Chapter 22: Immunobullous Diseases

The immunobullous diseases are uncommon chronic skin disorders caused by autoantibodies directed against various cutaneous proteins. These disorders primarily occur in older adults and can cause significant discomfort in affected patients and can even be fatal in the case of pemphigus. Patients with immunobullous diseases often have significant quality of life issues in questions pertaining to physical, emotional, and mental health.¹ Skin biopsies for routine histology and immunofluorescence are needed to confirm the diagnosis.

Introduction

Bullous pemphigoid is an uncommon blistering eruption that primary affects elderly patients. The mean age of onset ranges from 68 to 82 years of age.

The incidence is estimated to be between 4.5 and 14 new cases per million per year. It is more common in women.²

Pathophysiology

Bullous pemphigoid is an autoimmune disease associated with the production of autoantibodies targeting the basement membrane. The basement membrane is important for the adhesion of the epidermis to the dermis, and so when targeted, leads to a separation (blister) in this space. The antigens themselves are parts of the hemidesmosomes of the basal cells. The targets are BP 180 and BP 230.³ BP 180 is a transmembrane protein in basal cells, which is the extracellular noncollagenous domain of type 17 collagen. BP 230 is a cytoplasmic plakin family protein of the hemidesmosome. There is evidence for the pathogenic roles of these autoantibodies in this disease, especially against BP 180.

Clinical Presentation

History

Despite being labeled a blistering disorder, many patients will present initially with prebullous pemphigoid which presents as a pruritic urticarial rash without blisters.^4,5 The pruritus can be severe. When blisters develop, they are tense blisters because they are forming between the dermis and epidermis and do not easily rupture.

Physical Examination

In the prebullous phase, the patient has pruritic urticarial plaques. In the bullous phase, the patient develops blisters. Most commonly the tense blisters are bilateral, symmetric, and on the trunk and proximal flexural extremities (Figure 22-1). The blisters may or may not have surrounding erythema. Mucosa can be involved, but usually in less than 20% of patients.

Laboratory Findings

• Histopathology of a skin biopsy from the edge of an intact bulla shows a subepidermal bulla with a dermal eosinophil inflammatory component (Figure 22-2).

• Direct immunofluorescence of a skin biopsy taken of normal skin near a bulla shows a linear deposition of C3 and IgG along the basement membrane zone (Figure 22-3).

• Indirect immunofluorescence of the blood shows linear IgG along the blister roof on salt-split skin (Many patients do not have detectable circulating antibodies).

• An enzyme-linked immunosorbant assay (ELISA) for BP 180 and BP 230 is available.

Diagnosis

The key diagnostic features of pemphigoid are tense, pruritic vesicles and bullae.

Differential Diagnosis

In the prebullous phase

• ✓ Urticaria: The individual lesions of urticaria should last less than 24 hours.

• ✓ Drug rash: Usually truncal with macular papular erythema.

• ✓ Dermatitis: This eruption is usually eczematous.

• ✓ Other: primary pruritus.

In the bullous phase

• ✓ Other bullous disorders (Table 22-1).

• ✓ Other: epidermolysis bullosa acquisita, dermatitis herpetiformis, bullous drug reaction, bullous tinea, bullous diabeticorum, coma/pressure bullae, edema.

Management

Skin biopsies for routine histopathology should be done from the edge of the blister and skin biopsies from perilesional skin should be sent for direct immunofluorescence. Blood could be sent for indirect immunofluorescence. Tense bullae can be drained with a sterile needle leaving the roof intact to act as a biologic dressing. White petrolatum can be used with nonstick dressings for any eroded areas. Bullous pemphigoid can be a chronic relapsing disease.

Indications for Consultation

Patients with bullous pemphigoid should be referred to dermatology. One-year mortality rates range from 6% in the United States to 41% in France.² Therapies include oral and topical corticosteroids, azathioprine, methotrexate, mycophenolate mofetil, and tetracycline with nicotinamide.

Patient Information

International Pemphigus and Pemphigoid Foundation: www.pemphigus.org.

Introduction

Pemphigus vulgaris is a rare blistering disease of the skin and mucous membranes, which primarily affects older patients with an median age of onset of 71 years of age.²

Pathophysiology

Pemphigus vulgaris is an autoimmune blistering disease with IgG autoantibodies directed against desmogleins 3 and 1.^4–6 Desmogleins are the desmosomal protein members belonging to the cadherin family. These proteins help the keratinocytes in the epidermis attach to each other. When these proteins are targeted, intraepidermal blisters form usually just above the basal layer.

Clinical Presentation

History

Patients will have ongoing, painful, superficial blisters or erosions of the skin and/or mucosa. Some patients will only have mucosal involvement, usually the oral cavity.

Physical Examination

Because the blister is forming in the epidermis, it is flaccid and easily ruptured (Figure 22-4). Many patients will only have crusted erosions where the blisters used to be. The blisters and erosions are usually painful. The mucosal involvement is usually the oral cavity (Figure 22-5), but may involve the pharynx, larynx, esophagus, conjunctiva, and genitals. The skin rash typically involves the head, upper trunk, and intertriginous zones. When the patient has ongoing activity of the disease, a positive Nikolsky sign may be present at the edge of a blister (Figure 23-5). A Nikolsky sign is positive when the top layers of the skin slip away from the lower layers when rubbed, leaving a moist base.

Laboratory Findings

• A skin biopsy of the edge of a blister or erosion will show suprabasilar bulla with acantholysis and minimal inflammation (Figure 22-6).^4–6

• A skin biopsy for direct immunofluorescence of normal skin next to a blister or erosion will show intercellular IgG and C3 (Figure 22-7).

