Drug Eruptions

Drug eruptions can mimic a wide range of dermatoses. The morphologies are myriad and include morbilliform (most common, see image below), urticarial, papulosquamous, pustular, and bullous. Medications can also cause pruritus and dysesthesia without an obvious eruption. Both calcium channel blockers and interferon are strongly associated with eczematous eruptions.

A drug-induced reaction should be considered in any patient who is taking medications and who suddenly develops a symmetric cutaneous eruption. Medications that are known for causing cutaneous reactions include antimicrobial agents,[11] nonsteroidal anti-inflammatory drugs (NSAIDs), cytokines, chemotherapeutic agents, anticonvulsants, and psychotropic agents.

Prompt identification and withdrawal of the offending agent may help limit the toxic effects associated with the drug. The decision to discontinue a potentially vital drug often presents a dilemma.

Drug eruptions may be divided into immunologically and nonimmunologically mediated reactions.

Immunologically mediated reactions

Coombs and Gell proposed four types of immunologically mediated reactions, as follows:

• Type I is immunoglobulin E (IgE)–dependent reactions, which result in urticaria, angioedema, and anaphylaxis (see the image below).

  Urticaria.

• Type II is cytotoxic reactions, which result in hemolysis and purpura (see the image below).

  Oral ulcerations in a patient receiving cytotoxic therapy.

• Type III is immune complex reactions, which result in vasculitis, serum sickness, and urticaria.

• Type IV is delayed-type reactions with cell-mediated hypersensitivity, which result in contact dermatitis, exanthematous reactions, and photoallergic reactions.

Th17 T cells are implicated in many drug eruptions, and sulfamethoxazole induces a T-cell switch mechanism based on the TCRVβ20-1 domain altering peptide-HLA recognition. In severe drug reactions, micro RNA-18a-5p down-regulates the expression of the antiapoptotic B-cell lymphoma/leukemia-2–like protein 10 (BCL2L10), promoting apoptosis.

Insulin and other proteins are associated with type I reactions. Penicillin, cephalosporins, sulfonamides, and rifampin are known to cause type II reactions. Quinine, salicylates, chlorpromazine, and sulfonamides can cause type III reactions. Type IV reactions, the most common mechanism of drug eruptions, are often encountered in cases of contact hypersensitivity to topical medications, such as neomycin. Sulfonamides are most frequently associated with toxic epidermal necrolysis (TEN).

Although most drug eruptions are type IV hypersensitivity reactions, only a minority are IgE-dependent. That is, antibodies can be demonstrated in less than 5% of cutaneous drug reactions. Type IV cell-mediated reactions are not dose dependent, they usually begin 7-20 days after the medication is started, they may involve blood or tissue eosinophilia, and they may recur if drugs chemically related to the causative agent are administered.

Nonimmunologically mediated reactions

Nonimmunologically mediated reactions may be classified according to the following features: accumulation, adverse effects, direct release of mast cell mediators, idiosyncratic reactions, intolerance, Jarisch-Herxheimer phenomenon, overdosage, or phototoxic dermatitis. (Symptoms of Jarisch-Herxheimer reactions disappear with continued therapy. Drug therapy should be continued until the infection is fully eradicated.)

An example of accumulation is argyria (blue-gray discoloration of skin and nails) observed with use of silver nitrate nasal sprays.

Adverse effects are normal but unwanted effects of a drug. For example, antimetabolite chemotherapeutic agents, such as cyclophosphamide, are associated with hair loss.

The direct release of mast cell mediators is a dose-dependent phenomenon that does not involve antibodies. For example, aspirin and other NSAIDs cause a shift in leukotriene production, which triggers the release of histamine and other mast-cell mediators. Radiographic contrast material, alcohol, cytokines, opiates, cimetidine, quinine, hydralazine, atropine, vancomycin, and tubocurarine also may cause release of mast-cell mediators.

Idiosyncratic reactions are unpredictable and not explained by the pharmacologic properties of the drug. An example is the individual with infectious mononucleosis who develops a rash when given ampicillin.

Imbalance of endogenous flora may occur when antimicrobial agents preferentially suppress the growth of one species of microbe, allowing other species to grow vigorously. For example, candidiasis frequently occurs with antibiotic therapy.

Intolerance may occur in patients with altered metabolism. For example, individuals who are slow acetylators of the enzyme N -acetyltransferase are more likely than others to develop drug-induced lupus in response to procainamide.

Jarisch-Herxheimer phenomenon is a reaction due to bacterial endotoxins and microbial antigens that are liberated by the destruction of microorganisms. The reaction is characterized by fever, tender lymphadenopathy, arthralgias, transient macular or urticarial eruptions, and exacerbation of preexisting cutaneous lesions. The reaction is not an indication to stop treatment because symptoms resolve with continued therapy. This reaction can be seen with penicillin therapy for syphilis, griseofulvin or ketoconazole therapy for dermatophyte infections, and diethylcarbamazine therapy for oncocerciasis.

Overdosage is an exaggerated response to an increased amount of a medication. For example, increased doses of anticoagulants may result in purpura.

Phototoxic dermatitis is an exaggerated sunburn response caused by the formation of toxic photoproducts, such as free radicals or reactive oxygen species (see the image below).

Fibrosing reactions have been associated with a variety of chemical exposures. Nephrogenic systemic fibrosis has been associated with gadolinium contrast agents used for MRI studies. Individuals with renal failure may have a buildup gadolinium in the skin and other organs and may recruit CD34-positive bone marrow–derived fibrocytes into lesional areas. Toxic oil ingestion has been associated with morphea, and Texier disease has been associated with phytomenadione (vitamin-K1) injections.

