In diagnosing a cutaneous eruption that may be an adverse drug reaction it is important to decide whether the eruption is due to the disease, primarily due to the drug, or due possibly to an interaction between the disease and the drug. Cutaneous reactions frequently occur when patients are receiving a number of drugs, and thus etiological relationship may be difficult to assess. When patients take drugs for a febrile disorder that ultimately proves to be an infection, an eruption may be due to the underlying disorder or the prescribed drug. Some cutaneous drug reactions may be dose-dependent or due to exacerbation of underlying disease.
The terms considered here refer to adverse drug reactions that affect the skin prominently and are at times severe. Systemic disorders such as serum sickness may have skin manifestations but do not involve the skin primarily and are therefore discussed under different organ-systems. Other terms not considered are those that refer to such disorders as psoriasis, scleroderma, and systemic lupus erythematosus, disorders occasionally reported as drug-related but already clearly defined in the medical literature. However, when patients present with atypical signs and symptoms of such conditions as scleroderma and systemic lupus erythematosus, drugs as etiological factors should be considered; an example is the eosinophilia-myalgia syndrome, associated with l-tryptophan. Also not considered are terms for disorders of the hair and sweat glands and acneiform eruptions; these disorders are usually easy to describe and the terms used are not liable to misinterpretation.
Bullous reactions, i.e., reactions characterized by blisters, frequently reported in association with drugs include erythema multiforme, Stevens- Johnson syndrome, and toxic epidermal necrolysis. Bullae may also be a feature of photosensitivity reactions and fixed drug reactions. In assessing patients with blisters it is important to distinguish the condition from primary bullous diseases such as pemphigus and pemphigoid. The latter is seen mainly in the elderly, who may be taking multiple medications. It is important to be aware that many common skin disorders, e.g. insect-bite reactions and pompholyx eczema, may present with localized blisters.
Drug-induced alterations in the pigmentation of the skin usually take the form of hyperpigmentation; it may be due to excess melanin, as in melasma due to estrogen-containing drugs, or to other pigments — e.g. associated 9 with the use of minocycline or amiodarone. Drug-induced pigmentation is usually most marked in parts of the skin exposed to sun. Rash is an undesirable term for reporting a cutaneous drug reaction. Rash is essentially a lay term, usually implying sudden onset of skin lesions and therefore encompassing virtually all cutaneous adverse reactions. As a general rule, in reporting cutaneous drug reactions specific terms should be used, but only when the criteria for their use are fulfilled. If minimum criteria for a specific diagnosis cannot be met it is better to provide a description of the features of the case, including distribution, physical appearance, associated signs and symptoms, and laboratory findings. It is also important to give the evolutionary history of the reaction in relation to administration of the drug and final outcome. Validation of reports of cutaneous adverse reactions will usually require expert opinion.
The terms dermatitis and eczema are synonyms. The term contact dermatitis is used to describe dermatitis produced by direct contact with a causative agent, which may be an irritant or an allergen.
Dermatitis or eczema is a superficial skin inflammation. In the acute phase it is characterized by vesicles, redness, oedema, oozing and crusting. In the chronic phase there is marked scaling and thickening of the epidermis. There is usually itching. Basic requirements for use of the term
Skin eruptions as defined.
The terms erythroderma and exfoliative dermatitis are used synonymously.
Preference should be given to exfoliative dermatitis.
Exfoliative dermatitis is a potentially life-threatening inflammation of the
entire skin, characterized by redness of the skin and scaling, with acute onset.
10 Basic requirements for use of the term
Presence of skin eruption as defined. Cutaneous lymphoma, eczema and
psoriasis have to be excluded.
Fixed drug eruption
The term fixed drug eruption is preferred to fixed drug reaction.
The term drug eruption (drug rash) should not be used as a synonym of
fixed drug eruption or fixed drug reaction. The diagnosis should be
differentiated from erythema multiforme.
Fixed drug reaction is a skin or mucosal eruption characterized by solitary or multiple oval erythematous patches, initially with dark-coloured centres, which may progress to bullous formation, and tending to involve the face, hands, feet and genitalia. With each drug challenge the eruption rapidly occurs in the areas initially affected but new areas can also be affected. Eruptions may be followed by residual pigmentation. Basic requirements for use of the term
An eruption satisfying the above definition.
Lichenoid drug eruption
Lichenoid drug eruption is a skin reaction with some features of lichen planus. For reporting purposes the term lichenoid drug eruption should replace the term dermatitis lichenoid used in several terminologies.
Lichenoid drug eruption is a subacute violaceous papular/plaque eruption. Wiekham’s striae and polygonal configuration, characteristic of lichen planus, are not present, and the eruption does not always involve the sites most likely to be affected by lichen planus (i.e., the flexures of the wrists and ankles, and the oral mucosa).
Basic requirements for use of the term
Skin reaction as defined. Eosinophils in the infiltrate support a druginduced
reaction but do not prove it. Characteristic biopsy findings help to confirm the diagnosis.
