Principales logros del aprendizaje

E S S E N T I A L S O F D I A G N O S I S

» Usually, abrupt onset of widespread, symmetric erythematous eruption.

» May mimic any inflammatory skin condition.

» Constitutional symptoms (malaise, arthralgia, headache, and fever) may be present.

» General Considerations

Only a minority of cutaneous drug reactions result from allergy. Rashes are among the most common adverse reac-tions to medicareac-tions and occur in 2–3% of hospitalized patients. Amoxicillin, TMP-SMZ, and ampicillin or peni-cillin are the most common causes of urticarial and macu-lopapular reactions. SJS and TEN are most commonly produced by sulfonamides, anticonvulsants, allopurinol, and NSAIDs. Drug- induced hypersensitivity reaction (DIHS) (also known as drug eruption with eosinophilia and systemic symptoms [DRESS]) is most often caused by anticonvulsants, allopurinol, and sulfonamides. Phenol-phthalein, pyrazolone derivatives, tetracyclines, NSAIDs, TMP-SMZ, and barbiturates are the major causes of fixed drug eruptions. Calcium channel blockers are a common cause of pruritus and eczemas in the elderly.

Certain genetic polymorphisms of antigen presenting major histocompatibility (MHC) loci increases the risk for the development of severe drug eruptions, including SJS/

TEN and DIHS. Pharmacogenetic testing is becoming increasingly utilized to predict who is at risk for and there-fore should avoid certain medication exposures. For exam-ple, in Han Chinese, HLA typing is indicated before institution of carbamazepine treatment.

» Clinical Findings

Drug eruptions are generally classified as “simple” or “com-plex,” referring to the risk of morbidity and mortality asso-ciated with the specific eruption. Simple drug eruptions involve an exanthem, usually appear in the second week of drug therapy, and have no associated constitutional or laboratory findings. Antibiotics, including the penicillins and quinolones, are the most common causes. Complex drug eruptions include DIHS, SJS, and TEN.

DIHS occurs later than the simple morbilliform drug eruptions with signs and symptoms developing 2–6 weeks after the medication has been started and has associated constitutional and laboratory findings. These may include fevers, chills, hematologic abnormalities (especially eosin-ophilia), and abnormal liver or kidney function. The most common causes are sulfonamides, allopurinol, and anti-convulsants. Coexistent reactivation of certains viruses, such as Epstein-Barr virus, cytomegalovirus, and especially HHV-6, is often present and may be important in the pathogenesis of these complex drug eruptions. Table 6–3

Table 6–3. Skin reactions due to systemic drugs.

Reaction Appearance Distribution and Comments Common Offenders

Toxic erythema Morbilliform, maculopapular,

exanthematous reactions. The most common skin reaction to drugs. Initially begins on trunk 7–10 days after the medication has been started.

Spreads to extremities and begins to clear on the trunk over 3-5 days. In previously exposed patients, the rash may start in 2–3 days. Fever may be present.

Antibiotics (especially ampicillin and TMP-SMZ), sulfonamides and related compounds (including thiazide diuretics, furosemide, and sulfonylurea hypoglycemic agents), and barbiturates.

SJS/TEN Target-like lesions.

Bullae may occur.

Mucosal involvement.

Usually trunk and proximal

extremities. Sulfonamides, anticonvulsants, allopurinol, NSAIDs, lamotrigine.

Erythema nodosum Inflammatory cutaneous nodules.

Usually limited to the extensor aspects of the legs. May be accompanied by fever, arthralgias, and pain.

Oral contraceptives.

Allergic vasculitis The primary lesion is typically a 2–3 mm purpuric papule.

Other morphologies include urticaria that lasts over 24 hours, vesicles, bullae, or necrotic ulcers.

Most severe on the legs. Sulfonamides, phenytoin, propylthiouracil.

Exfoliative dermatitis and

erythroderma Red and scaly. Entire skin surface. Allopurinol, sulfonamides,

isonia-zid, anticonvulsants, or carbamazepine.

Photosensitivity: increased sensitivity to light, often of ultraviolet A wavelengths, but may be due to UVB or visible light as well

Sunburn, vesicles, papules in

photodistributed pattern. Exposed skin of the face, the neck, and the backs of the hands and, in women, the lower legs. Exaggerated response to ultraviolet light.

Sulfonamides and sulfonamide-related compounds (thiazide diuretics, furosemide, sulfonyl-ureas), tetracyclines, phenothi-azines, sulindac, amiodarone, voriconazole, and NSAIDs.

Drug-related subacute cutaneous lupus erythematosus (Drug-induced SLE rarely

produces a skin reaction)

May present with a photosensi-tive rash, annular lesions, or psoriasis on upper trunk.

Less severe than SLE, sparing the kidneys and central nervous system. Recovery often follows drug withdrawal.

Diltiazem, etanercept, hydrochlo-rothiazide, infliximab, lisinopril, terbinafine.

Lichenoid and lichen planus–like

eruptions Pruritic, erythematous to viola-ceous polygonal papules that coalesce or expand to form plaques.

May be in photo- or

nonphotodistributed pattern. Carbamazepine, furosemide, hydroxychloroquine, phenothi-azines, beta-blockers, quini-dine, quinine, sulfonylureas, tetracyclines, thiazides, and triprolidine.

Fixed drug eruptions Single or multiple demarcated, round, erythematous plaques that often become

hyperpigmented.

Recur at the same site when the drug is repeated. Hyperpig-mentation, if present, remains after healing.