Rates of reactions to commonly used drugs are as follows:

• Amoxicillin - 5.1%

• Trimethoprim sulfamethoxazole - 4.7%

• Ampicillin - 4.2%

• Semisynthetic penicillin - 2.9%

• Blood (whole human) - 2.8%

• Penicillin G - 1.6%

• Cephalosporins - 1.3%

• Quinidine - 1.2%

• Gentamicin sulfate - 1%

• Packed red blood cells - 0.8%

• Mercurial diuretics - 0.9%

• Heparin - 0.7%

Cutaneous reaction rates in patients with HIV infection are as follows[12] :

• Sulfasalazine - 20%

• Trimethoprim-sulfamethoxazole - 14.9%

• Dapsone - 3.1%

• Aminopenicillins - 9.3%

• Penicillins - 3.8%

• Anticonvulsants - 3.4%

• Penicillinase-resistant penicillins - 2.9%

• Cephalosporins - 2.7%

• Quinolones - 2.1%

• Ketoconazole - 2%

• Clindamycin - 1.8%

• Primaquine - 1.8%

• Tetracycline - 1.2%

• Pentamidine - 1%

• NSAIDs - 0.9%

• Erythromycin - 0.6%

• Zidovudine - 0.3%

Drugs that commonly cause serious reactions are as follows:

• Allopurinol

• Anticonvulsants

• NSAIDs

• Sulfa drugs

• Bumetanide

• Captopril

• Furosemide

• Penicillamine

• Piroxicam

• Thiazide diuretics

Drugs unlikely to cause skin reactions are as follows:

• Digoxin

• Meperidine

• Acetaminophen

• Diphenhydramine hydrochloride

• Aspirin

• Aminophylline

• Prochlorperazine

• Ferrous sulfate

• Prednisone

• Codeine

• Tetracycline

• Morphine

• Regular insulin

• Warfarin

• Folic acid

• Methyldopa

• Chlorpromazine

• Serotonin-specific reuptake inhibitors

• Topical gels (eg, 4% tetracaine gel may cause serious cutaneous adverse reactions)[13]

Drugs associated with specific morphologic patterns are described below. The following is a list of medications that have been reported to cause specific types of cutaneous reactions. However, not every possible type of drug eruption has been listed. In addition, exclusion of a drug from the following list does not imply that it is not the cause of a patient's eruption. A high index of suspicion must always be maintained when confronted with a new onset eruption in a patient on multiple medications. Note the following:

• Acneiform - Amoxapine, corticosteroids (see the image below), halogens, haloperidol, hormones, isoniazid, lithium, phenytoin, and trazodone

  Steroid acne. Note pustules and absence of comedones.

• AGEP - Most commonly beta-lactam antibiotics, macrolides, and mercury; less commonly acetaminophen, allopurinol, bufexamac, buphenine, carbamazepine, carbutamide, celecoxib, chloramphenicol, clindamycin, co-trimoxazole, clobazam, cyclins (eg, tetracycline), cytarabine, diltiazem, famotidine, furosemide, ginkgo biloba, hydrochlorothiazide, hydroxychloroquine, ibuprofen, imatinib, imipenem, isoniazid, IV contrast dye, lopinavir-ritonavir, mexiletine, morphine, nadoxolol, nifedipine, nystatin, olanzapine, phenytoin, pipemidic acid, piperazine, pseudoephedrine, pyrimethamine, quinidine, ranitidine, rifampicin, salbutiamine, sertraline, simvastatin, streptomycin, terbinafine, thallium, vancomycin, calcium channel blockers, ACE inhibitors (eg, captopril, ramipril), glyburide, and gemfibrozil.[14]

• Alopecia - ACE inhibitors, allopurinol, anticoagulants, azathioprine, bromocriptine, beta-blockers, cyclophosphamide, didanosine, hormones, indinavir, NSAIDs, phenytoin, methotrexate (MTX), retinoids, and valproate

• Bullous pemphigoid - Ampicillin, D-penicillamine, captopril, chloroquine, ciprofloxacin, enalapril, furosemide, neuroleptics, penicillins, phenacetin, psoralen plus UV-A, salicylazosulfapyridine, sulfasalazine, and terbinafine

• Dermatomyositislike[15] - BCG vaccine, hydroxyurea (most common[16] ), lovastatin, omeprazole, penicillamine, simvastatin, and tegafur

• DRESS syndrome - Most commonly, aromatic anticonvulsants (phenytoin, phenobarbital [phenobarbitone], carbamazepine), sulfonamides, minocycline, and doxycycline[17]

• Erythema nodosum - Echinacea, halogens, oral contraceptives (most common), penicillin, sulfonamides, and tetracycline

• Erythroderma - Allopurinol, anticonvulsants, aspirin, barbiturates, captopril, carbamazepine, cefoxitin, chloroquine, chlorpromazine, cimetidine, diltiazem, griseofulvin, lithium, nitrofurantoin, omeprazole, phenytoin, St. John's wort, sulfonamides, and thalidomide

• Fixed drug eruptions - Acetaminophen, ampicillin, anticonvulsants, aspirin/NSAID, barbiturates, benzodiazepines, butalbital, cetirizine, ciprofloxacin, clarithromycin, dapsone, dextromethorphan, doxycycline, fluconazole, hydroxyzine, lamotrigine, loratadine, metronidazole, oral contraceptives, penicillins, phenacetin, phenolphthalein, phenytoin, piperacillin/tazobactam,[18] piroxicam, saquinavir, sulfonamides, tetracyclines, ticlopidine, tolmetin, vancomycin, and zolmitriptan

• Hypersensitivity syndrome - Allopurinol, amitriptyline, carbamazepine, dapsone, lamotrigine, minocycline, NSAIDs, olanzapine, oxcarbazepine, phenobarbital, phenytoin, saquinavir, spironolactone, sulfonamides, zalcitabine, and zidovudine

