Chapter 9 Bullous diseases

Vesicles and bullae  accumulations of fluid within or under the epidermis. Causes: Genetic Causes: – Epidermolysis Bullosa – Ichthyosis Immunological causes: – Pemphigus – Bullous Pemphigoid Other Causes: Infections (Bacterial, Viral) Diabetic Bulla Frictional Drugs Insect Bites Edema Blisters

Subcorneal blisters: – Just beneath the stratum corneum – Have the thinner roofs. – Rupture easily & leave an oozing denuded surface Intra-epidermal blisters: – Within the prickle cell layer of the epidermis – Have thin roofs – Rupture easily & leave an oozing denuded surface Subepidermal blisters: – Between the dermis & epidermis – Their roofs are relatively thick – Tend to be tense – May contain blood

Diagnosis Morphology or distribution of a bullous eruption – Herpes simplex or zoster History – Cold or thermal injury, or in an acute contact dermatitis Biopsy to show the level of blisters

The pemphigus family Severe & life-threatening 2 main types 1.Pemphigus vulgaris Most common (75% of cases) Pemphigus vegetans (rare variant of pemphigus vulgaris). 2.Superficial pemphigus, also has 2 variants: Generalized foliaceus type Localized erythematosus type – Paraneoplastic pemphigus Rare With severe mucosal erosions Associated with a neoplasm (thymoma, Castleman’s tumour or lymphoma). A few drugs can trigger a pemphigus-like reaction, but abs are seldom found, like penicillamine

Cause Autoimmune diseases IgG Abs bind to Ag within the epidermis. The main antigens are – Desmoglein 1 in superficial pemphigus – Desmoglein 3 in pemphigus vulgaris Both are cell-adhesion molecules of the cadherin family found in desmosomes. The Ag–Ab reaction interferes with adhesion  acantholysis Pemphigus vulgaris is particularly common in – Ashkenazi Jews – People of Mediterranean or Indian origin There is linkage between it and certain HLA class II alleles.

Presentation Pemphigus vulgaris – Flaccid blisters of the skin & mouth. – The blisters rupture easily to leave – Widespread painful erosions – Most patients develop the mouth lesions first – +ve Nikolsky sign: Shearing stresses on normal skin  new erosions Vegetans variant – Heaped-up cauliflower-like weeping areas – Present in the groin and body folds Pemphigus foliaceus – Superficial blisters – Rupture so easily – The clinical picture is dominated more by weeping & crusting erosions than by blisters Rarer pemphigus erythematosus – The facial lesions are often pink, rough and scaly.

Fig. 9.2 Pemphigus vulgaris: widespread erosions that have followed blisters. Fig. 9.3 Painful sloughy mouth ulcers in pemphigus vulgaris.

Fig. 9.4 Pemphigus vegetans in the axilla, some intact blisters can be seen.

Course: The course of all forms is prolonged The mortality rate of pemphigus vulgaris is still at least 15%. Most patients suffer from – Side-effects of systemic corticosteroids (weight gain) – Lesions, which resist healing 1/3 of patients with pemphigus vulgaris will go into complete remission within 3 years. Complications: Side effects of high doses of steroids & immunosuppressive drugs may cause death Infections of all types are common (erosions). Severe oral ulcers make eating painful.

DDx: Widespread erosions – Pyoderma – Impetigo – Ecthyma – Epidermolysis bullosa Mouth ulcers – Aphthae – Behçet’s disease – Herpes simplex infection Scalp erosions – Bacterial or fungal infections Investigations: Biopsy shows – Intra-epidermal vesicles – With rounded keratinocytes floating freely within the blister cavity (acantholysis) Direct immunofluorescence of adjacent normal skin shows intercellular epidermal deposits of IgG & C3 Indirect immunofluorescence or ELISA show serum Abs The titre of these Abs guide the steroids treatment.

Treatment Treated by dermatologists Systemic steroids (prednisolone) – Up-regulates the expression of desmoglein molecules – Other effects above and beyond their anti-inflammatory ones – The dose is reduced only when new blisters stop appearing Immunosuppressive agents (azathioprine, gold salts or cyclophosphamide & mycophenylate mofetil) are often used as steroid-sparing agents Plasmapheresis and administration of IV Ig Rituximab – Humanized murine monoclonal antibody to CD20 – May knock out B cells, pre-B cells & Ab production Dapsone (allow healing) Prolonged maintenance therapy and regular follow-up after control has been achieved In superficial pemphigus, smaller doses of systemic corticosteroids are usually needed, and the use of topical corticosteroids may also help.

