Drug Eruptions

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Drug eruptions can mimic a wide range of dermatoses. The morphologies are myriad and include morbilliform (see the image below), urticarial, papulosquamous, pustular, and bullous. Medications can also cause pruritus and dysesthesia without an obvious eruption. A drug-induced reaction should be considered in any patient who is taking medications and who suddenly develops a symmetric cutaneous eruption. Morbilliform eruption localized to striae has been described with clindamycin. ^[1]

The first steps in the history are as follows:

Review the patient’s complete medication list, including prescription and over-the-counter drugs

Document any history of previous adverse reactions to drugs or foods

Consider alternative etiologies (eg, viral exanthems and bacterial infections)

Note any concurrent infections, metabolic disorders, or immunocompromise

In addition, the following should be noted and detailed:

Interval between introduction of a drug and onset of the eruption

Route, dose, duration, and frequency of drug administration

Use of parenterally administered drugs (more likely to cause anaphylaxis)

Use of topically applied drugs (more likely to induce delayed-type hypersensitivity)

Use of multiple courses of therapy and prolonged administration (risk of allergic sensitization)

Any improvement after drug withdrawal and any reaction with readministration

Physical examination should address clinical features that may indicate a severe, potentially life-threatening drug reaction, including the following:

Mucous membrane erosions

Blisters

Nikolsky sign

Confluent erythema

Angioedema and tongue swelling

Palpable purpura

Skin necrosis

Lymphadenopathy

High fever, dyspnea, or hypotension

It is important to appreciate the morphology and physical features of drug eruptions, as follows:

Acneiform

Acral erythema (erythrodysesthesia)

AGEP

Dermatomyositislike

DRESS

Erythema multiforme (EM), including EM minor, SJS, TEN, and SJS/TEN overlap

Erythema nodosum

Erythroderma

Fixed drug eruptions

Hypersensitivity syndrome

Leukocytoclastic vasculitis

Lichenoid

Lupus

Morbilliform or exanthematous

Pseudoporphyria ^[2]

Serum sickness and serum sickness–like

Sweet syndrome (acute febrile neutrophilic dermatosis)

Urticaria

Vesiculobullous

See Clinical Presentation for more detail.

With mild asymptomatic eruptions, the history and physical examination are often sufficient for diagnosis; with severe or persistent eruptions, further diagnostic testing may be required, as follows:

Biopsy

Complete blood count (CBC) with differential

Serum chemistry studies (especially for electrolyte balance and indices of renal or hepatic function in patients with severe reactions)

Antibody or immunoserology tests

Direct cultures to investigate a primary infectious etiology or secondary infection

Urinalysis, stool guaiac tests, and chest radiography for vasculitis

Skin prick or patch testing to confirm the causative agent

See Workup for more detail.

Principles of medical care are as follows:

The ultimate goal is to identify and discontinue the offending medication if possible

Patients can sometimes continue to be treated through morbilliform eruptions; 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, involving the administration of oral antihistamines, topical steroids, and moisturizing lotions

Severe reactions (eg, SJS, TEN, and hypersensitivity reactions) warrant hospital admission

TEN is best managed in a burn unit, and intravenous immunoglobulin (IVIG) may improve outcomes ^{[3, 4, 5]}

Hypersensitivity syndrome may have to be treated with liver transplantation if the offending drug is not stopped in time; treatment with systemic corticosteroids has been advocated in the acute phase; in the chronic phase, patients may require treatment for hypothyroidism or diabetes mellitus

For most drug eruptions, full recovery without any complications is expected; however, the following should be noted:

Patients with exanthematous eruptions should 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; there is also a risk of diabetes

The prognosis for patients with TEN is guarded; scarring, blindness, and death are possible

See Treatment and Medication for more detail.

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, ^[6] 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.

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).