Acute pustular eruptions are uncommon but often serious enough to merit hospitalization. The characteristic lesions are sterile pustules in the superficial part of the epidermis. The eruption resembles pustular psoriasis. The condition is a specific syndrome. Synonyms of pustular eruption are pustuloderma, pustular rashes, and acute generalized exanthemic pustulosis.
Pustular eruption is a sudden, symmetrical and widespread eruption consisting of numerous small sterile pustules arising on oedematous painful erythema. Lesions usually predominate in intertriginous areas. Fever, leukocytosis and eosinophilia are usual.
Basic requirements for use of the term
Presence of pustules as defined. Spontaneous regression of the eruption in less than two weeks is an important feature helping to differentiate pustular eruption from pustular psoriasis.
Urticaria / Angioedema
Urticaria is a very common skin reaction with many possible causes,
including insect stings, food and drugs. The basic lesions of urticaria are wheals, which are swellings of the skin originating in the dermis and having a white centre with a red edge. Characteristically, the lesions of urticaria may come and go. Individual lesions are of short duration. The term angioedema is used to describe a condition similar to urticaria but involving the deeper dermal and subcutaneous tissues. In everyday clinical use angioedema is a synonym of Quincke’s oedema and angioneurotic
oedema. Urticaria and angioedema may be part of a life-threatening anaphylaxis.
Urticaria is a skin eruption consisting of multiple transient wheals, usually
with itching. Angioedema is an eruption similar to urticaria but with larger, oedematous
wheals involving dermal, subcutaneous or submucosal tissues. It is sometimes associated with severe respiratory distress due to oedema of the upper airways.
Basic requirements for use of the terms
Presence of skin eruptions as defined. If individual wheals remain fixed for more than 48 hours or there is unexplained fever, alternative diagnoses, including vasculitis, should be considered.
Erythema multiforme, Stevens-Johnson syndrome,
Toxic epidermal necrolysis
(See Introduction to Skin and Appendages Disorders)
Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis are conditions characterized by blisters (bullous reactions); they have traditionally been regarded as related disorders, with occasionally overlapping signs and symptoms. Similar disorders include necrosis of
keratinocytes, leading to blisters and epidermal detachment.
Recent evidence suggests that erythema multiforme should be separated from Stevens-Johnson syndrome and toxic epidermal necrolysis: erythema multiforme is usually not caused by drugs, while Stevens-Johnson syndrome and toxic epidermal necrolysis in general are adverse drug
In some countries, the term erythema exudativum or erythema exudativum multiforme is used as a synonym of erythema multiforme. The term Lyell’s syndrome is considered a synonym of toxic epidermal necrolysis but its use is not recommended.
Erythema multiforme is an acute disease characterized by symmetrically distributed papular lesions affecting mainly the extremities, often with mucosal erosions. The typical lesion is target-shaped: it is concentrically organized with three different-coloured zones, often with a blister in the centre, and it is clearly demarcated from the surrounding skin. There may be general symptoms such as fever and malaise.
Stevens-Johnson syndrome (formerly also called erythema multiforme of major type) shows widespread skin lesions, which may either be targetshaped or consist of erythematous macules with epidermal detachment, together with severe mucosal erosions. Erosions of the skin do not exceed
10 per cent of body surface area. The general symptoms are more marked
than in erythema multiforme.
Toxic epidermal necrolysis is characterized by widespread erythematous areas with epithelial necrosis and epidermal detachment (> 10 per cent body surface area), leaving bare dermis. Initially there are often also small erythematous or purpuric lesions with or without blisters. Extensive mucosal erosion is frequent. General symptoms, usually severe, include high fever, malaise and painful skin.
Basic requirements for use of the terms Presence of typical skin lesions. Physical causes and autoimmune blistering diseases may have to be excluded; skin biopsy and clinical photographs are
Photosensitivity reaction, Phototoxic reaction, Photoallergic reaction
All forms of photosensitivity refer to exaggerated or abnormal responses to ultra-violet radiation or to light, and most commonly occur on exposed parts of the skin. Photosensitivity reactions may be pleomorphic and include dermatitis-like reactions.
Phototoxic reactions, which are non-immunological events caused by drugs or chemicals, are far more common than photoallergic reactions, which do signify an immunological response.
The terms phototoxic reaction and photoallergic reaction are considered more suitable than photosensitivity toxic reaction and photosensitivity allergic reaction, respectively. The terms phototoxic and photoallergic are specific and should be used with caution in the absence of expert investigation.
Photosensitivity reaction is an exaggerated ‘sunburn’ reaction.
Phototoxic reactions are exaggerated sunburn-like reactions resulting directly from the photosensitizing substance.
Photoallergic reactions are pleomorphic, immunologically mediated, skin reactions.
Basic requirements for use of all three terms
Cutaneous drug reactions satisfying the defined criteria, with special reference to the effects of exposure to light or ultra-violet radiation. Phototoxic reactions occur up to two days after exposure and are clearly limited to exposed areas of the skin. Photoallergic reactions occur only after a period of sensitization, and the skin reaction may extend beyond the exposed areas and may recur with re-exposure to sunlight even without further use of the drug (rechallenge).