Drug eruption

Examples of drug eruptions. (A) Bullous dermatitis caused by sulfathiazole (B) Fixed drug eruption caused by phenolphtalein (C) Bullous erythema multiforme (D) Diffuse photosensitivity reaction.

In medicine, a drug eruption is an adverse drug reaction of the skin. Most drug-induced cutaneous reactions are mild and disappear when the offending drug is withdrawn.[1] These are called "simple" drug eruptions. However, more serious drug eruptions may be associated with organ injury such as liver or kidney damage and are categorized as "complex".[2] Drugs can also cause hair and nail changes, affect the mucous membranes, or cause itching without outward skin changes.[3]

The use of synthetic pharmaceuticals and biopharmaceuticals in medicine has revolutionized human health, allowing us to live longer lives. Consequently, the average human adult is exposed to many drugs over longer treatment periods throughout a lifetime.[4] This unprecedented rise in pharmaceutical use has led to an increasing number of observed adverse drug reactions.[4]

There are two broad categories of adverse drug reactions. Type A reactions are known side effects of a drug that are largely predictable and are called, pharmatoxicologic.[5] Whereas Type B or hypersensitivity reactions, are often immune-mediated and reproducible with repeated exposure to normal dosages of a given drug.[5] Unlike type A reactions, the mechanism of type B or hypersensitivity drug reactions is not fully elucidated. However, there is a complex interplay between a patient's inherited genetics, the pharmacotoxicology of the drug and the immune response that ultimately give rise to the manifestation of a drug eruption.[5]

Because the manifestation of a drug eruption is complex and highly individual, there are many subfields in medicine that are studying this phenomenon. For example, the field of pharmacogenomics aims to prevent the occurrence of severe adverse drug reactions by analyzing a person's inherited genetic risk.[6] As such, there are clinical examples of inherited genetic alleles that are known to predict drug hypersensitivities and for which diagnostic testing is available.[6]

## Contents

* 1 Classification
* 1.1 By appearance
* 1.2 By mechanism
* 1.3 By drug
* 2 Diagnosis and screening tests
* 3 See also
* 4 References
* 5 External links

## Classification[edit | edit source]

Some of the most severe and life-threatening examples of drug eruptions are erythema multiforme, Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), hypersensitivity vasculitis, drug induced hypersensitivity syndrome (DIHS), erythroderma and acute generalized exanthematous pustulosis (AGEP).[4] These severe cutaneous drug eruptions are categorized as hypersensitivity reactions and are immune-mediated. There are four types of hypersensitivity reactions and many drugs can induce one or more hypersensitivity reactions.[4]

Hypersensitivity Reactions[4] Reaction  | Description  | Mediator  | Mechanism  | Clinical phenotype

|
|
|
|

Type I  | Immediate  | IgE  | antigen binds to mast cell/

basophil surface receptors

| Urticarial, anaphylaxis,

angioedema

TypeII  | Antibody-mediated  | IgM, IgG  | antibody binds antigen leading to

complement-driven cell lysis

| drug-induced thrombocytopenia,

hemolytic anemia, Goodpasture's, ANCA vasculitis

Type III  | Immune complex  | IgM, IgG, IgA  | antigen-antibody complex deposits

in tissues-triggers recruitment of leukocytes

| Serum sickness, Henoch-Schonlein Purpura
Type IV  | Delayed-type  | T-lymphocytes  | Activated T-cells produce cytokines causing

inflammation leading to tissue destruction

| Drug reaction with eosinophilia and systemic symptoms (i.e. DRESS syndrome or DIHS), Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis

### By appearance[edit | edit source]

The most common type of eruption is a morbilliform (resembling measles) or erythematous rash (approximately 90% of cases).[7] Less commonly, the appearance may also be urticarial, papulosquamous, pustular, purpuric, bullous (with blisters) or lichenoid.[3] Angioedema can also be drug-induced (most notably, by angiotensin converting enzyme inhibitors).

