• An adverse reaction to a drug that is manifested in the skin
• Probably the most frequent adverse reaction to drugs
• 3 major types of reactions
  • Nonimmune cutaneous reactions
    • Photosensitivity eruptions
    • Pigmentation changes
    • Warfarin necrosis of skin
    • Drug-induced hair disorders
    • Drug-induced nail disorders
    • Pruritus
  • Immune cutaneous reactions: benign
    • Maculopapular eruptions
    • Urticaria/angioedema
    • Fixed drug eruptions
  • Immune cutaneous reactions: severe
    • Vasculitis
    • Pustular eruptions: acute generalized exanthematous pustulosis (AGEP)
    • Hypersensitivity syndrome: drug reaction with eosinophilia and systemic symptoms (DRESS)
    • Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

Epidemiology

Prevalence

• >3 billion prescriptions for 60,000 drug products are written each year in the U.S.
• Acute cutaneous reactions to drugs affect 3% of hospital inpatients.
• In a systematic literature review of cutaneous reactions to drugs, reaction rates varied from 0–8% and were highest for antibiotics; rates may be even higher for anti-HIV agents.
  • Amoxicillin: 5.1%
  • Ampicillin: 4.5%
  • Cotrimoxazole: 3.7%
  • Semisynthetic penicillins: 2.9%
  • Penicillin G: 1.6%
  • Cephalosporins: 1.5%
  • Gentamicin: 1.0%
• Most frequent skin reactions in a series of 48,005 inpatients over 20 years
  • Morbilliform rash (i.e., resembles the measles rash) (91%)
  • Urticaria (localized edema presenting as wheals) (6%)
• Severe reactions
  • Incidence has been estimated to be in the range of 1 in 10,000 to 1 in 1 million users
• SJS and TEN
  • Perhaps the most important severe cutaneous reactions
  • The following medications are associated with the highest risk of these reactions:
    • Sulfonamide antibiotics
    • Allopurinol
    • Amine antiepileptic drugs (phenytoin and carbamazepine)
    • Lamotrigine
    • Oxicam NSAIDs (piroxicam, meloxicam)

HIV-infected persons

• Trimethoprim–sulfamethoxazole
  • Up to 40% of HIV-infected patients have skin reactions when treated with high doses of sulfamethoxazole.
  • About 15% reacted to the same dosage that induced eruptions in 3–5% of non-HIV-infected populations.
  • Desensitization can be accomplished.
• Dapsone, trimethoprim alone, and amoxicillin-clavulanate are frequent causes of drug eruptions.

Drugs of special interest

• Allopurinol
  • Induces frequently mild maculopapular eruptions (in at least 3% of users)
  • May also cause more severe reactions including hypersensitivity/DRESS and SJS/TEN
    • Because of increasing utilization, it is one of the most frequent causes of life-threatening reactions.
• Anti-HIV medications
  • In clinical trials, combinations of highly active antiretroviral treatments were frequently associated with ≥10% “drug eruptions.”
  • Nevirapine
    • High risk of maculopapular eruptions
    • Very high risk (about 1 in 1000) of SJS or TEN
  • Abacavir is associated with a 4–5% risk of a hypersensitivity reaction.
    • Risk is lower in patients of African ancestry and strongly correlated with HLAB*5701.
• Penicillin
  • Incidence of cutaneous reaction is about 1%.
    • 85% of reactions are morbilliform.
    • 10% of reactions are urticaria or angioedema.
• NSAIDs
  • 2 categories of allergy-like symptoms
    • 1% experience urticaria or angioedema.
    • 0.5% experience rhinosinusitis and asthma.
• Radiocontrast media
  • Higher-osmolality media are about 5 times more likely to cause urticaria (1%) or anaphylaxis than newer lower-osmolality media.
• Anticonvulsants
  • Lamotrigine: highest risk of severe cutaneous reaction among anticonvulsants
• Sulfonamides
  • Highest risk of cutaneous eruptions
• Vancomycin
  • Linear IgA bullous dermatosis: an autoimmune disorder characterized by pruritic vesiculobullous skin lesions favoring the trunk, proximal extremities, and acral region
  • "Red man syndrome"
    • Occurs during rapid intravenous infusion
    • Thought to be a histamine-related anaphylactoid reaction
    • Characterized by flushing, maculopapular eruption, hypotension, and (rarely) cardiac arrest
• Chemotherapeutic agents
  • May cause a wide range of manifestations involving the skin, nails, hair, and mucous membranes
• Glucocorticoids
  • Can cause a variety of skin changes, including acne, atrophy, striae
• Biologic therapies (cytokines and monoclonal antibodies)
  • Injection-site reactions are the most frequent adverse event.
  • Monoclonal antibodies may induce urticaria, angioedema, anaphylactic reactions, and serum sickness.
  • Interleukin 2 can be associated with exanthema, facial edema and erythema, xerosis, and pruritus.
• Antimalarial drugs
  • Pruritus: occurs in up to 50% of African patients receiving chloroquine
  • Can cause pigmentation disturbances
• Gold
  • Cutaneous reactions can develop as long as 2 years after initiation of therapy and take months to resolve.
• Propylthiouracil
  • May be associated with the development of antineutrophil cytoplasmic antibodies and an associated cutaneous or (rarely) systemic vasculitis