Fig. 9.5 Immunofluorescence (red) in bullous diseases.

Other causes of subcorneal and intra-epidermal blistering Bullous impetigo (S.aureus) Common cause of blistering in children Flaccid bullae, often contain pus Scalded skin syndrome (S.aureus) Painful and red skin Peels like a scald The toxin affect the same cadherin of P.foliaceuse Miliaria crystallina Occurs after a fever or heavy exertion Sweat accumulates under the S.corneum  uniformly vesicles without underlying redness. Vesicles look like droplets of water lying on the surface The skin is dry to the touch. The disorder is self-limiting

Subcorneal pustular dermatosis Small groups of pustules rather than vesicles Like vesico-pustules of chickenpox Oral dapsone suppress it Many patients have IgA Abs to intercellular epithelial antigens. Acute dermatitis Severe acute eczema, especially of the contact allergic type History of contact with plants Causes: Plants such as poison ivy, poison oak or primula Varied size of vesicles Close grouping Asymmetry Odd configurations (linear, square, rectilinear) Intense Itch

Pompholyx Very common Cause is not known Highly itchy Small eczematous vesicles Occur along the sides of the fingers, palms & soles Viral infections Herpes simplex and zoster  vesicles Blisters  destroying epithelial cells Transient acantholytic dermatosis (Grover’s disease) Cause is not known Middle-aged males May persistent despite its name. Itchy vesicles Sun-damaged skin of the trunk

The pemphigoid family Autoimmune disease Serum from about 70% of patients contains Abs that bind in vitro to normal skin at the BM zone the titre does not correlate with clinical disease activity. The IgG Abs bind to 2 main Ag: – Most commonly to BP230 (which anchors keratin intermediate filaments to the hemidesmosome) – Less often to BP180 (a transmembrane molecule with one end within the hemidesmosome and the other bound to the lamina lucida). Complement is then activated Eosinophils  epidermis separate from the dermis

Presentation Mainly affecting the elderly No precipitating factors (but rarely UV light or radiation therapy) Chronic itchy Smooth, itching red plaques in which tense vesicles & bullae form Occasionally they arise from normal skin. The flexures are often affected, but MM usually are not -ve Nikolsky test The disorder would not be fatal High risk include – Old age – Need for high steroid dosage – Low serum albumin levels Fig. 9.6 Blisters of pemphigoid arise as tense yellow bullae, often on a pink, urticated base.

Course: Usually self-limiting Complications: Discomfort Loss of fluid from ruptured bullae Side effects of systemic steroids and immunosuppressive agents DDx: Clinical diagnosis proves correct most of the time. Epidermolysis bullosa acquisita Bullous lupus erythematosus Dermatitis herpetiformis Pemphigoid gestationis Bullous erythema multiforme Linear IgA bullous disease Immunofluorescence helps to separate it from these

Investigations: Direct immunofluorescence shows a linear band of IgG and C3 along the BM zone. Indirect immunofluorescence  IgG antibodies that react with the BM in some 70% of patients Most patients have peripheral blood eosinophilia. Treatment: Potent topical steroids alone (mild) Prednisolone (acute phase) Immunosuppressive agents (azathioprine) Tetracyclines & niacinamide help some patients for unknown reasons Fig. 9.7 Indirect immunofluorescence using serum from a patient with pemphigoid, showing basement zone immunofluorescence.

Pemphigoid gestationis (herpes gestationis) Occurring in pregnancy or in the presence of a hydatidiform mole or a choriocarcinoma. Most patients have linear deposits of C3 & IgG (detected less often) along the BM zone The condition usually remits after the birth but may return in future pregnancies. Treatment is with systemic steroids. Oral contraceptives should be avoided, because their hormones may precipitate the disease.

Cicatricial pemphigoid Autoimmune skin disease Showing IgG and C3 deposition at the BM zone. The antigens are – Often as in pemphigoid, but other – Laminin 5 (in anchoring filaments). Differs from pemphigoid in that – Blisters and ulcers occur mainly on mucous membranes (conjunctivae, mouth & genital tract). – Bullae on the skin itself are uncommon. – Lesions heal with scarring  may cause blindness (esp. palpebral conjunctivae) The condition tends to persist Treatment is relatively ineffective Good eye hygiene & removal of ingrowing eyelashes are important.