* Drug eruption

* Drug eruption

* Drug eruption

### By mechanism[edit | edit source]

The underlying mechanism can be immunological (such as in drug allergies) or non-immunological (for example, in photodermatitis or as a side effect of anticoagulants). A fixed drug eruption is the term for a drug eruption that occurs in the same skin area every time the person is exposed to the drug. Eruptions can occur frequently with a certain drug (for example, with phenytoin[8]), or be very rare (for example, Sweet's syndrome following the administration of colony-stimulating factors[9]).

### By drug[edit | edit source]

The culprit can be both a prescription drug or an over-the-counter medication.

Examples of common drugs causing drug eruptions are antibiotics and other antimicrobial drugs, sulfa drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), biopharmaceuticals, chemotherapy agents, anticonvulsants and psychotropic drugs. Common examples include photodermatitis due to local NSAIDs (such as piroxicam) or due to antibiotics (such as minocycline), fixed drug eruption due to acetaminophen or NSAIDs (Ibuprofen), and the rash following ampicillin in cases of mononucleosis.[2]

Certain drugs are less likely to cause drug eruptions (rates estimated to be ≤3 per 1000 patients exposed). These include: digoxin, aluminum hydroxide, multivitamins, acetaminophen, bisacodyl, aspirin, thiamine, prednisone, atropine, codeine, hydrochlorothiazide, morphine, insulin, warfarin and spironolactone.[2]

## Diagnosis and screening tests[edit | edit source]

Drug eruptions are diagnosed mainly from the medical history and clinical examination. However, they can mimic various other conditions, thus delaying diagnosis (for example, in drug-induced lupus erythematosus, or the acne-like rash caused by erlotinib). A skin biopsy, blood tests or immunological tests can also be useful.

Drug reactions have characteristic timing. The typical amount of time it takes for a rash to appear after exposure to a drug can help categorize the type of reaction. For example, Acute generalized exanthematous pustulosis usually occurs within 4 days of starting the culprit drug. Drug Reaction with Eosinophilia and Systemic Symptoms usually occurs between 15 and 40 days after exposure. Toxic epidermal necrolysis and Stevens–Johnson syndrome typically occur 7–21 days after exposure. Anaphylaxis occurs within minutes. Simple exanthematous eruptions occur between 4 and 14 days after exposure.[2]

TEN and SJS are severe cutaneous drug reactions that involve the skin and mucous membranes. To accurately diagnose this condition, a detailed drug history is crucial.[4] Often, several drugs may be causative and allergy testing may be helpful.[4] Sulfa drugs are well-known to induce TEN or SJS in certain people. For example, HIV patients have an increased incidence of SJS or TEN compared to the general population and have been found to express low levels of the drug metabolizing enzyme responsible for detoxifying sulfa drugs.[5] Genetics plays an important role in predisposing certain populations to TEN and SJS. As such, there are some FDA recommended genetic screening tests available for certain drugs and ethnic populations to prevent the occurrence of a drug eruption.[5] The most well known example is carbamezepine (an anti-convulsant used to treat seizures) hypersensitivity associated with the presence of HLA-B*5801 genetic allele in Asian populations.[6]

Pharmacogenetic alleles associated with cutaneous drug reactions[5] Drug  | Allele  | Population  | Clinical syndrome  | FDA recommended Pharmacogenetic testing

|
|
|
|

Abacavir  | HLA-B*5701  | US European

US African

Australian

| DIHS  | Yes
Allopurinol  | HLA-B*5801  | Han, Korean,

Thai, European

| SJS, TEN, DIHS  | No
Carbamezepine  | HLA-B*1502  | Han, Thai,

Malaysian, Korean

| SJS, TEN  | Yes
Dapsone  | HLA-B*1301  | Chinese  | DIHS  | No
Lamotrigine  | HLA-B*38

HLA-B*1502

| European,

Han

| SJS, TEN  | no recommendation available
Methazolamide  | HLA-B*5901  | Korean  | SJS, TEN  | No
Phenytoin  | HLA-B*1502  | Thai, Han  | SJS, TEN  | Warning

DIHS is a delayed onset drug eruption, often occurring a few weeks to 3 months after initiation of a drug.[2] Worsening of systemic symptoms occurs 3–4 days after cessation of the offending drug.[5] There are genetic risk alleles that are predictive of the development of DIHS for particular drugs and ethnic populations.[5] The most important of which is abacavir (an anti-viral used in the treatment of HIV) hypersensitivity associated with the presence of the HLA-B*5701 allele in European and African population in the United States and Australians.[5]