Risk Factors

• Frequent high-dose and interrupted courses of therapy
• High-risk patients
  • Patients who have had bone marrow transplantation
  • HIV-infected persons
  • Persons with acute Epstein-Barr virus infection
  • Patients with collagen vascular diseases
• Genetic factors
  • Specific genetically determined defects in the ability of an individual to detoxify toxic reactive drug metabolites predispose such individuals to the development of drug toxicity.
  • Certain HLA genes, examples include:
    • HLA-B*1502
      • Carbamazepine-associated SJS and TEN occurs more frequently in patients with HLA-B*1502 (almost exclusively found in patients with Asian ancestry, including South Asian Indians)
    • HLA-B*5701
      • Abacavir hypersensitivity syndrome
      • HLA-B*5701 testing is recommended prior to initiating abacavir therapy to reduce the risk of hypersensitivity reaction.
• Increased risk for adverse response to aspirin
  • 10% of adults with asthma
  • One-third of patients with nasal polyposis and sinusitis

Etiology

Immunologic mechanisms (drug allergy)

• For most acute drug eruptions, benign or severe, accumulated data suggest an immunologic basis.
• IgE-dependent reactions
  • Immediate reactions may occur within minutes of drug exposure, and accelerated reactions occur hours or days after drug administration.
  • Release of chemical mediators, such as histamine, adenosine, leukotrienes, prostaglandins, platelet-activating factor, enzymes, and proteoglycans, results in vasodilation and edema.
  • Penicillins and myorelaxants used in general anesthesia are the most frequent causes.
• Immune complex reactions (serum sickness)
  • Because the use of nonhuman sera is now uncommon, this mechanism is rarely relevant to adverse reactions seen currently.
  • Cutaneous or systemic vasculitis, a relatively rare cutaneous complication of drugs, may be a result of immune complex deposition.
    • Drug or metabolite antigen remains in the circulation for prolonged periods so that when antibody is synthesized, circulating antigen–antibody complexes are formed.
    • Offending drugs include the penicillins, sulfonamides, thiouracils, cholecystographic dyes, phenytoin, aminosalicylic acid, heparin, antilymphocyte globulin, and biologic therapies.
• Cytotoxicity and delayed hypersensitivity
  • Drug antigens activate T-lymphocyte populations to produce cytokines such as interleukin 2 and interferon γ and subsequently activate cytotoxic T cells.
  • Probably the most important mechanisms in the etiology of:
    • Most common drug eruptions—morbilliform exanthems
    • Rare and severe forms such as:
      • Hypersensitivity syndrome
      • AGEP
      • SJS
      • TEN

Nonimmunologic mechanisms

• Nonimmunologic activation of effector pathways
  • Drugs may release mediators directly from mast cells and basophils and present as anaphylaxis, urticaria, and/or angioedema.
    • Reactions induced by opiates, polymyxin B, tubocurarine, radiocontrast media, and dextrans may occur by this mechanism.
  • Drugs may activate complement in the absence of antibody.
    • Reactions to radiocontrast media may occur partially by this mechanism.
  • Such drugs as aspirin and other NSAIDs may alter pathways of arachidonic acid metabolism and induce urticaria.
• Phototoxicity
  • Occurs when enough chromophore (drug or metabolic product) absorbs sufficient radiation to cause a reaction or interaction with target tissue
• Exacerbation of preexisting dermatologic conditions
  • A variety of agents can exacerbate preexisting diseases.
    • Lithium can exacerbate acne and psoriasis in a dose-dependent manner.
    • Beta blockers and interferon α may induce psoriasis.
    • Withdrawal of glucocorticoids can exacerbate psoriasis or atopic dermatitis.
• Inherited protein or enzyme deficiencies
  • Specific genetically determined defects in the ability to detoxify toxic reactive drug metabolites may predispose patients to severe drug reactions, especially hypersensitivity syndrome and perhaps TEN associated with use of sulfonamides and anticonvulsants.
• Alterations of immunologic status
  • Alterations in immunologic status may modify the risk of cutaneous reactions.
  • Patients with bone marrow transplants and HIV or Epstein–Barr virus (EBV) infection are at higher risk of cutaneous reactions to drugs (ex: reaction to amoxicillin in EBV-related mononucleosis).
• The mechanism of many drug reactions is unknown.