Bullous Dermatoses (Blisters and Bullae)

This is a range of conditions that are characterised by the appearance of blisters or bullae.

Pemphigus, pemphigoid and dermatitis herpetiformis all have their own articles. They are mentioned here but in less detail.

Hereditary epidermolysis bullosa (EB) is a group of rare inherited conditions with disturbance of the coherence of the epidermis causing blisters to form after trauma. It varies from very mild to severely mutilating and even lethal. OMIM lists a large number of such conditions including epidermolysis bullosa letalis,¹ generalised atrophic benign EB,² EB of hands and feet and a number of atrophic forms of EB. The severity is reflected in the name. Some are associated with other conditions too, including congenital deafness and limb girdle muscular dystrophy.

Classification is usually according to the location of blisters within the layers of the skin. The onset is usually in infancy, which is a very vulnerable time when the bullae may be complicated by infection, septicaemia and death. The very mildest forms may not present until adulthood.

The recessively inherited dystrophic epidermolyis bullosa (RDEB) is especially likely to lead to squamous cell carcinoma of skin and death from metastases, usually between the ages of 15 and 35. Dystrophic and junctional EB do not seem to have much adverse effect on life expectancy.

• Epidermolysis bullosa simplex (EBS) produces an intra-epidermal blistering caused by trauma. The commonest form of generalised EBS has its onset at birth or early infancy. Blisters affect sites subject to injury, especially feet, hands, elbows and knees. Blisters heal rapidly with minimal scarring.
• Localised EBS has an onset in childhood or later. This is the commonest form of EB. It presents with thick walled blisters on the feet and hands after heavy exercise. There is excessive sweating of palms and soles. Secondary infection can occur.
• Junctional EBS causes blisters that occur in the basement membrane zone. There are three main sub-types:
  • JEB gravis is generalised blistering at birth. The most serious form is epidermolysis bullosa letalis that has an 87% mortality rate in the first year.
  • JEB mitis gives moderate to severe blistering at birth but they usually survive infancy and the condition improves as they get older.
  • Generalised atrophic benign epidermolysis bullosa (GABEB) presents at birth as generalised blistering and erosions on extremities, trunk, face and scalp. They usually survive to adulthood but blistering continues in traumatised areas. Hypoplastic enamel predisposes to tooth decay.³ Nail dystrophy and alopecia are common.
• Dystrophic EB shows blistering occuring below the basal lamina and healing is accompanied by scarring.

Management

There is no specific treatment for EB. Steroids are of no value and could not be used long term. Careful wound management, infection control and adequate nutrition are important.⁴ Loss of skin and often poor absorption from the gut can lead to iron and folate deficiency, along with the extra stresses of recurrent infection. Genetic counselling is indicated and prenatal diagnosis is possible. These diseases may eventually be a suitable target for gene therapy.

Familial benign pemphigus is listed as benign chronic pemphigus or Hailey-Hailey disease in OMIM.⁵ It is an autosomal dominant of limited penetrance. It usually presents in late teens or early adulthood but it may not present until the 30s or 40s. It presents as an inflamed erosive, oozing condition with crusts on the nape of the neck, axillae, under the breasts, inguinal folds and scrotum with cracks and fissures. There may be longitudinal white bands on the nails in 70%.⁶ Diagnosis is confirmed by histology.

Management

The natural course of the disease is one of variable severity. Aluminium acetate compresses (1 in 40 dilution) are soothing. Mild steroid creams are beneficial. Topical antibiotics are of value but for more severe episodes systemic antibiotics are required and erythromycin and tetracycline are favoured. Bacterial culture can guide treatment. In severe and refractory case treatments that have been used include dapsone, steroids, retinoids, methotrexate and topical tacrolimus. Difficult cases have also responded to photodynamic therapy with 5-aminolevulinic acid. Patients should avoid being overweight to avoid rubbing skin and should wear soft loose clothing that keeps them cool.

Pemphigus vulgaris is a serious, autoimmune disease affecting the skin and mucous membranes. It is derived from the Greek word pemphix meaning bubble or blister. A number of variations of the disease have been described including drug induced pemphigus and IgA pemphigus. The best known drugs to induce it are penicillamine and captopril but rifampicin and emotional stress have been implicated. Pemphigus is a rare disease with an incidence between 0.5 and 3 cases per 100,000.

Presentation

• Age of onset is usually between 40 and 60 years but it can occur much younger, especially in Indian patients.⁷
• It presents with oral lesions in 50 to 70% and almost all have some mucosal lesions. Mucosal lesions may be the only feature but on average they precede skin lesions by 5 months.
• Blisters in the mouth are rarely intact. They are irregular, ill-defined and painful and slow to heal. Extensive lesions in the mouth may make eating and drinking very uncomfortable.
• Other mucous membranes to be involved include the conjunctiva, oesophagus, labia, vagina, cervix, penis, urethra, and anus.
• The lesion on the skin is a flaccid blister that usually appears on previously normal skin although sometimes it was erythematous before the appearance. There is often pain but not usually pruritus.
• Skin lesions are commonest on the scalp, face, chest, axillae, groin, umbilicus and in patients confined to bed, the back.
• Lesions in skin folds may develop vegetating granulations. .
• The Nikolsky sign is not specific for pemphigus but can occur with other blistering diseases. Firm, sliding pressure with a finger separates the underlying epidermis and produces an erosion. The Asboe-Hansen sign is that lateral pressure on the edge of a blister may spread the blister into clinically unaffected skin.
• Diagnosis is confirmed by histology of a biopsy with immunofluoresence of a fresh specimen. There is marked difference between experts in terms of diagnosis and treatment of this condition.⁸