AGEP is often caused by antimicrobial, anti-fungal or antimalarial drugs.[4] Diagnosis is often carried out by patch testing. This testing should be performed within one month after resolution of the rash and patch test results are interpreted at different time points: 48 hours, 72hours and even later at 96 hours and 120 hours in order to improve the sensitivity.[4]

[10]

## See also[edit | edit source]

* Fixed drug reaction
* List of cutaneous conditions
* List of human leukocyte antigen alleles associated with cutaneous conditions
* Stevens–Johnson syndrome

## References[edit | edit source]

1. ↑ Manders SM (June 1995). "Serious and life-threatening drug eruptions". Am Fam Physician. 51 (8): 1865–72. PMID 7762478.
2. ↑ 2.0 2.1 2.2 2.3 2.4 Schaffer (2012). Jean L. Bolognia; Joseph L. Jorizzo; Julie V. (eds.). Dermatology (3rd ed.). [Philadelphia]: Elsevier Saunders. ISBN 978-0723435716.
3. ↑ 3.0 3.1 Valeyrie-Allanore L, Sassolas B, Roujeau JC (2007). "Drug-induced skin, nail and hair disorders". Drug Saf. 30 (11): 1011–30. doi:10.2165/00002018-200730110-00003. PMID 17973540.
4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Adverse cutaneous drug eruptions. French, Lars E. Basel, Switzerland: Karger. 2012. ISBN 9783805599702. OCLC 798579099.`{{cite book}}`: CS1 maint: others (link)
5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Dyer, Jon A. (2015). "Immunology of Cutaneous Drug Eruptions". Cutaneous Drug Eruptions. Springer, London. pp. 3–12. doi:10.1007/978-1-4471-6729-7_1. ISBN 9781447167280.
6. ↑ 6.0 6.1 6.2 Pharmacogenomics : an introduction and clinical perspective. Bertino, Joseph S. New York: McGraw-Hill. 2013. ISBN 9780071741699. OCLC 793223356.`{{cite book}}`: CS1 maint: others (link)
7. ↑ Bigby, M. (2001-06-01). "Rates of cutaneous reactions to drugs". Archives of Dermatology. 137 (6): 765–770. ISSN 0003-987X. PMID 11405768.
8. ↑ Scheinfeld N (August 2003). "Phenytoin in cutaneous medicine: its uses, mechanisms and side effects". Dermatol. Online J. 9 (3): 6. PMID 12952753. Archived from the original on 2008-08-29. Retrieved 2020-12-05.
9. ↑ Cohen PR (2007). "Sweet's syndrome--a comprehensive review of an acute febrile neutrophilic dermatosis". Orphanet J Rare Dis. 2: 34. doi:10.1186/1750-1172-2-34. PMC 1963326. PMID 17655751.
10. ↑ Roujeau JC, Stern RS (November 1994). "Severe adverse cutaneous reactions to drugs". N. Engl. J. Med. 331 (19): 1272–85. doi:10.1056/NEJM199411103311906. PMID 7794310.

## External links[edit | edit source]

Classification|

* ICD-10: L27.0, L27.1
* ICD-9-CM: 692.3, 782.1
* MeSH: D003875

|

External resources|

* eMedicine: derm/104

* v
* t
* e

Diseases of the skin and appendages by morphology

Growths|

| Epidermal|

* Wart
* Callus
* Seborrheic keratosis
* Acrochordon
* Molluscum contagiosum
* Actinic keratosis
* Squamous-cell carcinoma
* Basal-cell carcinoma
* Merkel-cell carcinoma
* Nevus sebaceous
* Trichoepithelioma

|

Pigmented|

* Freckles
* Lentigo
* Melasma
* Nevus
* Melanoma

Dermal and
subcutaneous|

* Epidermal inclusion cyst
* Hemangioma
* Dermatofibroma (benign fibrous histiocytoma)
* Keloid
* Lipoma
* Neurofibroma
* Xanthoma
* Kaposi's sarcoma
* Infantile digital fibromatosis
* Granular cell tumor
* Leiomyoma
* Lymphangioma circumscriptum
* Myxoid cyst

