Aetiology

Any drug can cause any adverse effect on the skin. Adverse skin reactions are not associated pathognomonically with particular drugs, and no reactions are specific for drug-induced lesions. In most cases, no specific features distinguish patients who are at increased risk of adverse skin reactions. However, some well-described susceptibility factors, including the association between Epstein-Barr virus and cytomegalovirus infection and sensitivity to ampicillin/amoxicillin, infection with HIV, and specific human leukocyte antigen polymorphisms, are well recognised.[30]

Pathophysiology

In most patterns of drug reactions, the pathogenesis is unknown. Classic immune mechanisms do not appear responsible for most adverse drug reactions. However, the rapid reappearance of many reactions on re-exposure strongly suggests immunological memory.

The histological changes in certain lichenoid eruptions and fixed drug eruptions are not pathognomonic, but are sufficiently characteristic to be of importance in differential diagnosis. In lichenoid eruptions, the presence of focal parakeratosis, focal interruption of the granular layer, and cytoid bodies in the cornified and granular layers suggest a drug cause.[31] In the late phase of fixed eruptions, there is increased melanin in the epidermis and within melanophages in the dermis.

It is impossible to identify an offending drug on the basis of histopathology or clinical appearances alone. The drug-induced forms of skin lesions are often indistinguishable from non-drug-induced forms. However, a peripheral blood eosinophilia and tissue infiltration of eosinophilic polymorphonuclear leukocytes may suggest a drug-induced lesion.

Classification

Rawlins and Thompson pharmacological classification

The traditional classification of adverse drug reactions (ADRs) divides these into 2 major subtypes: type A reactions, which are dose-dependent and predictable, and type B, which are neither.[6] The majority of ADRs are predictable (type A) reactions. Unpredictable (type B) reactions include drug hypersensitivity reactions (DHRs). Predictable ADRs are usually dose-related and a function of the known pharmacological actions of the drug. Unpredictable reactions are dose-independent and not related to the pharmacological action of the drug. They may have a basis in pharmacogenetic variation, or in drug or metabolite detoxification or clearance.[7] However, this classification is likely to become obsolete as it is increasingly recognised that genetic factors such as human leukocyte antigen (HLA) alleles may predict hypersensitivity reactions, such as that seen with abacavir in those who are HLA-B*5701 carriers.[8]

Traditional classification of adverse drug reactions (still applies to most scenarios):[9]

Unpredictable

  • Non-immunological

    • Idiosyncrasy

    • Intolerance

  • Immunological

    • IgE-dependent drug reactions

    • Immune complex-dependent drug reactions

    • Cytotoxic drug-induced reactions

    • Cell-mediated reactions.

Predictable

  • Non-immunological

    • Accumulation

    • Delayed toxicity

    • Drug interactions

    • Chromosomal damage

    • Exacerbation of disease

    • Facultative effects

    • Metabolic alterations

    • Activation of effector pathways

    • Overdose

    • Side effects

    • Teratogenicity.

Gell and Coombs classification of immunological reactions[10]

Delineates 4 types of immunological reaction:

  • Type I: acute IgE-mediated reactions that cause mast cell degranulation (e.g., urticaria, angio-oedema, anaphylactic reactions)

  • Type II: cytotoxic reactions, due to antigen-antibody interactions that result in local production of anaphylotoxin (C5a), recruitment of polymorphonuclear leukocytes, and tissue injury due to the release of hydrolytic neutrophil enzymes (e.g., vasculitis, thrombocytopenic purpura)

  • Type III: delayed immune complex reactions, in which antigen-antibody complexes are formed in the circulation and deposited in the tissues (e.g., maculopapular rashes, interstitial nephritis)

  • Type IV: cell-mediated or delayed hypersensitivity reactions, in which T-lymphocytes are sensitised by a hapten-protein antigenic complex and inflammation results (e.g., contact dermatitis).

Allergy nomenclature

Drug reactions are classified as immunological (allergic or hypersensitivity) or non-immunological (nonallergic). When immunological mechanisms have been demonstrated, either antibody or cell-mediated, the reactions should be referred to as drug allergy.[11]

Allergic reactions are further classified as IgE mediated and non-IgE mediated.

Types of adverse skin reaction to systemic drugs

  • Allergic skin reactions to systemic drugs include maculopapular skin rashes, urticaria, and angio-oedema. The spectrum of skin lesions includes fixed drug eruptions, erythema multiforme, DRESS (drug reaction with eosinophilia and systemic symptoms; also called drug hypersensitivity syndrome), Stevens-Johnson syndrome, and toxic epidermal necrolysis. Together these account for most drug-induced skin manifestations.

  • Non-allergic reactions include acneiform eruptions; alopecia; bullous eruptions - pemphigus and pemphigoid; photosensitivity and phototoxicity reactions; purpura due to various causes; pustular eruptions (e.g., acute generalised exanthematous pustulosis); Sweet's syndrome (acute febrile neutrophilic dermatosis); and various forms of vasculitis. Contact dermatitis is common after the use of topical drugs and cosmetics.

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