Antimicrobials, analgesics, barbi-turates, cardiovascular drugs, heavy metals, antiparasitic agents, antihistamines, phe-nolphthalein, ibuprofen, and naproxen.

Urticaria Red, itchy wheals that vary in size from less than 1 cm to many centimeters. May be accompa-nied by angioedema.

Chronic urticaria is rarely caused

by medications. Acute urticaria: penicillins, NSAIDs, sulfonamides, opioids, and salicylates. Angioedema is common in patients receiving ACE inhibitors and angiotensin receptor blockers.

(continued)

Table 6–3. Skin reactions due to systemic drugs.

Reaction Appearance Distribution and Comments Common Offenders

Pigmentary changes Flat hyperpigmented areas. Forehead and cheeks (chloasma, melasma). The most common pigmentary disorder associ-ated with drug ingestion.

Improvement is slow despite stopping the drug.

Oral contraceptives are the usual cause.

Blue-gray discoloration. Light-exposed areas. Chlorpromazine and related phenothiazines.

Brown or blue-gray

pigmentation. Generalized. Heavy metals (silver, gold,

bismuth, and arsenic).

Yellow color. Generalized. Quinacrine.

Blue-black patches on the shins. Minocycline, chloroquine.

Blue-black pigmentation of the nails and palate and depig-mentation of the hair.

Chloroquine.

Slate-gray color. Primarily in photoexposed areas. Amiodarone.

Brown discoloration of the nails. Especially in more darkly

pig-mented patients. Hydroxyurea.

Psoriasiform eruptions Scaly red plaques. May be located on trunk and extremities. Palms and soles may be hyperkeratotic. May cause psoriasiform eruption or worsen psoriasis.

Antimalarials, lithium, beta-blockers, and TNF inhibitors.

Pityriasis rosea–like eruptions Oval, red, slightly raised patches with central scale.

Mainly on the trunk. Barbiturates, bismuth, captopril, clonidine, methopromazine, metoprolol, metronidazole, and tripelennamine.

ACE, angiotensin-converting enzyme; NSAIDs, nonsteroidal anti-inflammatory drugs; SJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysis; SLE, systemic lupus erythematosus; TMP-SMZ, trimethorim-sulfamethoxazole; TNF, tumor necrosis factor.

(continued)

summarizes the types of skin reactions, their appearance and distribution, and the common offenders in each case.

B. Laboratory Findings

Routinely ordered blood work is of no value in the diagno-sis of simple drug eruptions. In complex drug eruptions, the CBC, liver biochemical tests, and renal function tests should be monitored. Skin biopsies may be helpful in mak-ing the diagnosis. Serum PCR for HHV-6, Epstein-Barr virus, and cytomegalovirus are routinely performed in some centers.

» Differential Diagnosis

Observation after discontinuation, which may be a slow process, helps establish the diagnosis. Rechallenge, though of theoretical value, may pose a danger to the patient and is best avoided.

» Complications

Some cutaneous drug reactions may be associated with visceral involvement. The organ systems involved depend on the individual medication or drug class. Most common

is an infectious mononucleosis-like illness and hepatitis associated with administration of anticonvulsants. Myo-carditis may be a serious complication of drug-induced hypersensitivity syndrome. Months after recovering from DIHS patients may suffer hypothyroidism.

» Treatment

Systemic manifestations are treated as they arise (eg, ane-mia, icterus, purpura). Antihistamines may be of value in urticarial and angioneurotic reactions. Epinephrine 1:1000, 0.5–1 mL intravenously or subcutaneously, should be used as an emergency measure. In DIHS, systemic corticoste-roids are typically required, starting at about 1–1.5 mg/kg/day and tapering very slowly over a minimum of 6 weeks, since rapid taper leads to rebound and more recalcitrant disease.

B. Local Measures

SJS/TEN with extensive blistering eruptions resulting in erosions and superficial ulcerations demands hospitaliza-tion and nursing care as for burn patients.

» Prognosis

Drug rash usually disappears upon withdrawal of the medication and proper treatment. DIHS may be associated with autoimmune phenomena, including abnormal thy-roid function. This can occur months after the hypersensi-tivity syndrome has resolved.

Ahronowitz I et al. Severe drug-induced dermatoses. Semin Cutan Med Surg. 2014 Mar;33(1):49–58. [PMID: 25037258]

Bourgeois GP et al. A review of DRESS-associated myocarditis. J Am Acad Dermatol. 2012 Jun;66(6):e229–36. [PMID:

21658796]

Cheng CY et al. HLA associations and clinical implications in T-cell mediated drug hypersensitivity reactions: an updated review. J Immunol Res. 2014;2014:565320. [PMID: 24901010]

Dodiuk-Gad RP et al. Epidemiology of severe drug hypersensi-tivity. Semin Cutan Med Surg. 2014 Mar;33(1):2–9. [PMID:

25037253]

Husain Z et al. DRESS syndrome: Part II. Management and therapeutics. J Am Acad Dermatol. 2013 May;68(5):709.e1–9.

[PMID: 23602183]

Harp JL et al. Severe cutaneous adverse reactions: impact of immunology, genetics, and pharmacology. Semin Cutan Med Surg. 2014 Mar;33(1):17–27. [PMID: 25037255]

Mockenhaupt M. Stevens-Johnson syndrome and toxic epider-mal necrolysis: clinical patterns, diagnostic considerations, etiology, and therapeutic management. Semin Cutan Med Surg. 2014 Mar;33(1):10–6. [PMID: 25037254]