Rashes|

| With
epidermal
involvement|

| Eczematous|

* Contact dermatitis
* Atopic dermatitis
* Seborrheic dermatitis
* Stasis dermatitis
* Lichen simplex chronicus
* Darier's disease
* Glucagonoma syndrome
* Langerhans cell histiocytosis
* Lichen sclerosus
* Pemphigus foliaceus
* Wiskott–Aldrich syndrome
* Zinc deficiency

|

Scaling|

* Psoriasis
* Tinea (Corporis
* Cruris
* Pedis
* Manuum
* Faciei)
* Pityriasis rosea
* Secondary syphilis
* Mycosis fungoides
* Systemic lupus erythematosus
* Pityriasis rubra pilaris
* Parapsoriasis
* Ichthyosis

Blistering|

* Herpes simplex
* Herpes zoster
* Varicella
* Bullous impetigo
* Acute contact dermatitis
* Pemphigus vulgaris
* Bullous pemphigoid
* Dermatitis herpetiformis
* Porphyria cutanea tarda
* Epidermolysis bullosa simplex

Papular|

* Scabies
* Insect bite reactions
* Lichen planus
* Miliaria
* Keratosis pilaris
* Lichen spinulosus
* Transient acantholytic dermatosis
* Lichen nitidus
* Pityriasis lichenoides et varioliformis acuta

Pustular|

* Acne vulgaris
* Acne rosacea
* Folliculitis
* Impetigo
* Candidiasis
* Gonococcemia
* Dermatophyte
* Coccidioidomycosis
* Subcorneal pustular dermatosis

Hypopigmented|

* Tinea versicolor
* Vitiligo
* Pityriasis alba
* Postinflammatory hyperpigmentation
* Tuberous sclerosis
* Idiopathic guttate hypomelanosis
* Leprosy
* Hypopigmented mycosis fungoides

Without
epidermal
involvement|

| Red|

| Blanchable
Erythema|

| Generalized|

* Drug eruptions
* Viral exanthems
* Toxic erythema
* Systemic lupus erythematosus

|

Localized|

* Cellulitis
* Abscess
* Boil
* Erythema nodosum
* Carcinoid syndrome
* Fixed drug eruption

Specialized|

* Urticaria
* Erythema (Multiforme
* Migrans
* Gyratum repens
* Annulare centrifugum
* Ab igne)

Nonblanchable
Purpura|

| Macular|

* Thrombocytopenic purpura
* Actinic/solar purpura

|

Papular|

* Disseminated intravascular coagulation
* Vasculitis

Indurated|

* Scleroderma/morphea
* Granuloma annulare
* Lichen sclerosis et atrophicus
* Necrobiosis lipoidica

Miscellaneous
disorders|

| Ulcers|

|

Hair|

* Telogen effluvium
* Androgenic alopecia
* Alopecia areata
* Systemic lupus erythematosus
* Tinea capitis
* Loose anagen syndrome
* Lichen planopilaris
* Folliculitis decalvans
* Acne keloidalis nuchae

Nail|

* Onychomycosis
* Psoriasis
* Paronychia
* Ingrown nail

Mucous
membrane|

* Aphthous stomatitis
* Oral candidiasis
* Lichen planus
* Leukoplakia
* Pemphigus vulgaris
* Mucous membrane pemphigoid
* Cicatricial pemphigoid
* Herpesvirus
* Coxsackievirus
* Syphilis
* Systemic histoplasmosis
* Squamous-cell carcinoma

* v
* t
* e

Dermatitis and eczema

Atopic dermatitis|

* Besnier's prurigo

Seborrheic dermatitis|

* Pityriasis simplex capillitii
* Cradle cap

Contact dermatitis
(allergic, irritant)|

* plants: Urushiol-induced contact dermatitis
* African blackwood dermatitis
* Tulip fingers

* other: Abietic acid dermatitis
* Diaper rash
* Airbag dermatitis
* Baboon syndrome
* Contact stomatitis
* Protein contact dermatitis