Management

The disease was fatal before the advent of steroids and still has a 5 to 15% mortality rate. Most of this occurs in the first 2 years and deaths after 5 years are uncommon. Steroids are the main aspect of treatment but immunosuppressive drugs have been added including azathioprine,⁹ methotrexate and cyclophosphamide. Baths, wet dressings, topical steroids, antibiotics and IV fluids may all have a place. This is a potentially life threatening disease with a mortality between 5 and 15%. It is more dangerous in older patients and those with more extensive disease. Treatment contributes to morbidity. In particular, steroids can mask the signs of severe infection.¹⁰ The British Association of Dermatologists have developed guidelines for the management of pemphigus vulgaris.¹¹

This is a rare bullous disease of pregnancy that affects about 1 person in 2 million per year. It is autoimmune in origin.

Presentation

• Lesions may appear any time during pregnancy, but they most commonly develop during the second and third trimesters.¹²
• There is sudden onset of extremely pruritic urticarial papules and blisters on the abdomen and trunk. Pruritis is severe and unrelenting.
• Lesions start with erythematous urticarial patches and plaques around the umbilicus. They progress to tense vesicles and blisters. Sometimes urticarial plaques may never develop blisters. They differ from true urticaria because they are relatively fixed in nature.
• The rash spreads peripherally, often sparing the face, palms, and soles. Mucosal lesions occur in less than 20% of cases.
• Symptoms usually subside at delivery but dramatic flares can occur immediately post partum.
• It usually resolves within weeks to months after delivery and possibly quicker with breastfeeding. Disease persisting for years after delivery has been reported.
• It may recur with the resumption of menstruation, use of oral contraception, and subsequent pregnancies. This is unaffected by a change in partner.¹²

Medication is kept to a minimum in view of the pregnancy. Corticosteroids and antihistamines are used.

Outcome

• There is no increased maternal or child mortality
• There is a greater prevalence of premature or small for dates babies
• 5-10% of infants may have transient cutaneous involvement that clears as the maternal antibodies wane
• Patients are more susceptible to other autoimmune diseases, including Hashimoto's thyroiditis, Graves' disease, and pernicious anemia.

Bullous pemphigoid is a rare, chronic, autoimmune, subepidermal, blistering skin disease that rarely involves mucous membranes. It mainly affects people aged over 60 years with an average age of onset is 65. It has been reported to follow chronic skin diseases such as lichen planus and psoriasis. It can also follow ultraviolet and x-ray irradiation, vaccination in children¹³ and after some drugs. The most noted are furosemide, captopril, ibuprofen and other NSAIDs and penicillamine.

• It usually starts with a prodromal urticarial or papular lesion that heralds, by weeks or months, the sudden appearance of bullae that are large, tense, oval and contain serum or blood stained fluid. They usually collapse and form a crust.
• They are mainly in the axillae, medial aspect of thighs, groin, abdomen, flexor aspects of forearms and lower legs.
• Biopsy and direct immunofluoresence usually confirms the diagnosis.

Management

Oral prednisolone is often augmented by immunosuppression, most often with azathioprine. Milder cases may respond to dapsone. Often permanent remission requires no further therapy. Local recurrences may be controlled with strong topical steroids sometimes. A Cochrane review¹⁴ concluded that strong topical steroids are effective and safe. Oral prednisolone should not exceed a dose of 0.75mg per kg per day and often rather lower doses would suffice with fewer adverse effects.

Dermatitis herpetiformis is a chronic, recurrent disorder associated with a gluten sensitive enteropathy as is coeliac disease but it affects an older age group and 90% have no gastro-intestinal symptoms. Dermatitis herpetiformis has its own article that is much more extensive.

Presentation

• Skin lesions are extremely itchy and groups of vesicles appear most frequently on extensor surfaces. There is burning, stinging, and intense pruritus, often before new lesions appear.
• Erythematous vesicles appear in a typical pattern. They are symmetrical over the extensor surfaces including elbows, knees, buttocks, shoulders, and the nuchal area.
• Erythematous papules and plaques of urticaria occur less frequently whilst bullae are rare.
• There may be crusts or erosions if there are no vesicles.
• Patients often complain of stinging or burning of the skin before the appearance of new lesions.
• Oral mucosa, palms and soles are rarely involved.

Management

• About 80% will show improvement with a gluten-free diet and some will be able to stop medication but it may take 6 to 12 months before this can be done.
• Dapsone is usually first line with sulfapyridine for patients unable to tolerate dapsone. Improvement with dapsone may be dramatic with benefit apparent within a few hours. No new lesions form for up to 2 days after a dose of dapsone but it does not improve the pathology of the intestinal mucosa.