Autoimmune blistering diseases

Autoimmune blistering diseases are skin conditions characterized by the formation of blisters due to autoimmune destruction of cellular or extracellular adhesion molecules. The most common autoimmune blistering disease is bullous pemphigoid, which is a chronic, relapsing-remitting disease that primarily affects older adults. It typically manifests with large, tense, pruritic vesicles and bullae and usually responds well to treatment with potent topical glucocorticoids. Pemphigus vulgaris manifests with painful mucosal and/or cutaneous lesions that rupture easily, forming crusted erosions. First-line therapy for most patients consists of systemic glucocorticoids and adjunctive immunosuppressants. Extensive pemphigus vulgaris typically requires hospitalization. Complications may be life-threatening. Dermatitis herpetiformis is characterized by intensely pruritic papules and vesicles and primarily affects the extensor surfaces of the extremities. It is considered a cutaneous manifestation of celiac disease. The prognosis is good for patients who adhere to a lifelong gluten-free diet. Oral dapsone rapidly improves cutaneous lesions. Direct immunofluorescence microscopy of perilesional skin is the gold standard for the diagnosis of all three diseases. Serology using indirect immunofluorescence or ELISA to detect autoantibodies confirms the diagnosis, especially if other findings are equivocal or atypical.

In bullows (bullous) pemphigoid, antibodies attack the hemidesmosomes located below the epidermis.

• Less common causes of autoimmune blistering disease include:
  • Pemphigus foliaceus
  • Paraneoplastic pemphigus ^[4]
  • IgA pemphigus ^[5]
  • Epidermolysis bullosa acquisita
  • Mucus membrane pemphigoid
  • Gestational pemphigoid
  • Anti-p200 pemphigoid ^[6]

Definition

Bullous pemphigoid is a chronic relapsing-remitting autoimmune blistering disease that primarily affects older adults.

Clinical features ^[1][7]

• Prodromal (nonbullous) stage
  • Pruritus with or without urticarial and/or papular lesions
  • May last several weeks to months
  • Approx. 20% of patients do not progress to the bullous stage. ^[1]
• Bullous stage
  • Large (1–4 cm), tense, pruritic vesicles and bullae on erythematous base
    • Distribution: often symmetric
    • Common sites: trunk and flexural surfaces of the limbs
    • Typically heal without scarring, but may result in pigmentation changes
  • Oral involvement in 10–30% of patients (other mucosal involvement is rare) ^[1]
  • No Nikolsky sign
• Features of associated diseases, e.g.: ^[1][7]
  • Clinical features of multiple sclerosis
  • Clinical features of Parkinson disease
  • Clinical features of major neurocognitive disorder

Disease extent can be assessed using the Bullous Pemphigoid Disease Activity Index or daily blister count. ^[1]

Diagnosis ^[1][7]

Approach

• Obtain perilesional and lesional punch biopsies in patients with characteristic clinical features..
• Atypical clinical features: Obtain serologies.
• Refer to dermatology if there is diagnostic uncertainty.

Clinical criteria ^[1]

Bullous pemphigoid is likely in patients with at least three of the following:

• Patient age > 70 years
• No mucosal involvement
• No atrophic scars
• No head and neck involvement

Biopsy

• Direct immunofluorescence microscopy (gold standard)
  • Sample: perilesional punch biopsy
  • Findings: linear deposits of IgG and/or complement C3 along the basement membrane zone
• Histopathology
  • Sample: lesional punch biopsy
  • Findings
    • Subepidermal blistering
    • Eosinophilic infiltration and, occasionally, neutrophils and mononuclear cells

Serology

• Methods: ELISA and indirect immunofluorescence
• Findings: IgG autoantibodies against BPAg1 (BP230) and/or BPAg2 (BP180)

Diagnosing nonbullous disease can be challenging and may require additional immunopathological studies.

Management ^[1][7]

All patients should be managed by a dermatologist.

