Many skin diseases mainly affect the epidermis, causing the formation of a blister either in or immediately beneath the epidermis.
If the blisters are small (less than 5 mm in diameter), they are known as vesicles; if they are larger (greater than 5 mm in diameter), they are termed bullae. 

Intraepidermal blisters may form through one of three different mechanisms

Intraepidermal blisters may form as a result of excess fluid accumulation (spongiosis), separation of abnormal keratinocyte attachments (acantholysis), or because of degeneration of keratinocytes (reticular degeneration).

Spongiosis is by far the most common cause of intraepidermal blister formation, but it tends to produce much smaller blisters (vesicles) than the other mechanisms; it is the cause of blistering in many forms of acute dermatitis including atopic dermatitis, seborrhoeic dermatitis and contact dermatitis.

Acantholysis is the cause of blister formation in pemphigus vulgaris, in which large, flaccid bullae form on reddened skin, affecting the middle-aged and elderly.
Blisters arise spontaneously in buccal mucosa and skin, but can be induced by rubbing apparently normal skin (Nikolsky's sign).
The disease is thought to be immunologically mediated.

Reticular degeneration  blisters are associated with necrosis of epidermal keratinocytes, often following a phase of marked keratinocyte swelling (ballooning degeneration).
It is the pattern responsible for viral blisters such as herpes and varicella, and viral inclusions are present in the degenerating and dying keratinocytes.
It may also be seen in some forms of blistering drug reaction, e.g. erythema multiforme.

Basal blisters arise by separation of the epidermis from the basement membrane, or of epidermis and basement membrane from the underlying dermis

The exact site of separation is often difficult to determine once the blister has formed; electron microscopy of a very early separation is required if identification is to be accurate. In most cases the specific site of separation is not relevant to the diagnosis, but in the important inherited disease epidermolysis bullosa the site of separation is vital to classify the type. Accurate classification of the type is important in prognosis and genetic counselling.

The various types are:

• Epidermolysis bullosa simplex. Separation occurs above the basement membrane, through the basal cell cytoplasm. This form has a good prognosis, is inherited as an autosomal dominant condition, and the blisters heal without scarring or deformity.

• Junctional epidermolysis bullosa Separation occurs through the lamina lucida of the basement membrane, separating and damaging the hemidesmosomal attachments of the basal cell to the basement membrane. Also known as the lethal variant, it is present at birth, the child usually dying within the first few weeks of life. The defect also affects other squamous epithelia, e.g. in the oesophagus, leading to blistering in sites other than the skin.

• Dystrophic epidermolysis bullosa. Separation occurs below the basement membrane, by separation of the anchoring fibrils. Because the separation is below the basement membrane, in the upper dermis, this type leads to dermal scarring and considerable tissue 
destruction in some of the more severe forms.

The likely cause of a basal blister can be determined by the nature of associated inflammatory cells

Blisters forming around the basement membrane often do so in an area that shows infiltration by inflammatory cells, and the nature of the inflammatory cell gives a clue to the diagnosis. For example, eosinophils are characteristic of pemphigoid (a blistering disease of the elderly) and herpes gestationis (a rare but important blistering rash occurring in mid or late pregnancy), and neutrophil polymorphs are mainly seen in dermatitis herpetiformis (an itchy, blistering disease in young and middle-aged adults, which is associated with coeliac disease). Lymphocytes are seen in cases of blistering lichen planus and erythema multiforme.

Some basal blisters form in areas in which there is no inflammatory cell infiltrate; the most common example is the friction blister formed by shearing forces in non-specialized skin, e.g. ankle blisters from badly fitting shoes. Epidermolysis bullosa is another condition in which there are no inflammatory cells.

Small vessel vasculitis may be confined to the skin, or the skin can be one of many tissues affected

The most frequently involved vessels are the small capillaries, arterioles and venules in the upper dermis. Vasculitic damage to the walls leads to extravasation of red cells into the upper dermis, producing the lesions known as petechiae (when minute) or purpura (when larger). Some lesions may be slightly raised and nodular (palpable purpura); the lesions may be widespread, but the lower limb (particularly the area below the knee) is by far the most common site. 