• Lichenoid[19] - Amlodipine, antimalarials, beta-blockers, captopril, diflunisal, diltiazem, enalapril, furosemide, glimepiride, gold, leflunomide, levamisole, L-thyroxine, orlistat, penicillamine, phenothiazine, pravastatin, proton pump inhibitors, rofecoxib, salsalate, sildenafil, tetracycline, thiazides, and ursodeoxycholic acid

• Linear IgA dermatosis[20] - Atorvastatin, captopril, carbamazepine, diclofenac, glibenclamide, lithium, phenytoin, and vancomycin

• Lupus erythematosus[21] : Drug-induced SLE is most commonly associated with hydralazine, procainamide, and minocycline. Beta-blockers, chlorpromazine, cimetidine, clonidine, estrogens, isoniazid, lithium, lovastatin, methyldopa, oral contraceptives, quinidine, sulfonamides, tetracyclines, and tumor necrosis factor (TNF)–alpha inhibitors have been reported. Drug-induced SCLE is most commonly associated with hydrochlorothiazide. Calcium channel blockers, cimetidine, griseofulvin, leflunomide, terbinafine, and TNF-alpha inhibitors have been reported.

• Morbilliform (exanthematous) - ACE inhibitors, allopurinol, amoxicillin, ampicillin, anticonvulsants, barbiturates, carbamazepine, cetirizine, ginkgo biloba, hydroxyzine, isoniazid, nelfinavir, NSAIDs, phenothiazine, phenytoin, quinolones, sulfonamides, thalidomide, thiazides, trimethoprim-sulfamethoxazole, and zalcitabine

• Pemphigus[22] : Thiols include captopril, D-penicillamine, gold sodium thiomalate, mercaptopropionylglycine, pyritinol, thiamazole, and thiopronine. Nonthiols include aminophenazone, aminopyrine, azapropazone, cephalosporins, heroin, hydantoin, imiquimod, indapamide, levodopa, lysine acetylsalicylate, montelukast, oxyphenbutazone, penicillins, phenobarbital, phenylbutazone, piroxicam, progesterone, propranolol, and rifampicin.

• Photosensitivity - ACE inhibitors, amiodarone, amlodipine, celecoxib, chlorpromazine, diltiazem, furosemide, griseofulvin, lovastatin, nifedipine, phenothiazine, piroxicam, quinolones, sulfonamides, tetracycline, and thiazide

• Pseudoporphyria - Amiodarone, bumetanide, chlorthalidone, cyclosporine, dapsone, etretinate, 5-fluorouracil, flutamide, furosemide, hydrochlorothiazide/triamterene, isotretinoin, NSAIDs (including nalidixic acid and naproxen), oral contraceptive pills, and tetracycline

• Psoriasis[23, 24, 25] - ACE inhibitors, angiotensin receptor antagonists, antimalarials, beta-blockers, bupropion, calcium channel blockers, carbamazepine, interferon (IFN) alfa, lithium, metformin, NSAIDs, terbinafine, tetracyclines, valproate sodium, and venlafaxine

• Serum sickness[26] - Antithymocyte globulin for bone marrow failure, human rabies vaccine, penicillin, pneumococcal vaccine (in AIDS patients), and vaccines containing horse serum derivatives

• Serum sickness–like - Beta-lactam antibiotics,[27] cefaclor (most common), minocycline, propranolol, streptokinase, sulfonamides, and NSAIDs

• SJS[28, 29, 30] - Allopurinol, anticonvulsants, aspirin/NSAIDS, barbiturates, carbamazepine, cimetidine, ciprofloxacin, codeine, didanosine, diltiazem, erythromycin, furosemide, griseofulvin, hydantoin, indinavir, nitrogen mustard, penicillin, phenothiazine, phenylbutazone, phenytoin, ramipril, rifampicin, saquinavir, sulfonamides, tetracyclines, and trimethoprim-sulfamethoxazole

• Sweet syndrome - All-trans -retinoic acid, celecoxib, granulocyte colony-stimulating factor, nitrofurantoin, oral contraceptives, tetracyclines, and trimethoprim-sulfamethoxazole

• TEN - Alfuzosin, allopurinol, anticonvulsants, aspirin/NSAIDs, sulfadoxine and pyrimethamine (Fansidar), isoniazid, lamotrigine, lansoprazole, letrozole, penicillins, phenytoin, prazosin, sulfonamides, tetracyclines, thalidomide, trimethoprim-sulfamethoxazole, and vancomycin

• Urticaria - ACE inhibitors, alendronate, aspirin/NSAIDs, blood products, cephalosporins, cetirizine, clopidogrel, dextran, didanosine, infliximab, inhaled steroids, nelfinavir, opiates, penicillin, peptide hormones, polymyxin, proton pump inhibitors, radiologic contrast material, ranitidine, tetracycline, vaccines, and zidovudine

• Vasculitis - Adalimumab, allopurinol, aspirin/NSAIDs, cimetidine, gold, hydralazine, indinavir, leflunomide, levofloxacin, minocycline, montelukast, penicillin, phenytoin, propylthiouracil, proton pump inhibitors, quinolones, ramipril, sulfonamide, tetracycline, thiazides, and thioridazine

• Vesiculobullous (other) - ACE inhibitors, aspirin/NSAIDs, barbiturates, captopril, cephalosporins, entacapone, estrogen, furosemide, griseofulvin, influenza vaccine, penicillamine, penicillins, sertraline sulfonamides, and thiazides

• Photosensitivity reaction - Long-term use of voriconazole causes significantly increased photosensitivity, resulting in some patients developing squamous cell carcinoma[31] and melanoma.[32] Recent studies have shown dose-dependent increased risk for squamous cell carcinoma: 5.6% with each 60-day exposure at a standard dose of 200 mg twice daily. At 5 years after transplantation, voriconazole conferred an absolute risk increase for squamous cell carcinoma of 28%.