Linear IgA bullous disease Affects children as well as adults. Linear deposits of IgA & C3 at the BM zone. IgG is sometimes also found. Blisters arise on urticarial plaques More often are grouped & on extensor surfaces, so-called string of pearls sign: is the presence of blistering around the rim of polycyclic urticarial plaques. The conjunctivae may be involved. Responds well to oral dapsone. Fig. 9.8 Long-standing cicatricial pemphigoid. Adhesions are now forming between the upper & lower eyelids.

Acquired epidermolysis bullosa (mechanobullos) Look like pemphigoid 2 important extra features: 1.Many of the blisters arise in response to trauma on otherwise normal skin; 2.Milia are a feature of healing lesions. The target of the autoantibodies is type VII collagen in anchoring fibrils. The antigen lies on the dermal side of the lamina densa, while in pemphigoid lie on the epidermal side (demonstrated by IF) Salt-split technique: the BM is split at the lamina densa by incubating skin in a saline solution. The condition responds poorly to systemic corticosteroids or immunosuppressive agents.

Dermatitis herpetiformis Very itchy chronic subepidermal vesicular disease Herpetiformis  means erupt in groups Caused by Gluten-sensitive enteropathy (sprue, adult coeliac disease) A range of antibodies directed against: – Tissue transglutaminase – Reticulin – Gliadin – Endomysium – a component of smooth muscle. In a minority of patients with gluten-sensitive enteropathy, IgA Abs against tissue transglutaminase crossreact with antigens of epidermal transglutaminase  granular deposits of IgA & then C3 in the superficial dermis under the BM zone  induce a neutrophil-rich inflammation, which separates the epidermis from the dermis. The IgA deposits in skin clear slowly after gluten-free diet. There is a strong association with HLA-DR3 & HLA-DQw2.

Presentation Extremely itchy Grouped vesicles Urticated papules over the elbows, knees, buttocks & shoulders. They are often broken by scratching before they reach any size. A typical patient therefore shows only grouped excoriations. Sometimes a 2 0 eczematous dermatitis develops from fierce scratching. Dermatitis comes from scratching Herpetiformis comes from grouping of vesicles and crusts. Course: Lasts for decades unless patients avoid gluten entirely. Complications: Diarrhoea & Abdominal pain Anaemia Malabsorption (rarely). Small bowel lymphomas Associated with other autoimmune diseases (mostly thyroid).

Fig. 9.9 The typical small tense grouped itchy blisters of dermatitis herpetiformis. Fig The itchy blisters of dermatitis herpetiformis favour the points of the elbows and knees, where they are quickly destroyed by scratching

DDx : Scabies Excoriated eczema Insect bites Neurodermatitis Investigations : Biopsy of vesicles before it is scratched away – Subepidermal blister – Neutrophils packing the adjacent dermal papillae. Direct immunofluorescence shows granular deposits of IgA & C3 in the dermal papillae & superficial dermis. Serum antibody tests – Anti-endomysial antibodies – Tissue transglutaminase Small bowel biopsy is no longer recommended as routine Tests for malabsorption are seldom needed.

Treatment Gluten-free diet – Supervised by a dietitian. – Monitored using the titer of antibodies. – The bowel changes revert quickly to normal – But IgA deposits remain longer in the skin Combination between diet with dapsone or sulfapyridine at the start, although both can cause: – Severe rashes – Haemolytic anaemia (especially in G6PD) – Leucopenia – Thrombocytopenia – Methaemoglobinaemia – Peripheral neuropathy. Regular blood checks are therefore necessary.22

Other causes of subepidermal blisters Porphyria cutanea tarda Flaccid bullae and erosions Occur on sunlight exposed areas as the backs of the hands. Blisters in diabetes and renal disease A few diabetics develop unexplained blisters on their legs or feet. The backs of the hands of patients with chronic renal failure may show changes rather like those of porphyria cutanea tarda (pseudoporphyria). Furosemide (frusemide) can contribute to blister formation. Bullous lupus erythematosus Vesicles and bullae (severe active SLE) Bullae respond to dapsone; but non-cutaneous manifestations not. Bullous erythema multiforme In the Stevens–Johnson syndrome form

Toxic epidermal necrolysis (Lyell’s disease) Caused by: – Drug reaction Sulphonamides Lamotrigine Barbiturates Carbamazepine Allopurinol – Graft-vs.-host disease There is an increased incidence in patients with AIDs. Fig The burn-like appearance of toxic epidermal necrolysis.

