic and therapeutic approaches—EBS is an inherited genetic disorder present from birth requiring supportive care, while EBA is an acquired autoimmune disease in adults requiring immunosuppression. 1, 2
Epidermolysis Bullosa Simplex (EBS)
Diagnosis
EBS diagnosis follows a sequential "onion skin" approach starting with determining the level of skin cleavage through immunofluorescence antigen mapping (IFM) and transmission electron microscopy. 1
Cleavage level identification: EBS shows intraepidermal blistering at the basal or suprabasal level, distinguishing it from junctional (lamina lucida) and dystrophic (sublamina densa) forms 2
Clinical phenotype assessment: Document distribution patterns, severity of cutaneous and extracutaneous involvement, age of onset (typically birth or early childhood), and specific diagnostic features like absence of scarring 1, 2
Genetic testing: Identify mutations in genes encoding keratin 5, keratin 14 (basal forms), or transglutaminase 5, plakophilin 1, desmoplakin, or plakoglobin (suprabasal forms) 2
Inheritance pattern: Determine autosomal dominant or recessive inheritance through family history 1
Treatment
Management focuses on preventing complications and treating symptoms, as no curative therapy exists for this genetic disorder. 1
Wound care: Minimize trauma to prevent blister formation, use non-adherent dressings, and maintain skin hydration 1
Emerging therapies: Gene therapy, cell-based therapies, and protein replacement therapies are under investigation but not yet standard of care 1
Surveillance: EBS itself does not carry increased squamous cell carcinoma (SCC) risk, unlike dystrophic forms 3
Epidermolysis Bullosa Acquisita (EBA)
Diagnosis
EBA diagnosis requires demonstrating linear IgG deposits along the dermal-epidermal junction with autoantibodies binding to the dermal side on salt-split skin immunofluorescence, targeting type VII collagen. 2, 4
Essential Diagnostic Steps:
Direct immunofluorescence (DIF): Obtain perilesional skin biopsy showing linear deposits of IgG, IgA, and/or C3 along the dermal-epidermal junction with a u-serrated pattern 4
Salt-split skin immunofluorescence: Demonstrates autoantibody binding to the dermal (floor) side, distinguishing EBA from bullous pemphigoid (which binds to the epidermal roof) 2, 4
Histopathology: Shows pauci-inflammatory subepidermal cleavage or neutrophilic infiltrate 5
Serological confirmation: ELISA for anti-type VII collagen autoantibodies (positive in many but not all cases), or immunoblotting using recombinant NC1 domains of type VII collagen 6, 4
Clinical Variants to Recognize:
Mechanobullous variant: Skin fragility, bullae with minimal inflammation, erosions in acral distribution healing with scarring and milia formation 5, 7
Inflammatory variant: Urticarial inflammatory plaques with tense bullae resembling bullous pemphigoid, or mucosal lesions causing permanent scarring in ocular, oral, esophageal, and urogenital regions 5, 7
Treatment Algorithm
Treatment response is variable, with complete remission more common in children and worse prognosis in adults with mucosal involvement. 5
Mild Disease:
- First-line: Systemic corticosteroids combined with immunomodulators (colchicine or dapsone) 5
Severe or Refractory Disease:
Corticosteroids plus immunosuppressants: Add azathioprine, mycophenolate mofetil, or cyclosporine to systemic corticosteroids 5
Intravenous immunoglobulin (IVIG): Effective in refractory cases with excellent tolerability and sustained remission for 1-3 years 8, 5
Rituximab: Anti-CD20 monoclonal antibody showing extraordinary skin improvement and disease control for 1-3 years in treatment-resistant cases 8, 5, 7
Infliximab: TNF-alpha inhibitor demonstrating efficacy in severe cases with excellent tolerability 8
Treatment Monitoring:
Mucosal surveillance: Aggressive monitoring and treatment of ocular, oral, esophageal, and urogenital involvement to prevent permanent dysfunction 5
Associated conditions: Screen for malignant tumors, inflammatory bowel disease, and other autoimmune disorders, which occur in association with EBA 6
Common Diagnostic Pitfalls
Do not rely on clinical appearance alone: EBA inflammatory variant mimics bullous pemphigoid, mucous membrane pemphigoid, Brunsting-Perry pemphigoid, and linear IgA dermatosis—immunopathologic confirmation is mandatory 7, 4
Proper biopsy handling: DIF specimens require snap-freezing in liquid nitrogen or transport in Michel's medium to prevent false-negative results 2
ELISA limitations: ELISA alone is insufficient due to false-positive results; immunofluorescence studies remain the gold standard 2
Salt-split skin is essential: This technique definitively distinguishes EBA (dermal binding) from bullous pemphigoid (epidermal binding) when both show linear IgG on standard DIF 2, 4