View source for Drug eruption

{{Infobox medical condition (new)
| name            = Drug eruption
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| image           = Drug eruptions.jpg
| caption         = 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]].
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In [[medicine]], a '''drug eruption''' is an [[adverse drug reaction]] of the [[Human skin|skin]]. Most drug-induced cutaneous reactions are mild and disappear when the offending drug is withdrawn.<ref name="pmid7762478">{{cite journal |author=Manders SM |title=Serious and life-threatening drug eruptions |journal=Am Fam Physician |volume=51 |issue=8 |pages=1865–72 |date=June 1995 |pmid=7762478 }}</ref> 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".<ref name="Bolognia">{{cite book|last1=Schaffer|editor1=Jean L. Bolognia|editor2=Joseph L. Jorizzo|editor3=Julie V.|title=Dermatology|date=2012|publisher=Elsevier Saunders|location=[Philadelphia]|isbn=978-0723435716|edition=3rd}}</ref> Drugs can also cause [[hair disease|hair]] and [[nail disease|nail]] changes, affect the [[mucous membranes]], or cause [[itching]] without outward skin changes.<ref name="pmid17973540" />

The use of synthetic pharmaceuticals and [[biopharmaceutical]]s 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.<ref name=":1">{{Cite book|title=Adverse cutaneous drug eruptions|date=2012|publisher=Karger|others=French, Lars E.|isbn=9783805599702|location=Basel, Switzerland|oclc=798579099}}</ref> This unprecedented rise in pharmaceutical use has led to an increasing number of observed adverse drug reactions.<ref name=":1" />

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.'''''<ref name=":0">{{Cite book|title=Cutaneous Drug Eruptions|last=Dyer|first=Jon A.|date=2015|publisher=Springer, London|isbn=9781447167280|pages=3–12|language=en|doi=10.1007/978-1-4471-6729-7_1|chapter = Immunology of Cutaneous Drug Eruptions}}</ref> Whereas '''''Type B''''' or '''''hypersensitivity''''' reactions, are often immune-mediated and reproducible with repeated exposure to normal dosages of a given drug.<ref name=":0" /> 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.<ref name=":0" />

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.<ref name=":2">{{Cite book|title=Pharmacogenomics : an introduction and clinical perspective|date=2013|publisher=McGraw-Hill|others=Bertino, Joseph S.|isbn=9780071741699|location=New York|oclc=793223356}}</ref> As such, there are clinical examples of inherited genetic [[allele]]s that are known to predict drug hypersensitivities and for which diagnostic testing is available.<ref name=":2" />

==Classification==
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]], [[DRESS syndrome|drug induced hypersensitivity syndrome]] (DIHS), [[erythroderma]] and [[acute generalized exanthematous pustulosis]] (AGEP).<ref name=":1" /> 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.<ref name=":1" />

{| class="wikitable"
|+Hypersensitivity Reactions<ref name=":1" />
!Reaction
!Description
!Mediator
!Mechanism
!Clinical phenotype
|-
|Type I
|Immediate
|IgE
|antigen binds to mast cell/
basophil surface receptors
|[[Hives|Urticarial (hives)]], [[anaphylaxis]],
[[angioedema]]
|-
|TypeII
|Antibody-mediated
|IgM, IgG
|antibody binds antigen leading to
complement-driven cell lysis
|drug-induced [[thrombocytopenia]],
[[hemolytic anemia]], Goodpasture's, [[Anti-neutrophil cytoplasmic antibody|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===
The most common type of eruption is a [[morbilliform]] (resembling [[measles]]) or [[erythematous rash]] (approximately 90% of cases).<ref>{{Cite journal|last=Bigby|first=M.|date=2001-06-01|title=Rates of cutaneous reactions to drugs|journal=Archives of Dermatology|volume=137|issue=6|pages=765–770|issn=0003-987X|pmid=11405768}}</ref> Less commonly, the appearance may also be [[urticaria]]l, [[papulosquamous disorder|papulosquamous]], [[pustular rash|pustular]], [[purpura|purpuric]], [[bullous]] (with blisters) or [[lichenoid eruption|lichenoid]].<ref name="pmid17973540">{{cite journal |vauthors=Valeyrie-Allanore L, Sassolas B, Roujeau JC |title=Drug-induced skin, nail and hair disorders |journal=Drug Saf |volume=30 |issue=11 |pages=1011–30 |year=2007 |pmid=17973540 |doi= 10.2165/00002018-200730110-00003|s2cid=25391301 }}</ref> [[Angioedema]] can also be drug-induced (most notably, by [[angiotensin converting enzyme inhibitors]]).

