Blistering Diseases of the Skin

Pemphigus – autoimmune blistering disease, more common in the middle aged

IgG antibodies target self desmosomes leading to desmosome destruction and cell disadhesion
Release of protease and activation of complement by antibody complexes are also proposed mechanisms
Treatment: systemic corticosteroids along with immunosuppressive agents

Direct Immunofluorescence shows IgG deposited on the cell surface of keratinocytes. Many patients may also have the complement component C3 deposited on the keratinocyte surface as well.

Indirect Immunofluorescence – (e.g. testing circulating antibodies) the majority of patients will have circulating IgG antibodies that will bind keratinocytes. The titer of antibody correlates with the severity of the disease.

Pemphigus vulgaris (predominant form)

Flaccid (loose) blisters (bullae) on scalp, face, axilla, groin, and oral cavity (oral mucous membrane involvement in the majority of patients). Blisters are fragile and break easily leaving large confluent erosions.

Histologically, suprabasal acantholytic blisters.

IgG’s target a 130KD molecule in the Pemphigus complex that corresponds to desmoglein III (a component of desmosomes; desmosomes hold keratinocytes together) linked to plakoglobin

A severe disease. Before corticosteroids patients died from losing their skin. Currently ~ 10% mortality.

Pemphigus foliaceus

Superficial blister that is easily broken, manifests as shallow erosions with erythema, scaling, and crusting. Lesions on face, scalp, upper chest and back

Mucous membrane involvement is almost never seen.

Histologically, subcorneal acantholytic blister.

IgG’s target a 160KD molecule, desmoglein I (also a component of desmosomes) linked to plakoglobin

More chronic than pemphigus vulgaris with a lower mortality rate.

Bullous Pemphigoid – an autoimmune blistering disease, more common in the elderly.

Primary lesion is a tense blister occurring on normal or erythematous skin
Lesions occur most commonly on the flexor surfaces of the arms, legs, abdomen, and groin

Oral mucous membrane involvement in 30% of patients.

Histologically, a subepidermal blister (at dermal/epidermal junction) with eosinophil predominant infiltrate.
Low mortality even without treatment. Usually lasts less than 5 years.

Direct Immunofluorescence – Linear IgG and C3 deposits at epidermal basement memb zone.

Indirect Immunofluorescence – circulating IgG antibodies directed against the epidermal basement membrane zone.
The circulating antibody reacts with antigen present in the hemidemosomes
The actual blister develops at the level of the epidermal basement membrane (lamina lucida) that seperates the underlying lamina densa from the plasma membrane of the basal cells
Two components of hemidesmosomes are now recognized as bullous pemphigoid antigens 1 and 2

It is the binding of auto-antibodies to these antigen which results in the fixation of complement and the subsequent tissue injury at this site through locally recruited eosinophils and neutrophils

The result is destruction of the dermal-epidermal junction with subepidermal blister formation.

Treatment: systemic corticosteroids usually required. Immunosuppresives used if corticosteroids are contraindicated.

Epidermolysis Bullosa Acquisita – an autoimmune blistering disease most common in middle age.

Acrally distributed blisters that heal with scarring and milia formation. (at sites of pressure, rubbing, trauma)
Histologically, a subepidermal blister
Either Inflammatory, moderate cellular infiltrate of lymphocytes, neutrophils, and eosinophils, or Noninflammatory – little or no cellular infiltrate

Direct Immunofluorescence – All patients have linear deposits of IgG at the basement membrane zone

Autoantibodies directed against the epidermis bullosa acquisita antigen (which is the carboxy domain of type VII procollagen)

Indirect Immunofluorescence – about 50% of patients have circulating IgG antibody directed at the basement membrane zone.

Circulating antibodies may bind to the antigen in the BM zone forming a complement activating immune complex
This complex would initiate an inflammatory response and eventual destruction of the BM zone.

Treatment: Most patients respond poorly to therapy. Corticosteroids and immunosuppressive agents are used often.

Dermatitis Herpetiformis – a chronic blistering disease most common in young adults.

Severe pruritis is a common presentation; supposedly the only dermatological condition (other than scabies infestation) that can cause itching that wakes from sleep
Primary lesions are grouped vesicles on an erythematous base – patients usually excoriate them; erosions and crusts are often major clinical findings.
Most common sites; symmetric distribution over elbows, knees, scalp, neck, and buttock.
Subclinical Gluten-sensitive enteropathy is strongly associated, with 80% of patients having improvement when on a gluten free diet. Also associated are the HLA-B8 and HLA-DRW3 haplotypes and thyroid disease.
Histologically, subepidermal cleft formation with neutrophilic microabsesses found at the dermal papillae/epidermal junction (D/E junction).

Direct Immunofluorescence – all patients have IgA deposited in microabsesses at the D/E junction. Some also have C3 deposits

Indirect Immunofluorescence – is not helpful.
There are two hypothesis to explain the pathogenesis of this disease:

(1) Cutaneous IgA is produced in the gut as a response to a dietary Ag, which then cross reacts with the skin of patients with dermatitis herpetiformis.
(2) IgA produced in the gut binds antigen and is then deposited in the skin as an antibody-antigen complex.

Treatment – Gluten free diet and/or Dapsone (a sulfa drug) for life-long treatment of this chronic disease.