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DEFINITIONS
AND BASIC REQUIREMENTS
FOR
THE USE OF TERMS FOR REPORTING
ADVERSE
DRUG REACTIONS
Skin and Appendages Disorders
(SOC 0100)
Introduction
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.
Terms
Dermatitis (Eczema)
Preamble
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.
Definition
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.
Reference 7b
Dermatitis exfoliative
Preamble
The terms erythroderma and exfoliative dermatitis
are used synonymously.
Preference should be given to exfoliative dermatitis.
Definition
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.
Reference 7b
Fixed drug eruption
Preamble
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.
Definition
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.
Reference 7b
Lichenoid drug eruption
Preamble
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.
Definition
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.
Reference 7b
Pustular eruption
Preamble
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.
Definition
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.
Reference 7b
Urticaria / Angioedema
Preamble
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.
Definition
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.
Reference 7b
Erythema multiforme, Stevens-Johnson syndrome,
Toxic epidermal necrolysis
Preamble
(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
reactions.
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.
Definitions
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.
Reference 7b
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.
Reference 7b
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
helpful.
Reference 7b
Photosensitivity reaction, Phototoxic reaction,
Photoallergic reaction
Preamble
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.
Definitions
Photosensitivity reaction is an exaggerated ‘sunburn’ reaction.
Reference 7b
Phototoxic reactions are exaggerated sunburn-like
reactions resulting directly from the photosensitizing substance.
Reference 7b
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).
Reference 7b
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