Psychotropic drugs associated with specific morphologic patterns are as follows[33] :

• Alopecia - Carbamazepine, fluoxetine, lamotrigine, lithium, gabapentin, and valproic acid

• EM - Barbiturates, carbamazepine, diazepam overdose, fluoxetine, gabapentin, lithium plus trazodone concurrently, phenobarbital, risperidone, sertraline, and valproic acid

• Morbilliform (exanthematous) - Alprazolam, barbiturates, bupropion, carbamazepine, chlorpromazine, desipramine, fluoxetine, lithium, maprotiline, nefazodone, risperidone, and trazodone

• Photosensitivity - All antipsychotics, barbiturates, carbamazepine, chlorpromazine, doxepin, imipramine, thioridazine, and valproic acid

• Pigmentation - Amitriptyline, carbamazepine, chlorpromazine, clozapine, diazepam following dermabrasion, gabapentin, haloperidol, lamotrigine, perphenazine, and thioridazine

• Urticaria - Bupropion, carbamazepine, chlordiazepoxide, fluoxetine, imipramine, lamotrigine, lithium, paroxetine, and trazodone

• Vasculitis - Fluoxetine, maprotiline, paroxetine, and trazodone

Chemotherapeutic agents associated with specific morphologic patterns are as follows:

• Acneiform - Cetuximab,[34] dactinomycin, erlotinib,[34] fluoxymesterone, gefitinib, medroxyprogesterone, and vinblastine[35]

• Acral erythema (erythrodysesthesia) - Capecitabine, cisplatin, clofarabine, cyclophosphamide, cytarabine, docetaxel, doxorubicin, fluorouracil, gemcitabine, MTX, tegafur, and vinorelbine

• Alopecia: All classes of chemotherapeutic agents are associated with alopecia. Commonly associated drugs include alkylating agents, anthracyclines, bleomycin, doxorubicin, hydroxyurea, MTX, mitomycin, mitoxantrone, vinblastine, and vincristine. Busulfan and cyclophosphamide administered in combination can cause permanent hair loss. Nilotinib (Tasigna) is a potent and selective bcr-abl kinase inhibitor currently used to treat imatinib-resistant chronic myeloid leukemia. Clinically, the reaction can present as pink/fleshy perifollicular papules with diffuse alopecia, without follicular drop-out. Histologically, it can demonstrate scarring or nonscarring alopecia with mixed features.[36, 37] Note the images below.

  Male-pattern diffuse hair loss.

  Pink/fleshy perifollicular papules with diffuse alopecia.

  Horizontal section shows perifollicular fibrosis consistent with scarring alopecia.

• EM - Busulfan, chlorambucil, cyclophosphamide, diethylstilbestrol (DES), etoposide, hydroxyurea, mechlorethamine, MTX, mitomycin C, mitotane, paclitaxel, and suramin

• Erythema nodosum - Busulfan, DES, and imatinib

• Fixed drug eruptions - Dacarbazine, hydroxyurea, paclitaxel, and procarbazine

• Hyperpigmentation - Bischloroethylnitrosourea (BCNU; carmustine), bleomycin, busulfan, brequinar, cisplatin, cyclophosphamide, dactinomycin, daunorubicin, docetaxel, doxorubicin, fluorouracil, fotemustine, hydroxyurea, ifosfamide, MTX, mithramycin, mitoxantrone, nitrogen mustard, procarbazine, tegafur, thiotepa, and vinorelbine

• Lichenoid - Hydroxyurea, imatinib, and tegafur

• Lupus - Aminoglutethimide, DES, hydroxyurea, leuprolide, and tegafur

• Morbilliform (exanthematous) - Bleomycin, carboplatin, cis -dichloro-trans -dihydroxy-bis -isopropylamine platinum (CHIP), chlorambucil, cytarabine, docetaxel, DES, doxorubicin, etoposide, 5-fluorouracil, hydroxyurea, MTX, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, procarbazine, suramin, and thiotepa

• TEN - Asparaginase, bleomycin, chlorambucil, cladribine, cytarabine, doxorubicin, 5-fluorouracil, MTX, plicamycin, procarbazine, and suramin

• Urticaria[38] - Amsacrine, bleomycin, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cytarabine, daunorubicin, diaziquone, didemnin, DES, docetaxel, doxorubicin, epirubicin, etoposide, 5-fluorouracil, mechlorethamine, melphalan, MTX, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, procarbazine, teniposide, thiotepa, trimetrexate, vincristine, and zinostatin

• Vasculitis - Busulfan, cyclophosphamide, cytarabine, hexamethylene bisacetamide (HMBA), hydroxyurea, imatinib, levamisole, 6-mercaptopurine, MTX, mitoxantrone, rituximab, and tamoxifen

Cutaneous reactions to targeted chemotherapy are as follows:

• Epidermal growth factor receptor inhibitors (eg, gefitinib, cetuximab, erlotinib[39] - Abnormal scalp, face hair, and/or eyelash growth, anaphylactic infusion reaction (cetuximab), papules and annular plaques, paronychia with/without pyogenic granulomas, telangiectasias, and xerosis.[40] See the images below.

  Paronychia.

  Papules and annular plaques.

  Superficial and mid-dermal perivascular infiltrate of lymphocytes and eosinophils. Foci of extravasation of erythrocytes.

• Sorafenib[41] (a novel multikinase inhibitor) - Hand-foot skin reaction, facial and scalp eruption, scalp dysesthesia, subungual splinter hemorrhages, alopecia, body hair loss, stomatitis, nipple hyperkeratosis or pain, and eruptive facial cysts

• Vemurafenib is a systemic medication recently approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma. Vemurafenib selectively targets a specific BRAF mutation, V600E, in melanoma cells that allows unchecked proliferation of malignant cells. An unintended consequence of this medication has been the development of squamous cell carcinomas and keratoacanthomas in approximately a fourth of patients receiving the drug. There are some reports discussing the development of nonmalignant milia in a patient treated with vemurafenib.[42] See the images below.