• Indirect immunofluorescence of the blood will show intercellular IgG deposition on stratified squamous epithelium. The titer level will usually parallel disease activity.

• ELISA for desmogleins 3 and 1 are available and may also parallel disease activity.

Diagnosis

The key diagnostic findings of pemphigus are flaccid bullae with a positive Nikolsky sign.

Differential Diagnosis

Because the blister is superficial, other eroding diseases must be considered.

• ✓ Staph-scalded skin: Patients have sheets of exfoliating skin related to a staph producing toxin.

• ✓TEN: Clinically ill patients with significant crusting of the lips, nose, and eyes.

• ✓Other: herpetic eruptions, impetigo, IgA pemphigus, and vasculitis.

Management

A skin biopsy for routine histopathology should be done from the edge of a blister and a skin biopsy for immunofluorescence should be done from skin near a lesion. Blood for indirect immunofluorescence or ELISA should be sent. Eroded areas should be covered with white petrolatum and nonstick dressings. Culture as appropriate for superinfection.

Indications for Consultation

If left untreated this disease is fatal and must be referred to dermatology immediately or hospitalized preferably in a burn unit if the patient has widespread disease. Systemic corticosteroids are the initial drug of choice. Other treatments include azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, IVIG, plasmapheresis, and rituximab.

Patient Information

International Pemphigus and Pemphigoid Foundation: www.pemphigus.org

Introduction

Dermatitis herpetiformis is an autoimmune blistering disease, which can involve a younger subset of patients when compared to pemphigus vulgaris and bullous pemphigoid. The typical age of onset is between 30 and 40 years of age, with men more affected than women. A genetic predilection is found in families and associated HLA-DQ2 and HLA-DQ8.

Pathophysiology

Dermatitis herpetiformis is linked to celiac disease and dietary gluten. Both celiac disease and dermatitis herpetiformis have gluten-sensitive enteropathy. IgA autoantibodies are found in both conditions. In dermatitis herpetiformis, epidermal transglutaminase is the main antigen.⁷ In celiac disease, the main antigen is tissue transglutaminase. In the skin, transglutaminase is found in the dermal capillaries and the basal cells of the epidermis. Transglutaminase is a cytoplasmic calcium-dependent enzyme that catalyzes crosslinks between glutamine and lysine. Transglutaminase modifies the gliadin portion of gluten and make it an autoantigen. Protein to protein crosslinking between transglutaminase and gliadin complexes causes an intense autoantibody response. Due to the inflammation in the skin, a blister is formed in the basement membrane zone between the epidermis and dermis.

Clinical Presentation

History

The patient will usually present with excoriations and complaints of intense pruritus and may have gastrointestinal symptoms such as diarrhea and abdominal cramping.

Physical examination

Because the blister is forming between the dermis and the epidermis, it should be a tense blister. However, since this condition is so pruritic, most patients will have scratched the blister off leaving only erosions and excoriations (Figure 22-8). The eruption is classically symmetric with a distribution on the extensor surfaces of the extremities, elbows, knees, buttocks, scalp, and neck. Face and groin may also be involved, but rarely the mucosa.

Laboratory Findings

• Histopathology of a skin biopsy of an intact blister/vesicle (if it can be found) will show a subepidermal blister with neutrophils and some eosinophils in the tips of the dermal papillae (Figure 22-9).⁸

• A biopsy of perilesional skin for immunofluorescence will show granular deposits of IgA at the tips of the dermal papillae (Figure 22-10).

• Indirect immunofluorescence of the blood for antiendomysial antibodies is specific for dermatitis herpetiformis.

A total IgA level should be done before any other serological tests as selective IgA deficiency is more common in celiac patients with celiac disease and needs to be considered in the evaluation of patients with dermatitis herpetiformis. ELISA for IgA antitissue transglutaminase is available. Studies are reviewing the ELISA for IgA antiepidermal transglutaminase and this may become a very useful tool.

Diagnosis

The key diagnostic features of dermatitis herpetiformis are erosions and excoriated papules on the extensor surfaces of the extremities, elbows, knees, buttocks, scalp, and neck.

Differential Diagnosis

• ✓ Scabies: Pruritic papules on elbows, knees, body folds, volar wrists, and finger web spaces. Scabies mite are often seen in skin scrapings.

• ✓ Bullous pemphigoid: Tense bullae in a bilateral symmetric distribution.

• ✓ Other: Linear IgA bullous dermatosis, atopic dermatitis, and urticaria.

Management

A strict gluten free diet is a mainstay of therapy and consultation with a dietician is important as this diet is difficult to maintain. Even with a strict gluten free diet, the skin lesions are slow to respond.⁹ Dapsone and sulfapyridine rapidly control the skin lesions.⁸ Systemic corticosteroids are not helpful in this disease. Antihistamines may help with pruritus.

Dermatitis herpetiformis is associated with other immune-mediated conditions and screening studies for thyroid disease, diabetes, and connective tissue disease should be considered.^7,10 If clinical signs of gastrointestinal disease or non-Hodgkin lymphoma are present, a work-up must be done as these diseases are associated with dermatitis herpetiformis. Patients with gastrointestinal disease are at risk for splenic atrophy and a blood smear should be done to detect Howell-Jolly bodies and other abnormalities.

Indications for Consultation

Dermatitis herpetiformis is a complex blistering disorder that can be difficult to diagnosis. Patients should be referred to dermatology for diagnosis and management.

Patient Information

Celiac Disease Foundation: www.celiac.org