Pharmacotherapy ^[1][7]

• First-line: potent topical glucocorticoids, e.g., clobetasol propionate (off-label) ^[1][7]
• Rapidly progressive or extensive disease : systemic glucocorticoids, e.g., prednisone (off-label) ^[1]
• Options for relapsing or refractory disease or contraindications to systemic glucocorticoids include:
  • Steroid-sparing immunosuppressants, e.g., azathioprine, mycophenolate mofetil, methotrexate
  • Tetracyclines, e.g., doxycycline
  • Biologics, e.g., rituximab, omalizumab, dupilumab
  • Intravenous immunoglobulin

Disposition

• Admit the following individuals for initial inpatient management:
  • Patients with extensive disease
  • Older adults
  • Patients with multimorbidity

Prognosis ^[7]

• Long-term remission is possible.
• Relapse occurs in ∼ 30% of patients within 12 months of treatment and in ∼ 50% of patients after stopping treatment. ^[1]

Special patient groups

Gestational pemphigoid ^[8]

• Definition: bullous, pemphigoid-like dermatosis during pregnancy of unknown cause (most likely immunological)
• Epidemiology: 1:50,000 pregnancies (in the US)
• Clinical features
  • Commonly starts in the periumbilical region during the 2^nd and 3^rd trimester
  • Intensely pruritic, mostly nonblistering lesions (eczema, urticarial or papular lesions) on extremities and mucous membranes
  • Grouped vesicles with herpetiform appearance (“gestational herpes”) usually occur as the disease advances.
• Diagnosis: The diagnosis is confirmed via biopsy and immunofluorescence.
• Treatment: glucocorticoids (topical or systemic) at the lowest dose needed to control disease ^[6]
• Prognosis
  • Usually self-limited; heals spontaneously after delivery; , but associated with complications (e.g., premature labor; , increased lifetime risk of autoimmune disease)
  • Recurrence is possible, especially appearing:
    • Spontaneously in the postpartum period
    • In subsequent pregnancies
    • When taking contraceptives containing progestin or estrogen
    • During menstruation
  • Infants born to women with gestational pemphigoid can develop transient blistering that resolves spontaneously.

Definition

Pemphigus vulgaris is an autoimmune blistering disease that causes painful mucosal and/or cutaneous lesions.

Clinical features ^[9][10][11]

Pemphigus vulgaris may manifest as mucosal-dominant, mucocutaneous, or, less commonly, cutaneous-only disease.

• Mucosal involvement: flaccid blisters that rupture easily, causing painful erosions
  • Typically precedes cutaneous involvement
  • Often starts in the oral mucosa
  • Common site: buccal mucosa
  • Possible malnutrition and weight loss due to painful oral erosions
• Cutaneous involvement: erythematous macules that evolve into flaccid blisters with clear fluid and rupture to form painful, often crusted erosions
  • Often occurs weeks to months after mucosal lesions
  • Localized or generalized
  • Common sites: areas of mechanical stress, seborrheic regions (e.g., head, trunk, groin)
  • Typically heals without scarring, but may cause pigmentation changes
  • Possible Nikolsky sign during active disease ^[9]

Disease extent can be assessed using the Pemphigus Disease Area Index or the Autoimmune Bullous Skin Disorder Intensity Score. ^[9][10]

Diagnosis ^[9][10][12]

Approach

• Consider pemphigus vulgaris in patients with characteristic clinical features.
• Obtain perilesional and lesional punch biopsies.
• Obtain serologies.
• Refer to dermatology if there is diagnostic uncertainty.

Biopsy

• Direct immunofluorescence (gold standard) ^[9]
  • Sample: perilesional punch biopsy
  • Finding: reticular IgG and complement C3 deposits on keratinocytes
• Histopathology
  • Sample: lesional punch biopsy
  • Findings
    • Intraepidermal acantholysis
    • Basal keratinocytes adherent to the basement membrane (referred to as the “tombstone effect”)
    • Occasional eosinophilic or neutrophilic infiltrates

Serology

• Indirect immunofluorescence: IgG autoantibodies bind to epithelial cells in a reticular pattern.
• ELISA: IgG antibodies against desmoglein 1 and/or desmoglein 3

Management ^[10]

Pharmacotherapy ^[10]

Prescribe the following in consultation with a dermatologist.