  Numerous milia in a patient treated with vemurafenib.

  Dilated infundibular cyst.

• Ipilimumab and vemurafenib each improve the overall survival of patients with metastatic melanoma. Patients with stage IV melanoma harboring a BRAF V600E mutation treated with vemurafenib after receiving ipilimumab can develop a pruritic, grade 3 (severe), maculopapular within 6-8 days after the start of treatment with vemurafenib.[43] .

• Tamoxifen, an antiestrogenic agent, has been widely used as adjuvant hormonal therapy in the treatment of breast cancer. Distinctive cutaneous eruptions present clinically as papules and plaques and histopathologically are characterized by squamous metaplasia of eccrine ductal epithelium. The condition has varied etiologies and can occur as a drug reaction, with chemotherapeutic drugs being frequently implicated.[44]

Cutaneous reactions to cytokine therapy are as follows[45] :

• Erythropoietin - Abnormal hair growth, localized rash, palpebral edema, and widespread eczema

• Granulocyte colony stimulating factor - Exacerbation of preexisting psoriasis, leukocytoclastic, localized erythema, localized pruritus, Sweet syndrome, and vasculitis

• Granulocyte macrophage colony-stimulating factor - Alopecia, epidermolysis, exacerbation of vasculitis, exfoliative dermatitis, flushing, localized erythema, localized wheals, maculopapular eruptions, pruritus, purpura, and urticaria

• IFN-alfa - Alopecia, anasarca, cutaneous vascular lesions, eosinophilic fasciitis, exacerbation of preexisting herpes labialis, facial erythema, fixed drug eruption, hyperpigmentation, nummular eczema, paraneoplastic pemphigus, pruritus, psoriasis, sarcoidosis, SLE, urticaria, and xerostomia

• IFN-beta - Fatal pemphigus vulgaris (when used in combination with interleukin (IL)–2, localized reactions (common), and urticaria

• IFN-gamma - Increased relapses in melanoma and localized inflammation

• IL-1alpha - Mucositis, phlebitis, Shwartzman reaction, and xerostomia

• IL-1beta - Erythema at surgical wound sites, phlebitis, and rash

• IL-2 - Blisters, cutaneous ulcers, desquamation, erythema, erythema nodosum, erythroderma, exacerbation of autoimmune skin disorders, flushing, hypersensitivity to iodine contrast material, necrosis, pruritus, telogen effluvium, TEN, and urticaria

• IL-3 - Facial flushing, hemorrhagic rash, thrombophlebitis, and urticaria

• IL-4 - Facial and peripheral edema, Grover disease, and papular rash

• IL-6 - Diffuse erythematous scaling macules and papules

• TNF-alpha antagonists can also cause Sweet-like hypersensitivity reactions and neutrophilic eccrine hidradenitis in addition to pustular folliculitis, psoriasis, interface dermatitis, lupus, vasculitis, and palmoplantar pustulosis.[46]

• IL-12 and IL-23 monoclonal antibodies[47] - Injection site reactions

United States

Drug eruptions occur in approximately 2-5% of inpatients and in greater than 1% of outpatients.

International

Drug eruptions occur in approximately 2-3% of inpatients.

Sex

Adverse cutaneous reactions to drugs are more prevalent in women than in men.

Age

Elderly patients have an increased prevalence of adverse drug reactions.

Most drug eruptions are mild, self-limited, and usually resolve after the offending agent has been discontinued. Even after the responsible agent is discontinued, drug eruptions may clear slowly or worsen over the next few days. The degree of eosinophilia is predictive of the severity of the drug eruption.[48, 49] The time required for total clearing may be 1-2 weeks or longer.

Severe and potentially life-threatening eruptions occur in approximately 1 in 1000 hospital patients. Mortality rates for erythema multiforme (EM) major are significantly higher. Stevens-Johnson syndrome (SJS) has a mortality rate of less than 5%, whereas the rate for TEN approaches 20-30%; most patients die from sepsis.

Patients with exanthematous eruptions should be counseled to expect mild desquamation as the rash resolves.

Patients with hypersensitivity syndrome are at risk of becoming hypothyroid, usually within the first 4-12 weeks after the reaction.

The prognosis for patients with TEN is guarded. Scarring, blindness, and death are possible.

If the responsible drug is identified, advise the patient to avoid that drug in the future. Clearly label the medical record. Advise patients to carry a card or some other form of emergency identification in their wallets that lists drug allergies and/or intolerances, especially if they have had a severe reaction.

Advise patients about drugs that are cross-reactive and about drugs that must be avoided. For example, penicillin allergy reactions have cross-reactivity with cephalosporins, phenytoin hypersensitivity syndrome has cross-reactivity with phenobarbital and carbamazepine, and sulfonamide reactions cross-react with other sulfa-containing drugs.

For patient education resources, see the Allergy Center.

The first step is to review the patient's complete medication list, including over-the-counter supplements. Document any history of previous adverse reactions to drugs or foods. Consider alternative etiologies, especially viral exanthems and bacterial infections. Exanthematous eruptions in children are more likely to be due to a viral infection than another infection; however, most such reactions in adults are due to medications.

Note any concurrent infections, metabolic disorders, or immunocompromise (eg, due to HIV infection, cancer, chemotherapy) because these increase the risk of drug eruptions. Immunocompromised persons have a 10-fold higher risk of developing a drug eruption than the general population. Although HIV infection causes profound anergy to other immune stimuli, the frequency of drug hypersensitivity reactions, including severe reactions (eg, TEN), is markedly increased in HIV-positive individuals. Patients with advanced HIV infection (CD4 count < 200 cells/µL) have a 10- to 50-fold increased risk of developing an exanthematous eruption to sulfamethoxazole.

