Drug Eruptions

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Drug Eruptions

• David McSwain, M.D.

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Drug Eruptions

• DRESS Sydrome
• Urticaria
• Angioedema/anaphylaxis
• Drug-induced exanthems
• Hypersensitivity vasculitis
• Exfoliative dermatitis/Erythroderma
• SJS/TEN
• Fixed drug eruption
• Photosensitivity

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DRESS Syndrome

• Drug Rash with Eosinophilia and Systemic Symptoms
• Formerly called Hypersensitivity Syndrome (HSS)
• Typically presents with rash and fever (87),
  classically erythematous follicular papules and
  pustules, but may also include bullae or purpura.
  
• Other severe systemic manifestations such as
  hepatitis (51), arthralgias, lymphadenopathy
  (75), interstitial nephritis (11), or
  hematologic abnormalities (30).
• Hematologic abnormalities include eosinophilia,
  thrombocytopenia, neutropenia, and atypical
  lymphocytosis.
• Other symptoms pruritis, nephritis, oliguria,
  hepato-renal syndrome, athralgia, and asthenia.
• Can affect any organ system (lungs, CNS, GI,
  etc.)
• DDx includes SJS/TEN, hypereosinophilic syndrome,
  and Stills disease.
• Skin biopsy is non-specific.

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DRESS Syndrome

• Common causes aromatic anticonvulsants
  (oxcarbazepine, carbamazepine, phenytoin,
  phenobarbital, etc.) and sulfonamides.
• Other drugs implicated
• lamotrigine
• allopurinol
• NSAIDs
• captopril
• CCBs
• mexiletine
• fluoxetine
• dapsone
• metronidazole
• minocycline
• antiretrovirals.

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DRESS Syndrome

• Overall risk for phenytoin is between 0.1-0.01.
• Usually occurs 2-6 weeks after initiation of the
  medication, which is later than most drug
  eruptions. May be difficult to distinguish from
  serum sickness and vasculitis.
• Median onset of DRESS syndrome after initiation
  of therapy with Trileptal is 13 days (range
  4-60).
• No definite evidence of cross-reactivity with
  other agents, but it is a possibility.
• Treatment is supportive.
• Medication should be stopped as soon as the
  diagnosis is suspected.
• Severity is dependent upon the amount of time the
  drug is continued after hypersensitivity occurs.
• Corticosteroids have been required in some cases,
  but their use is controversial.

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Urticaria

• Time to onset immediate, accelerated (hours), or
  delayed (days).
• Type I hypersensitivity reactions antibiotics
  (especially PCN, cephalosporins, and
  sulfonamides), local anesthetics, radiocontrast
  media, blood products, and gamma globulin.
• Non-immune urticaria radiocontrast media and
  long-acting ACE-inhibitors (due to changes in
  vascular response to bradykinin).
• Mast cell degranulation by non-IgE mechanisms
  opiate analgesics, anesthetic muscle relaxants,
  and Vancomycin (Red Man Syndrome, which can be
  worsened by concommitant opiate use).

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Angioedema/Anaphylaxis

• Caused by degranulation of mast cells in the
  deeper dermis and subcutaneous tissues.
• May occur along with urticaria (50 of cases)
• Can be life-threatening if it causes laryngeal
  edema or tongue swelling.
• Can be non-mast cell mediated, as in the case of
  ACE-inhibitors.

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Drug-induced Exanthems

• Account for close to 75 of all drug eruptions.
• Morbilliform, maculopapular eruptions.
• Most commonly implicated medications are the most
  commonly prescribed medications (antibiotics,
  sulfa).
• Usually begin in dependent areas and generalize.
• Often associated with pruritis, low-grade fever,
  eosinophilia.
• May be the early stage of more severe reactions
  such as toxic epidermal necrolysis, DRESS, or
  serum sickness
• Onset within 2 weeks of starting a new drug, or
  within days of re-exposure.
• Delayed (type IV) hypersensitivity is most likely
  etiology.
• More common in patients with altered immunity,
  such as those with HIV or mononucleosis
  (ampicillin rash).
• Treatment is dicontinuation of the drug.
  Antihistamines, topical steroids, and topical
  antipruritics may also help.