===By mechanism===
The underlying mechanism can be immunological (such as in [[drug allergy|drug allergie]]s) 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]]<ref name="pmid12952753">{{cite journal |author=Scheinfeld N |title=Phenytoin in cutaneous medicine: its uses, mechanisms and side effects |journal=Dermatol. Online J. |volume=9 |issue=3 |pages=6 |date=August 2003 |doi=10.5070/D32197W4T4 |pmid=12952753 |url=http://dermatology.cdlib.org/93/reviews/dilantin/scheinfeld.html|url-access=subscription }}</ref>), or be very rare (for example, [[Sweet's syndrome]] following the administration of [[colony-stimulating factor]]s<ref name="pmid17655751">{{cite journal |author=Cohen PR |title=Sweet's syndrome--a comprehensive review of an acute febrile neutrophilic dermatosis |journal=Orphanet J Rare Dis |volume=2 |pages=34 |year=2007 |pmid=17655751 |pmc=1963326 |doi=10.1186/1750-1172-2-34 |doi-access=free }}</ref>).

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

Examples of common drugs causing drug eruptions are [[antibiotic]]s and other [[antimicrobial]] drugs, [[sulfa drugs]], [[nonsteroidal anti-inflammatory drugs]] (NSAIDs), [[biopharmaceutical]]s, [[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 [[Infectious mononucleosis|mononucleosis]].<ref name="Bolognia" />

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.<ref name="Bolognia" />

==Diagnosis and screening tests==
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 test]]s or [[immunology|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.<ref name=Bolognia />

TEN and SJS are severe cutaneous drug reactions that involve the skin and [[mucous membrane]]s. To accurately diagnose this condition, a detailed drug history is crucial.<ref name=":1" /> Often, several drugs may be causative and allergy testing may be helpful.<ref name=":1" /> 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.<ref name=":0" /> Genetics plays an important role in predisposing certain populations to TEN and SJS. As such, there are some [[Food and Drug Administration|FDA]] recommended genetic screening tests available for certain drugs and ethnic populations to prevent the occurrence of a drug eruption.<ref name=":0" /> 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.<ref name=":2" />

{| class="wikitable"
|+Pharmacogenetic alleles associated with cutaneous drug reactions<ref name=":0" />
!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.<ref name="Bolognia" /> Worsening of systemic symptoms occurs 3–4 days after cessation of the offending drug.<ref name=":0" /> There are genetic risk alleles that are predictive of the development of DIHS for particular drugs and ethnic populations.<ref name=":0" /> 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.<ref name=":0" />

AGEP is often caused by antimicrobial, anti-fungal or antimalarial drugs.<ref name=":1" /> Diagnosis is often carried out by [[patch test]]ing. 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.<ref name=":1" />

<ref name="pmid7794310">{{cite journal|date=November 1994|title=Severe adverse cutaneous reactions to drugs|journal=N. Engl. J. Med.|volume=331|issue=19|pages=1272–85|doi=10.1056/NEJM199411103311906|pmid=7794310|vauthors=Roujeau JC, Stern RS}}</ref>

==See also==
* [[Fixed drug reaction]]
* [[List of cutaneous conditions]]
* [[List of human leukocyte antigen alleles associated with cutaneous conditions]]
* [[Stevens–Johnson syndrome]]

==References==
{{Reflist}}

== External links ==
{{Medical resources
|  DiseasesDB     =  
|  ICD10          = {{ICD10|L|27|0|l|20}}, {{ICD10|L|27|1|l|20}} 
|  ICD9           = {{ICD9|692.3}}, {{ICD9|782.1}} 
|  ICDO           =  
|  OMIM           =  
|  MedlinePlus    =  
|  eMedicineSubj  = derm 
|  eMedicineTopic = 104 
|  MeshID         = D003875
}}
{{Diseases of the skin and appendages by morphology}}
{{Dermatitis and eczema}}
{{Urticaria and erythema}}
{{Skin and subcutaneous tissue symptoms and signs}}
{{Hypersensitivity and autoimmune diseases}}
{{External causes of morbidity and mortality}}

{{Authority control}}

[[Category:Drug eruptions| ]]
[[Category:Clinical pharmacology]]