Note and detail the following:

• All prescription and over-the-counter drugs, including topical agents, vitamins, and herbal and homeopathic remedies

• The interval between the introduction of a drug and onset of the eruption

• Route, dose, duration, and frequency of drug administration

• Use of parenterally administered drugs, which are more likely than oral agents to cause anaphylaxis

• Use of topically applied drugs, which are more likely than other drugs to induce delayed-type hypersensitivity reactions

• Use of multiple courses of therapy and prolonged administration of a drug, which can cause allergic sensitization

• Any improvement after drug withdrawal and any reaction with readministration

Although most drug eruptions are exanthematous, different types of drug eruptions are described.

With every drug eruption, it is important to evaluate for certain clinical features that may indicate a severe, potentially life-threatening drug reaction, such as TEN or hypersensitivity syndrome. Such features include the following:

• Mucous membrane erosions

• Blisters (Blisters herald a severe drug eruption.)

• Nikolsky sign (epidermis sloughs with lateral pressure; indicates serious eruption that may constitute a medical emergency)

• Confluent erythema

• Angioedema and tongue swelling

• Palpable purpura

• Skin necrosis (see the image below)

  Warfarin (Coumadin) necrosis involving the leg.

• Lymphadenopathy

• High fever, dyspnea, or hypotension

Appreciating the morphology and features of drug eruptions is important. This can help the clinician determine the causative medication and the most appropriate treatment.

Acneiform

This is characterized by inflammatory papules or pustules that have a follicular pattern. They are localized primarily on the upper body. In contrast to acne vulgaris, comedones are absent in acneiform eruptions.

Acral erythema (erythrodysesthesia)

This is a relatively common reaction to chemotherapy and is characterized by symmetric tenderness, edema, and erythema of the palms and soles. It is thought to be a direct toxic effect on the skin. Acral erythema often resolves 2-4 weeks after chemotherapy is discontinued.

Acute generalized exanthematous pustulosis (AGEP)

Acute-onset fever and generalized scarlatiniform erythema occur with many small, sterile, nonfollicular pustules. The clinical presentation is similar to pustular psoriasis, but AGEP has more marked hyperleukocytosis with neutrophilia and eosinophilia. Most cases are caused by drugs (primarily antibiotics) often in the first few days of administration. A few cases are caused by viral infections, mercury exposure, or UV radiation. AGEP resolves spontaneously and rapidly, with fever and pustules lasting 7-10 days then desquamation over a few days.

Dermatomyositis like

Cutaneous findings include dermatomyositis (eg, Gottron papules), but patients tend to lack muscle involvement, associated malignancy, and antinuclear antibodies. Improvement is usually noted after the drug is withdrawn.

DRESS (ie, drug reaction with eosinophilia and systemic symptoms) syndrome or DIHS drug-induced hypersensitivity syndrome

These are characterized by the triad of fever, skin eruption, and internal organ involvement, and they usually are associated with intake of anticonvulsant drugs.

Erythema multiforme

This includes a spectrum of diseases (eg, EM minor, EM major), as described below; however, many authorities categorize SJS and TEN as EM major and differentiate them by body surface involvement

• EM minor - Overall, this is a mild disease; patients are healthy. It is characterized by target lesions distributed predominantly on the extremities (see the images below). Mucous membrane involvement may occur but is not severe. Patients with EM minor recover fully, but relapses are common. Most cases are due to infection with herpes simplex virus, and treatment and prophylaxis with acyclovir is helpful.

  Erythema multiforme.

  Target lesions of erythema multiforme.

• SJS: This is characterized by widespread skin involvement, large and atypical targetoid lesions, significant mucous membrane involvement, constitutional symptoms, and sloughing of 10% of the skin. SJS can be caused by drugs and infections (especially those due to Mycoplasma pneumoniae).

• SJS/TEN overlap: Epidermal detachment involves 10-30% of body surface area.

• TEN: This is a severe skin reaction that involves a prodrome of painful skin (not unlike sunburn) quickly followed by rapid, widespread, full-thickness skin sloughing. It typically affects 30% or more the total body surface area (see the images below). Secondary infection and sepsis are major concerns, and pneumonia may develop from aspiration of sloughed mucosa. Most cases are due to drugs. The risk of TEN in HIV-positive patients is 1000-fold higher than in the general population.

  Toxic epidermal necrolysis.

  Stevens-Johnson syndrome.

Erythema nodosum

This is characterized by tender, red, subcutaneous nodules that typically appear on the anterior aspect of the legs. Lesions do not suppurate or become ulcerated (see the image below). It is a reactive process often secondary to infection, but it may be due to medications, especially oral contraceptives and sulfonamides.

Erythroderma

This is widespread inflammation of the skin (see the image below), and it may result from an underlying skin condition, drug eruption, internal malignancy, or immunodeficiency syndrome. Lymphadenopathy is often noted, and hepatosplenomegaly, leukocytosis, eosinophilia, and anemia may be present.

Fixed drug eruptions

Lesions recur in the same area when the offending drug is given (see the image below). Circular, violaceous, edematous plaques that resolve with macular hyperpigmentation is characteristic. Lesions occur 30 minutes to 8 hours after drug administration. Perioral and periorbital lesions may occur, but the hands, feet, and genitalia are the most common locations.

Hypersensitivity syndrome

This is a potentially life-threatening complex of symptoms often caused by anticonvulsants. Patients have fever, sore throat, rash, lymphadenopathy, hepatitis, nephritis, and leukocytosis with eosinophilia. It usually begins within 1-3 weeks after a new drug is started, but it may develop 3 months or later into therapy. Aromatic anticonvulsant drugs cross-react (ie, phenytoin, phenobarbital, carbamazepine); valproic acid is a safe alternative.