Presentation: Red and intensely painful skin Then begins to come off in sheets like a scald. This leaves an eroded painful glistening surface. +ve Nikolsky’s sign. The MM may be affected (mouth, eyes & bronchial tree). Course Usually clears if the patient lives & the drug is stopped. Complications: Fatal (skin emergency) Infection Loss of fluids & electrolytes are life-threatening Painful denuded skin surfaces make life a misery. Corneal scarring may remain when the acute episode has settled.

DDx: Staphylococcal scalded skin syndrome – Only the stratum corneum is lost. – Seen in infancy or early childhood. – Histology differentiates the two. Pemphigus – Starts more slowly – More localized. Severe graft-vs.-host reactions can also cause this syndrome. Some believe that toxic epidermal necrolysis can evolve from Stevens–Johnson syndrome because some patients have the clinical features of both. Investigations: Biopsy Subepidermal split Necrotic epidermis Frozen section

Treatment Drug must be stopped Symptomatic management – Intensive nursing care and medical support including Central venous lines IV fluids and electrolytes. – Air suspension beds increase comfort. IV IgG Ciclosporin (decreased mortality rates). Plasmapheresis may remove – Triggering drugs – Inflammatory mediators.

Epidermolysis bullosa (mechanobullous disorders) 5 main types, characterized by – Inherited tendency to develop blisters after minimal trauma – At different levels in the skin. – The more severe types have a catastrophic impact on life. – Acquired epidermolysis bullosa is not inherited

Fig Levels of blister formation in epidermolysis bullosa at the dermo-epidermal junction.

Simple epidermolysis bullosa Several subtypes – Weber–Cockayne (mainly hands and feet) – Dowling–Meara (herpetiform blisters on the trunk). Most are inherited as AD Caused by abnormalities in genes responsible for production of the paired keratins (K5 and K14) expressed in basal keratinocytes (see Fig. 2.4). Most common types on chromosomes 17 and 12. Blisters form within or just above thethe basal cell layers So tend to heal without scarring. Involvement of nails and mucosae is frequent but subtle. The problems are made worse by sweating and ill-fitting shoes. Blistering can be minimized by – Avoiding trauma – Wearing soft wellfitting shoes – Using foot powder. Large blisters should be pricked with a sterile needle and dressed. Their roofs should not be removed. Local antibiotics may be needed.

Junctional epidermolysis bullosa The separation occurs in the lamina lucida of the BM Usually following mutations in the genes responsible for laminin formation This rare and often lethal condition is evident at birth. The newborn child has large raw areas and flaccid blisters, which are slow to heal. The perioral and perianal skin is usually involved, as are the nails and oral mucous membrane. There is no effective systemic treatment. Hopes for the future include adding the normal gene to epidermal stem cells, and then layering these onto the denuded skin.

Fig Junctional epidermolysis bullosa: minor trauma has caused large blisters and erosions which will heal slowly or not at all.

AD dystrophic epidermolysis bullosa Blisters appear in late infancy. Most common on friction sites (knees, elbows and fingers) Healing with scarring and milia formation. The nails may be deformed or even lost. The mouth is not affected. The only treatment is to avoid trauma and to dress the blistered areas.

AR dystrophic epidermolysis bullosa Tragic form, Blisters start in infancy. May be filled with blood. Heal with scarring, which can be so severe that – The nails are lost – Webs form between the digits. The hands & feet may become useless balls, having lost all fingers & toes. The teeth, mouth and upper part of the oesophagus are all affected; Oesophageal strictures may form. Squamous cell carcinomas of the skin are a late complication.

Fig Autosomal recessive dystrophic epidermolysis bullosa: note large blood-filled blister. Scarring has led to fixed deformity of the fingers and loss of nails.

Treatment Treatment is unsatisfactory. Phenytoin, which reduces the raised dermal collagenase levels found in this variant Systemic steroids are disappointing. It is especially important to minimize trauma Maintain nutrition Prevent – Contractures and web formation between the digits – Combat anaemia – Secondary infection. Referral to centres with expertise in management of these patients is strongly recommended.