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

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 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 ^[7] :

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) ^[8]

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

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. ^[9]

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 ^[10] – BCG vaccine, hydroxyurea (most common ^[11] ), lovastatin, omeprazole, penicillamine, simvastatin, and tegafur

DRESS syndrome – Most commonly, aromatic anticonvulsants (phenytoin, phenobarbital [phenobarbitone], carbamazepine), sulfonamides, minocycline, and doxycycline ^[12]

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, ^[13] 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 ^[14] – 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 ^[15] – Atorvastatin, captopril, carbamazepine, diclofenac, glibenclamide, lithium, phenytoin, and vancomycin

Lupus erythematosus ^[16] : 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 ^[17] : 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 ^{[18, 19, 20]} – 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 ^[21] – 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, ^[22] cefaclor (most common), minocycline, propranolol, streptokinase, sulfonamides, and NSAIDs

SJS ^{[23, 24, 25]} – 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 ^[26] and melanoma. ^[27] 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 ^[28] :

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, ^[29] dactinomycin, erlotinib, ^[29] fluoxymesterone, gefitinib, medroxyprogesterone, and vinblastine ^[30]

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. ^{[31, 32]} Note the images below.

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 ^[33] – 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 ^[34] – Abnormal scalp, face hair, and/or eyelash growth, anaphylactic infusion reaction (cetuximab), papules and annular plaques, paronychia with/without pyogenic granulomas, telangiectasias, and xerosis. ^[35] See the images below.

Sorafenib ^[36] (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. ^[37] See the images below.

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. ^[38] .

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. ^[39]

Cutaneous reactions to cytokine therapy are as follows ^[40] :

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. ^[41]

IL-12 and IL-23 monoclonal antibodies ^[42] – Injection site reactions

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

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

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

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. ^{[43, 44]} 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.

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Jonathan E Blume, MD Instructor in Clinical Dermatology, Columbia University College of Physicians and Surgeons; Dermatologist, Westwood Dermatology and Dermatologic Surgery Group PA

Jonathan E Blume, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, International Society of Dermatology

Disclosure: Nothing to disclose.

Liaqat Ali, MD Assistant Professor, Department of Dermatology, Wayne State University School of Medicine; Dermatopathologist, Pinkus Dermatopathology Laboratory, Monroe, MI

Liaqat Ali, MD is a member of the following medical societies: American Society for Clinical Pathology, American Society of Dermatopathology, College of American Pathologists, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Michelle Ehrlich, MD Director of Cosmetic Dermatology and Surgery Residency Program, Harbor-UCLA Medical Center; Clinical Instructor, Department of Dermatology, University of California, Los Angeles, David Geffen School of Medicine

Michelle Ehrlich, MD is a member of the following medical societies: American Academy of Cosmetic Surgery, American Academy of Dermatology

Disclosure: Nothing to disclose.

Thomas N Helm, MD Clinical Professor of Dermatology and Pathology, University of Buffalo, State University of New York School of Medicine and Biomedical Sciences; Director, Buffalo Medical Group Dermatopathology Laboratory

Thomas N Helm, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society of Dermatopathology

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, American College of Rheumatology

Disclosure: Received income in an amount equal to or greater than $250 from: Lilly; Amgen <br/>Received honoraria from UpToDate for author/editor; Received honoraria from JAMA Dermatology for associate editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Allergen; Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Neil Shear, MD Professor and Chief of Dermatology, Professor of Medicine, Pediatrics and Pharmacology, University of Toronto Faculty of Medicine; Head of Dermatology, Sunnybrook Women’s College Health Sciences Center and Women’s College Hospital, Canada

Neil Shear, MD is a member of the following medical societies: Canadian Medical Association, Ontario Medical Association, Royal College of Physicians and Surgeons of Canada, Canadian Dermatology Association, American Academy of Dermatology, American Society for Clinical Pharmacology and Therapeutics

Disclosure: Nothing to disclose.

Charles Camisa, MD Head of Clinical Dermatology, Vice-Chair, Department of Dermatology, Cleveland Clinic Foundation

Charles Camisa, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Drug Eruptions

Research & References of Drug Eruptions|A&C Accounting And Tax Services
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