Leukocytoclastic vasculitis

This is the most common severe drug eruption seen in clinical practice (see the image below). It is characterized by blanching erythematous macules quickly followed by palpable purpura. Fever, myalgias, arthritis, and abdominal pain may be present. It typically appears 7-21 days after the onset of drug therapy, and a laboratory evaluation to exclude internal involvement is mandatory.

Lichenoid

This reaction appears similar to lichen planus and may be severely pruritic (see the image below). The eruption may include eczematous or psoriasiform papules.

Lupus

Drug-induced systemic lupus erythematosus (SLE) produces symptoms identical to those of SLE, but skin findings are uncommon. Lesions are also identical to drug-induced subacute cutaneous lupus erythematosus (SCLE), which is characterized by annular, psoriasiform, nonscarring lesions in a photodistributed pattern.

Morbilliform or exanthematous

This is the most common pattern of drug eruptions; it is the quintessential drug rash. Exanthem is typically symmetric, with confluent erythematous macules and papules that spare the palms and soles. It typically develops within 2 weeks after the onset of therapy.

Pseudoporphyria[7]

While largely a drug-induced condition, it can also occur with use of tanning beds and hemodialysis. Patients have blistering and skin fragility that is clinically and pathologically (see the image below) identical to that of porphyria cutanea tarda, but hypertrichosis and sclerodermoid changes are absent and urine and serum porphyrin levels are normal. Treatment is sun protection and withdrawal of the medication.

Serum sickness and serum sickness–like

These are type III hypersensitivity reactions mediated by the deposition of immune complexes in small vessels, activation of complement, and recruitment of granulocytes. Cutaneous signs typically begin with erythema on the sides of the fingers, hands, and toes and progress to a widespread eruption (most often morbilliform or urticarial). Viscera may be involved, and fever, arthralgia, and arthritis are common. Serum sickness–like reactions have a clinical presentation similar to that of serum sickness reactions, without the immune complex deposition. Renal involvement is rare. Serum sickness–like reactions usually occur with antibiotic therapy, especially with cefaclor.

Sweet syndrome (acute febrile neutrophilic dermatosis)

Tender erythematous papules and plaques occur most often on the face, neck, upper trunk, and extremities. The surface of the lesions may become vesicular or pustular. Systemic findings are common and include fever (most often), arthritis, arthralgias, conjunctivitis, episcleritis, and oral ulcers. Laboratory evaluation usually reveals an elevated sedimentation rate, neutrophilia, and leukocytosis. Sweet syndrome often occurs in association with cancers, inflammatory disorders, pregnancy, and medication use.

Urticaria

This usually occurs as small wheals that may coalesce or may have cyclical or gyrate forms. Lesions usually appear shortly after the start of drug therapy and resolve rapidly when the drug is withdrawn (see the image below). Giant urticaria is easily mistaken for EM.

Vesiculobullous

These reactions can resemble pemphigus, bullous pemphigoid, linear immunoglobulin A (IgA) dermatosis, dermatitis herpetiformis, herpes gestationis, or cicatricial pemphigoid. Most causative drugs have a thiol group, disulfide bonds, or sulfur-containing rings that are metabolized to thiol forms. Thiol-induced pemphigus tends to resemble pemphigus foliaceus or pemphigus erythematosus; nonthiol eruptions may resemble pemphigus vulgaris or pemphigus vegetans. Mucosal findings may be most common with nonthiol drugs. Results from direct and indirect immunofluorescence may be positive in persons with drug-induced pemphigus and bullous pemphigoid. Eruptions usually resolve after the inducing drug is discontinued, but D-penicillamine–induced pemphigus may take months to resolve and corticosteroids are often needed.

(Also see the Pill Identifier tool.)

The diagnosis and management of adverse reactions attributable to cancer therapies is a rapidly growing and evolving area. The side effects of conventional cytotoxic chemotherapies are extensive and include mucositis, alopecia, pigmentary changes and changes attributable to cytopenias.

Diffuse hyperpigmentation can be seen in busulfan therapy.  Flagellate serpentine pigmentation can be seen with ifosfamide, docetaxel, and other agents in addition to bleomycin.  Taxanes are strongly associated with onycholysis and paronychia.   

Targeted therapies such as epidermal growth factor inhibitors (EGFR inihibitors) often trigger papulopustular reactions.   KIT and BCR-ABL inhibitors are associated with exanthems, hypopigmentation, and hand-foot reactions.  mTOR inhibitors (everolimus,rapamycin, sirolimus) are associated with stomatitis. 

Some adverse effects may be helpful in predicting a beneficial clinical effect and good prognosis.  Accurately documenting adverse reactions in a uniform manner is therefore of great importance. 

The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) is used to document and grade toxic effects of oncologic treatments. More information can be found here.

History and physical examination are often sufficient for diagnosing mild asymptomatic eruptions. Severe or persistent eruptions may require further diagnostic testing.

Much research is directed at identifying laboratory techniques that can establish a diagnosis of a drug eruption. In current practice, most of these techniques are still too early in development for routine clinical use. Diagnostic tools for the assessment of allergic rashes usually still depend on challenges to identify causative agents.[50]

Biopsy can be helpful in confirming the diagnosis of a drug eruption (eg, by showing eosinophils in morbilliform eruptions or numerous neutrophils without vasculitis in persons with Sweet syndrome). Drug eruptions are associated with a wide range of histologic findings, and immunomodulating medications can alter the histologic picture.[51]

CBC count with differential may show leukopenia, thrombocytopenia, and eosinophilia in patients with serious drug eruptions.

Serum chemistry studies may be useful. Liver involvement leading to death can occur in persons with hypersensitivity syndromes. Special attention should be paid to the electrolyte balance and renal and/or hepatic function indices in patients with severe reactions such as SJS, TEN, or vasculitis.

Antibody and/or immunoserology tests may be ordered. Antihistone antibodies are noted in persons with drug-induced SLE, whereas anti-Ro/SS-A antibodies are most common in persons with drug-induced SCLE.