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Hypersensitivity vasculitis

• American College of Rheumatology proposed the
  following five criteria. The presence of three
  or more had a sensitivity of 71 and a
  specificity of 84 for the diagnosis
• Age gt 16
• Use of possible offending drug in temporal
  relation to symptoms
• Palpable purpura
• Maculopapular rash
• Biopsy of a skin lesion showing neutrophils
  around an arteriole or venule.
• Most likely due to drugs that can act as haptens
  to stimulate the immune response PCN,
  cephalosporins, sulfonamides, phenytoin, and
  allopurinol.
• Additional findings fever, urticaria,
  arthralgias, LAD, low complement levels, and
  elevated ESR.

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Exfoliative dermatitis/ Erythroderma

• Erythroderma is defined as a cutaneous reactional
  state with chronic erythema and scale involving
  greater than 50 of the body surface area. It
  can result from drugs, atopic dermatitis,
  psoriasis, and malignancies such as cutaneous
  T-cell lymphoma.
• Drugs, including gold, arsenic, mercury, PCN, and
  barbituates, are implicated in about 10 of
  cases.
• Usually begins as an eczematous or morbilliform
  eruption and progresses.

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SJS/TEN

• Stevens-Johnson Syndrome and toxic epidermal
  necrolysis are likely two manifestations on the
  same spectrum. The disease is best termed SJS
  when epidermal detachment involves less than 10
  of the body surface area, whereas TEN involves
  greater than 30.
• SJS is distinct from erythema multiforme major,
  which is usually caused by infections and runs a
  benign course. SJS is usually drug induced and
  can be fatal.
• SJS and TEN usually occur 1-3 weeks after
  exposure, but can occur more rapidly with
  re-exposure, which suggests an immunologic
  mechanism.
• Mucosal involvement is seen in 90 of cases,
  including painful crusts and erosions on the oral
  mucosa, conjuntivae, and genital mucosa.

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SJS/TEN

• Frozen section of the denuded epidermis will
  reveal full-thickness epidermal necrosis.
• Differential includes exfoliative erythroderma,
  paraneoplastic pemphigus, acute exanthematous
  pustulosis, and staph scalded skin syndrome, but
  none of these disorders displays full-thickness
  epidermal necrosis.
• Patients are best managed as burn victims.
• Corticosteroids are not recommended.

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Fixed Drug Eruptions

• Drug eruption that occurs at the same location
  every time a particular medication is used.
• Begins as an erythematous, edematous plaque with
  a grayish center or frank bullae, then
  progresses to dark, post-inflammatory
  pigmentation.
• Sites include the mouth, genetalia, face, and
  acral areas.
• Causes include phenolphthalein, tetracyclines,
  barbituates, sulfonamides, NSAIDs, and
  salicylates.

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Photosensitivity

• Two types include phototoxic eruptions and
  photoallergic eruptions.
• Phototoxic eruptions are due to absorption of UV
  light (usually UVA) by the drug, which causes a
  release of energy and damage to cells. Looks
  like a bad sunburn, which may blister.
• Photoallergic eruptions are a lymphocyte-mediated
  reaction caused by exposure to UVA, which
  converts the drug to an immunologically active
  compound that activates lymphocytes, causing an
  eczematous reaction in a photodistribution.
• Usually due to topical agents including
  fragrances and biocides in soaps.
• Both types can be caused by phenothiazines,
  chlorpromazine, sulfa, and NSAIDS, although
  phototoxic reactions are more common with these
  agents.

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Reference

• Volcheck, GW. Clinical evaluation and management
  of drug hypersensitivity. Immunol Allergy Clin N
  Am. 24(2004) 357-371.
• UpToDate. Drug Eruptions. Andrew D. Samuel, MD.
  Topic last revised 12/11/2002.
  Http//www.uptodate.com
• Images provided by the Dermatology Image Atlas -
  Johns Hopkins University. http//dermatlas.med.jhm
  i.edu/derm/
• Novartis. Important Drug Warning. 4/18/2005