The most common causes of a vasculitic rash of this type are drug reaction, systemic connective tissue disease (e.g. SLE), and bacteraemia or septicaemia (particularly acute meningococcal type).

Although the skin lesion is the most obvious manifestation, there may be evidence of other system involvement, e.g. joint and abdominal symptoms in Henoch،Sch÷nlein purpura.

When larger blood vessels are involved, the vasculitis occurs in the mid and deep dermis or sub-cutis. Larger, deeper, ill-defined nodules develop, again commonly on the lower limb. The most common cause is polyarteritis nodosa.
Some vasculitic lesions in the lower limb lead to necrosis of epidermis and dermis, producing an ulcer that is characterized by a raised, purplish edge.

Most acute purpuric vasculitic lesions of the skin show destruction of the vessel wall, with an associated neutrophil polymorph infiltrate (neutrophilic or leukocytoclastic vasculitis), occasionally with fibrinoid necrosis of the vessel wall. Sometimes the infiltrate in the vessel wall is largely composed of lymphocytes (lymphocytic vasculitis) without fibrinoid necrosis. This pattern shows less red-cell extravasation, and purpura is not such an important clinical feature; often the lesion appears to be a localized area of erythema. Lymphocytic vasculitis is particularly seen in association with systemic connective tissue disease (e.g. SLE, rheumatoid arthritis), and as a drug reaction. 

Many skin lesions are iatrogenic, due to ingested drugs

Skin lesions of this nature are becoming increasingly common and show a wide variation in appearance, pattern and duration. The most common pattern is a {\B toxic erythema,} clinically and histologically identical to that seen as an indirect effect of virus infection.

Skin reactions to drugs can mimic almost any other type of inflammatory skin disease. Common patterns are:

• Lichenoid drug eruptions, resembling lichen planus both clinically and histologically.

• Vasculitic eruptions, usually a small-vessel neutrophilic vasculitis in the upper dermis, producing purpura.

• Urticarial eruptions, producing blotchy, raised, itchy rashes.

• Blistering and exfoliating eruptions, particularly erythema multiforme and toxic epidermal necrolysis. The latter is the most severe, and often fatal, drug reaction in the skin, leading to extensive shedding of epidermis, together with severe metabolic disorder.

• Erythema nodosum, a characteristic deep dermal and subcutaneous reaction that produces firm, reddish purple nodules, usually on the legs 

In general, skin rashes due to drugs develop at least a week after first exposure, improving within 3-4 days of stopping the drug; the rash recurs within 20 days of re-exposure. However, certain drug rashes persist for a very long time after the drug is stopped, e.g. the extensive erythematous rash following ingestion of captopril and enalapril.

Typical erythema nodosum on the shins (in this case the result of an adverse reaction to sulphonamide therapy).

In this case the erythema multiforme was due to an adverse reaction to antibiotics.

Many systemic diseases have cutaneous manifestations

Many systemic diseases have skin lesions as part of their general picture, and the first manifestation of disease may be the skin lesions. The most important group are the systemic autoimmune diseases such as SLE and systemic sclerosis. These diseases are dealt with in more detail in multisystem diseases, and the skin lesions are discussed there. 

Other systemic diseases in which there are important cutaneous manifestations are diabetes mellitus and sarcoidosis. In diabetes mellitus some patients develop red or yellowish, shiny, depressed plaques on the leg, due to degeneration of dermal collagen, known as necrobiosis lipoidica.

In sarcoidosis, cutaneous sarcoid granulomas are very common and can have many different clinical patterns, although the presence of non-caseating giant-cell granulomas is common to them all. Patients with sarcoidosis may also present with, or develop, erythema nodosum.
Internal malignant disease may be associated with the development of a range of skin lesions (such as dermatomyositis), many of which are bizarre both clinically and histologically.