Eczema|

* Autoimmune estrogen dermatitis
* Autoimmune progesterone dermatitis

* Breast eczema
* Ear eczema
* Eyelid dermatitis
* Topical steroid addiction
* Hand eczema
* Chronic vesiculobullous hand eczema
* Hyperkeratotic hand dermatitis

* Autosensitization dermatitis/Id reaction
* Candidid
* Dermatophytid
* Molluscum dermatitis
* Circumostomy eczema
* Dyshidrosis
* Juvenile plantar dermatosis
* Nummular eczema
* Nutritional deficiency eczema
* Sulzberger–Garbe syndrome
* Xerotic eczema

Pruritus/Itch/
Prurigo|

* Lichen simplex chronicus/Prurigo nodularis

* by location: Pruritus ani
* Pruritus scroti
* Pruritus vulvae
* Scalp pruritus

* Drug-induced pruritus
* Hydroxyethyl starch-induced pruritus
* Senile pruritus
* Aquagenic pruritus
* Aquadynia

* Adult blaschkitis
* due to liver disease
* Biliary pruritus
* Cholestatic pruritus
* Prion pruritus
* Prurigo pigmentosa
* Prurigo simplex
* Puncta pruritica
* Uremic pruritus

Other|

* substances taken internally: Bromoderma
* Fixed drug reaction

* Nummular dermatitis
* Pityriasis alba
* Papuloerythroderma of Ofuji

* v
* t
* e

Urticaria and erythema

Urticaria
(acute/chronic)|

| Allergic urticaria|

* Urticarial allergic eruption

|

Physical urticaria|

* Cold urticaria
* Familial
* Primary cold contact urticaria
* Secondary cold contact urticaria
* Reflex cold urticaria

* Heat urticaria
* Localized heat contact urticaria
* Solar urticaria

* Dermatographic urticaria
* Vibratory angioedema
* Pressure urticaria
* Cholinergic urticaria
* Aquagenic urticaria

Other urticaria|

* Acquired C1 esterase inhibitor deficiency
* Adrenergic urticaria
* Exercise urticaria
* Galvanic urticaria
* Schnitzler syndrome
* Urticaria-like follicular mucinosis

Angioedema|

* Episodic angioedema with eosinophilia
* Hereditary angioedema

Erythema|

| Erythema multiforme/
drug eruption|

* Erythema multiforme minor
* Erythema multiforme major
* Stevens–Johnson syndrome, Toxic epidermal necrolysis
* panniculitis (Erythema nodosum)
* Acute generalized exanthematous pustulosis

|

Figurate erythema|

* Erythema annulare centrifugum
* Erythema marginatum
* Erythema migrans
* Erythema gyratum repens

Other erythema|

* Necrolytic migratory erythema
* Erythema toxicum
* Erythroderma
* Palmar erythema
* Generalized erythema

* v
* t
* e

Signs and symptoms relating to skin and subcutaneous tissue

Disturbances of
skin sensation|

* Hypoesthesia
* Paresthesia
* Formication
* Hyperesthesia

* Hypoalgesia
* Hyperalgesia

Circulation|

* Cyanosis
* Pallor
* Livedo
* Livedo reticularis
* Flushing
* Petechia
* Blanching

Edema|

* Peripheral edema
* Anasarca

Other|

* Rash
* Desquamation
* Induration
* Diaphoresis
* Mass
* Neck mass

Skin|

* Asboe-Hansen sign
* Auspitz's sign
* Borsari's sign
* Braverman's sign
* Crowe sign
* Dennie–Morgan fold
* Darier's sign
* Fitzpatrick's sign
* Florid cutaneous papillomatosis

* Gottron's sign
* Hutchinson's sign
* Janeway lesion
* Kerr's sign
* Koebner's phenomenon
* Koplik's spots
* Leser-Trelat sign
* Nikolsky's sign
* Pastia's sign
* Russell's sign
* Wickham striae
* Wolf's isotopic response
* Munro's microabscess