• First-line
  • Systemic glucocorticoids, e.g., prednisone (off-label) with or without mycophenolate mofetil OR azathioprine ^[10]
  • OR rituximab with or without systemic glucocorticoids
• Additional therapies
  • Severe or refractory disease: IVIg, plasmapheresis
  • Symptomatic relief (especially for mucosal lesions): topical glucocorticoids, anesthetic gels
  • Pain management
  • Antibiotic therapy for skin and soft tissue infections as needed

Supportive care ^[13]

• Hemodynamic support, e.g., IV fluid therapy as needed
• Electrolyte repletion
• Local wound care

Complications ^[13]

• Dehydration
• Secondary infection
• Venous thromboembolism

Complications from the disease and its treatment may be life-threatening without adequate treatment. ^[10]

Disposition ^[10]

• Consult a dermatologist for all patients.
• Patients with extensive pemphigus vulgaris typically require hospital admission.

• Etiology: : autoimmune disease (only antibodies against desmoglein 1 detectable)
• Clinical features
  • Bullae in the epidermis; , which burst spontaneously because of their superficial location
  • Localized mainly on the face, head, stomach, and back
  • Almost never with mucosal involvement (unlike pemphigus vulgaris)
• Treatment
  • First-line: systemic glucocorticoids
  • Dapsone
  • Topical glucocorticoids

Definition

Dermatitis herpetiformis is an autoimmune blistering disease that is considered a cutaneous manifestation of celiac disease.

Clinical features ^[3][16]

• Cutaneous manifestations
  • Intensely pruritic, grouped, symmetric vesicles, papules, and erosions
    • Common sites: elbows, knees, buttocks, shoulders, and back
    • Typically heal without scarring but may cause pigmentation changes
  • Purpura and petechiae on fingers and toes
• Oral involvement (rare)
  • Vesicles, erosions, and erythematous macules on the oral mucosa
  • Dry mouth, oral pain, burning
  • Enamel defects
• Features of associated diseases
  • Clinical features of celiac disease (e.g., diarrhea, abdominal pain, bloating, symptoms of malabsorption)
  • Clinical features of Graves disease
  • Clinical features of Hashimoto thyroiditis
  • Clinical features of diabetes mellitus type 1
  • Clinical features of non-Hodgkin lymphomas
  • Clinical features of chronic lymphocytic leukemia

Dermatitis herpetiformis is considered a cutaneous manifestation of celiac disease and is associated with several autoimmune disorders and certain malignancies. ^[17]

Diagnosis ^[2][3][18]

Approach

• Consider dermatitis herpetiformis in patients with characteristic clinical features.
• Obtain perilesional and lesional punch biopsies.
• Consistent or equivocal biopsy findings: Obtain serologies.
• Assess for associated conditions (e.g., celiac disease, thyroid disease, type I diabetes mellitus).
• Refer to dermatology if there is diagnostic uncertainty.

Dermatitis herpetiformis is confirmed in patients with characteristic clinical features and positive direct immunofluorescence microscopy.

Biopsy ^[3]

• Direct immunofluorescence microscopy (gold standard)
  • Sample: perilesional punch biopsy
  • Typical finding: granular IgA deposits in the papillary dermis
• Histopathology ^[3]
  • Sample: lesional punch biopsy
  • Typical findings: papillary neutrophilic microabscesses, papillary edema, subepidermal splitting in fully developed lesions

Laboratory studies ^[2][3]

• Serology (ELISA or indirect immunofluorescence)
  • Total IgA
  • Anti-tTG IgA
  • Anti-eTG IgA (if available)
  • Anti-endomysial IgA
• Assessment of associated diseases
  • All patients: TFTs, diabetes screening
  • Additional tests depending on clinical findings (e.g., CBC and serum ferritin to assess for iron deficiency anemia)
• Genetic testing: Consider HLA haplotype genotyping (high sensitivity) to rule out dermatitis herpetiformis.