Direct cultures may be needed to investigate a primary infectious etiology or secondary infection.

Urinalysis, stool guaiac tests, and chest radiography are important for patients with vasculitis.

Chest radiography, along with urinalysis and stool guaiac tests, is important for patients with vasculitis.

Rechallenge tests by means of skin prick or patch testing to confirm the causative agent is of limited value. Skin tests may be hazardous to patients who have had severe reactions. With the possible exception of acute generalized exanthematous pustulosis (AGEP), patch tests have a low sensitivity and specificity and are not useful.[52]

In some cases, biopsy may be helpful in establishing a diagnosis of a drug reaction.

Histopathology of an exanthematous drug eruption may show both superficial and deep perivascular inflammatory cell infiltrates. Eosinophils in the infiltrate suggest such a drug eruption (see the image below).

In patients with Sweet syndrome, biopsy reveals edema of the superficial dermis and a dense infiltrate of neutrophils. Leukocytoclasia may be present, but vasculitis is absent.

Histopathology of TEN shows subepidermal split, full-thickness epidermal necrosis and a sparse perivascular lymphocytic infiltrate (see the image below).

The ultimate goal is always to discontinue the offending medication if possible. Individuals with drug eruptions are often the most ill patients taking the most medications, many of which are essential for their survival. However, all nonessential medications should be limited. Once the offending drug has been identified, it should be promptly discontinued. Knowledge of the common eruption inducing–medications may help in identifying the offending drug.

Patients can possibly continue to be treated through morbilliform eruptions (ie, continue medication even in patients with a rash). The eruption often resolves, especially if the individual is being treated with antihistamines. Most authorities believe that exanthematous drug eruptions are not a precursor to severe reactions, such as TEN. Nevertheless, all patients with severe morbilliform eruptions should be monitored for mucous membrane lesions, blistering, and skin sloughing.

Treatment of a drug eruption depends on the specific type of reaction. Therapy for exanthematous drug eruptions is supportive in nature. First-generation antihistamines are used 24 h/d. Mild topical steroids (eg, hydrocortisone, desonide) and moisturizing lotions are also used, especially during the late desquamative phase.

Severe reactions, such as SJS, TEN, and hypersensitivity reactions, warrant hospital admission. TEN is best managed in a burn unit with special attention given to electrolyte balance and signs of secondary infection. Because adhesions can develop and result in blindness, evaluation by an ophthalmologist is mandatory. In addition, mounting evidence indicates that intravenous immunoglobulin (IVIG) may improve outcomes for TEN patients.[8, 9, 10]

Hypersensitivity syndrome, a systemic reaction characterized by fever, sore throat, rash, and internal organ involvement, is potentially life threatening. Timely recognition of the syndrome and immediate discontinuation of the anticonvulsant or other offending drug are crucial. Patients may require liver transplantation if the drug is not stopped in time. Treatment with systemic corticosteroids has been advocated.

Oncodermatology

Many reactions can be managed symptomatically but should be monitored closely. Life threatening reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and drug rash with eosinophilia and systemic symptoms (DRESS) can begin as an inoccuous appearing macular exanthem. Stopping therapy immediately in those situations may be critical along with a careful discussion with the oncology team regarding risks and benefits.

Acneiform eruptions due to EGFR inhibitors respond to tetracyclines. Retinoic acid-, benzoyl peroxide-, and salicylic acid-containing topical products are contraindicated.[53]

A current and thorough review provides useful specifics for certain reaction patterns.[53]

Therapy for most drug eruptions is mainly supportive in nature. Morbilliform eruptions are treated with oral antihistamines and topical steroids. IVIG is currently the most common agent used to treat TEN. Cyclosporine may also have a role in the treatment of TEN. Prednisone may be used in the treatment of hypersensitivity syndrome with heart and lung involvement, severe serum sickness–like reaction, and Sweet syndrome.

Class Summary

These agents antagonize H1 receptors and block release of histamine. They provide symptomatic relief of pruritus and help improve eruptions.

Hydroxyzine HCl (Anxanil, Atarax, Atozine, Durrax, Vistaril)

Hydroxyzine antagonizes H1 receptors in the periphery. It may suppress histamine activity in the subcortical CNS. Hydroxyzine is available as 10-, 25-, 50-, or 100-mg tablets.

Diphenhydramine HCl (Benadryl, Benylin, Diphen, AllerMax)

Diphenhydramine is used for symptomatic relief of allergic symptoms caused by the release of histamine in immune reactions.

Class Summary

These agents cause less, if any, drowsiness than first-generation agents.

Loratadine (Claritin)

Loratadine selectively inhibits peripheral histamine H1 receptors.

Class Summary

Topical agents provide symptomatic relief of pruritus. Systemic steroids are used in persons with hypersensitivity syndrome, severe serum sickness–like reactions, and Sweet syndrome.

Desonide

Desonide is for inflammatory dermatoses responsive to steroids; it decreases inflammation by suppressing the migration of PMN leukocytes and reversing capillary permeability.

Prednisone (Deltasone, Orasone, Sterapred)

Prednisone is an immunosuppressant for the treatment of immune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity; it is available in 2.5-, 5-, 10-, 20-, or 50-mg tablets.

Class Summary

These agents are used to treat TEN.

Intravenous immunoglobulin (Gammagard, Gamimune)

Intravenous immunoglobulin is a blood product prepared from the pooled plasma of healthy donors. The following features are possibly relevant to efficacy: neutralization of circulating myelin antibodies through anti-idiotypic antibodies; down-regulation of proinflammatory cytokines, including IFN-gamma; blockade of Fc receptors on macrophages; suppression of inducer T and B cells and augmentation of T-suppressor cells; blockade of complement cascade; promotion of remyelination; and 10% increase in CSF IgG.