Nails|

* Aldrich-Mees' lines
* Beau's lines
* Muehrcke's lines
* Terry's nails

* v
* t
* e

Hypersensitivity and autoimmune diseases

Type I/allergy/atopy
(IgE)|

| Foreign|

* Atopic eczema
* Allergic urticaria
* Allergic rhinitis (Hay fever)
* Allergic asthma
* Anaphylaxis
* Food allergy
* common allergies include: Milk
* Egg
* Peanut
* Tree nut
* Seafood
* Soy
* Wheat
* Penicillin allergy

|

Autoimmune|

* Eosinophilic esophagitis

Type II/ADCC

*     * IgM
* IgG

| Foreign|

* Hemolytic disease of the newborn

|

Autoimmune|

| Cytotoxic|

* Autoimmune hemolytic anemia
* Immune thrombocytopenic purpura
* Bullous pemphigoid
* Pemphigus vulgaris
* Rheumatic fever
* Goodpasture syndrome
* Guillain–Barré syndrome

|

"Type V"/receptor|

* Graves' disease
* Myasthenia gravis
* Pernicious anemia

Type III
(Immune complex)|

| Foreign|

* Henoch–Schönlein purpura
* Hypersensitivity vasculitis
* Reactive arthritis
* Farmer's lung
* Post-streptococcal glomerulonephritis
* Serum sickness
* Arthus reaction

|

Autoimmune|

* Systemic lupus erythematosus
* Subacute bacterial endocarditis
* Rheumatoid arthritis

Type IV/cell-mediated
(T cells)|

| Foreign|

* Allergic contact dermatitis
* Mantoux test

|

Autoimmune|

* Diabetes mellitus type 1
* Hashimoto's thyroiditis
* Multiple sclerosis
* Coeliac disease
* Giant-cell arteritis
* Postorgasmic illness syndrome
* Reactive arthritis

GVHD|

* Transfusion-associated graft versus host disease

Unknown/
multiple|

| Foreign|

* Hypersensitivity pneumonitis
* Allergic bronchopulmonary aspergillosis
* Transplant rejection
* Latex allergy (I+IV)

|

Autoimmune|

* Sjögren syndrome
* Autoimmune hepatitis
* Autoimmune polyendocrine syndrome
* APS1
* APS2
* Autoimmune adrenalitis
* Systemic autoimmune disease

* v
* t
* e

Adverse drug reactions

Antibiotics|

* Penicillin drug reaction
* Sulfonamide hypersensitivity syndrome
* Urticarial erythema multiforme
* Adverse effects of fluoroquinolones
* Red man syndrome
* Jarisch–Herxheimer reaction

Hormones|

* Steroid acne
* Steroid folliculitis

Chemotherapy|

* Chemotherapy-induced acral erythema
* Chemotherapy-induced hyperpigmentation
* Scleroderma-like reaction to taxanes
* Hydroxyurea dermopathy
* Exudative hyponychial dermatitis

Anticoagulants|

* Anticoagulant-induced skin necrosis
* Warfarin necrosis
* Vitamin K reaction
* Texier's disease

Immunologics|

* Adverse reaction to biologic agents
* Leukotriene receptor antagonist-associated Churg–Strauss syndrome
* Methotrexate-induced papular eruption
* Adverse reaction to cytokines

Other drugs|

* Anticonvulsant hypersensitivity syndrome
* Allopurinol hypersensitivity syndrome
* Vaccine adverse event
* Eczema vaccinatum
* Bromoderma
* Halogenoderma
* Iododerma

General|

| Skin and body membranes|

* Acute generalized exanthematous pustulosis
* Bullous drug reaction
* Drug-induced acne
* Drug-induced angioedema
* Drug-related gingival hyperplasia
* Drug-induced lichenoid reaction
* Drug-induced lupus erythematosus
* Drug-induced nail changes
* Drug-induced pigmentation
* Drug-induced urticaria
* Stevens–Johnson syndrome
* Injection site reaction
* Linear IgA bullous dermatosis
* Toxic epidermal necrolysis
* HIV disease-related drug reaction
* Photosensitive drug reaction

|

Other|

* Drug-induced pseudolymphoma
* Fixed drug reaction
* Serum sickness-like reaction

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