Small bowel biopsy is not part of the routine workup for dermatitis herpetiformis. ^[2][18]

Management ^[2][3]

General principles

• Multidisciplinary management (i.e., dermatologist, gastroenterologist, and dietician)
• Lifelong gluten-free diet: Remission typically takes 6–24 months. ^[3][18]
• Oral dapsone for rapid improvement of cutaneous lesions
• Adjunctive high-potency topical glucocorticoids (e.g., clobetasol) for pruritus

A lifelong gluten-free diet is the preferred long-term treatment for dermatitis herpetiformis. Oral dapsone resolves cutaneous symptoms within days.

Dapsone therapy ^[2][3]

Screen for G6PD deficiency before starting dapsone therapy, and monitor frequently for adverse drug effects (e.g., agranulocytosis, aplastic anemia, hemolytic anemia, hepatitis, methemoglobinemia).

• Baseline evaluation
  • CBC with differential and reticulocyte count
  • BMP
  • LFTs
  • Urinalysis
  • G6PD level
• Dosage: dapsone ^[3][18]
• Monitoring ^[3]
  • Clinical assessment including for peripheral neuropathy
  • CBC with differential and reticulocyte count : Stop dapsone if WBC < 4000/mm³.
  • BMP and LFTs every 3–4 months
  • Methemoglobin levels every 3 months if daily dose > 150 mg
• Discontinuation: Taper off after clinical remission with a strict gluten-free diet.

Prognosis

Dermatitis herpetiformis is a lifelong condition with a good prognosis for patients who adhere to a strict gluten-free diet.

Epidermolysis bullosa acquisita (EBA) ^[19][20]

• Definition: acquired autoimmune disease with subepidermal blistering; associated with other autoimmune diseases
• Epidemiology: onset in adulthood (usually 40–60 years of age)
• Etiology: autoantibodies targeted against type VII collagen
• Clinical features
  • Non-inflammatory form (most common): tense vesicles and blisters on extensor surfaces that are prone to trauma (e.g., hands, knees, knuckles)
  • Inflammatory form: tense bullae and vesicles similar to bullous pemphigoid
• Diagnostics
  • Direct/indirect immunofluorescence
  • ELISA: detection of IgG antibodies against type VII collagen
• Management
  • Systemic glucocorticoids, immunosuppressants
  • Avoid physical trauma to skin

Epidermolysis bullosa simplex (EBS)

• Definition: a genetic condition that causes the skin to become very fragile and blister easily in response to minor injury or friction
• Epidemiology: EBS is the most common type of EB.
• Etiology
  • Autosomal dominant inheritance
  • Mutations in keratin genes (e.g., KRT5, KRT14)
• Pathophysiology: mutations in keratin proteins → defective assembly of keratin filaments → disruption of the basal layer of keratinocytes → ↑ fragility of epithelial tissue

• Diagnostics
  • First-line: skin biopsy; (e.g., showing intraepidermal cleavage in localized EBS) ^[23]
  • Genetic testing may be considered to screen for EBS in the presence of family history.
• Management: mostly supportive, including wound care and pain management (nonopioid analgesics, e.g., acetaminophen)

• Definition: : chronic autoimmune blistering disease that affects the mucous membranes and heals with scarring
• Epidemiology: : most frequently affects elderly individuals
• Etiology
  • Deposition of autoantibodies against components of the epithelial basement membrane
  • Associated with HLA-DQB1*0301 allele
• Clinical presentation
  • Blistering lesions primarily in the oral mucosa and conjunctiva, but the nasal and genital mucosa may also be affected
  • In ⅓ of patients, skin involvement with scarring is also observed.
  • If only the conjunctiva are affected: ocular cicatricial pemphigoid
• Treatment: glucocorticoids (additional/other immunosuppressants according to severity)