Drug Eruptions

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 - Immunoglobulin E (IgE)-dependent reactions, which result in urticaria, angioedema, and anaphylaxis (see the first image below)
• Type II - Cytotoxic reactions, which result in hemolysis and purpura (see the second image below)
• Type III - Immune complex reactions, which result in vasculitis, serum sickness, and urticaria
• Type IV - 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 (eg, neomycin). Sulfonamides are most frequently associated with TEN.

Although most drug eruptions are type IV hypersensitivity reactions, only a minority are IgE-dependent. That is, antibodies can be demonstrated in fewer 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
• Phototoxic dermatitis

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.

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. This reaction can be seen with penicillin therapy for syphilis, griseofulvin or ketoconazole therapy for dermatophyte infections, and diethylcarbamazine therapy for oncocerciasis. It does not constitute an indication for stopping treatment; symptoms of Jarisch-Herxheimer reactions resolve with continued drug therapy, which should be maintained until the infection is fully eradicated.

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 in magnetic resonance imaging (MRI). Individuals with renal failure may have a buildup of 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 (TMP-SMX) - 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 (RBCs) - 0.8%
• Mercurial diuretics - 0.9%
• Heparin - 0.7%

Cutaneous reaction rates in patients with HIV infection are as follows ^[14] :

• Sulfasalazine - 20%
• TMP-SMX - 14.9%
• Aminopenicillins - 9.3%
• Penicillins - 3.8%
• Anticonvulsants - 3.4%
• Dapsone - 3.1%
• 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 include the following:

• Allopurinol
• Anticonvulsants
• Bumetanide
• Captopril
• Furosemide
• NSAIDs
• Penicillamine
• Piroxicam
• Sulfa drugs
• Thiazide diuretics

Drugs unlikely to cause skin reactions include the following:

• Acetaminophen
• Aminophylline
• Aspirin
• Chlorpromazine
• Codeine
• Digoxin
• Diphenhydramine hydrochloride
• Ferrous sulfate
• Folic acid
• Meperidine
• Methyldopa
• Morphine
• Prednisone
• Prochlorperazine
• Regular insulin
• Serotonin-specific reuptake inhibitors
• Tetracycline
• Topical gels (eg, 4% tetracaine gel may cause serious cutaneous adverse reactions) ^[15]
• Warfarin

Medications associated with specific types of cutaneous reactions

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 one is confronted with a new-onset eruption in a patient on multiple medications.

Acneiform

Causative agents include amoxapine, corticosteroids (see the image below), halogens, haloperidol, hormones, isoniazid, lithium, phenytoin, and trazodone.

Acute generalized exanthematous pustulosis

The most common causative agents include beta-lactam antibiotics and antibacterial sulfonamides, ^[16]  diltiazem, antimalarials, macrolides,  mercury, quinolones, and terbinafine.

Less common causative agents include acetaminophen, allopurinol, bufexamac, buphenine, carbamazepine, carbutamide, celecoxib, chloramphenicol, clindamycin, TMP-SMX, clobazam, cyclins (eg, tetracycline), cytarabine, famotidine, furosemide, ginkgo biloba, hydrochlorothiazide, hydroxychloroquine, ibuprofen, imatinib, imipenem, isoniazid, intravenous (IV) contrast dye, lopinavir-ritonavir, mexiletine, morphine, nadoxolol, nifedipine, nystatin, olanzapine, phenytoin, pipemidic acid, piperazine, pseudoephedrine, pyrimethamine, quinidine, ranitidine, rifampicin, salbutamine, sertraline, simvastatin, streptomycin, terbinafine, thallium, vancomycin, calcium-channel blockers, angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, ramipril), glyburide, and gemfibrozil. ^{[17, 18]}

Alopecia

Causative agents include ACE inhibitors, allopurinol, anticoagulants, azathioprine, bromocriptine, beta blockers, cyclophosphamide, didanosine, hormones, indinavir, NSAIDs, phenytoin, methotrexate (MTX), retinoids, and valproate.

Bullous pemphigoid

Causative agents include aspirin, ampicillin, D-penicillamine, captopril, chloroquine, ciprofloxacin, enalapril, etanercept, ^[19]  everolimus, furosemide, ibuprofen, levofloxacin neuroleptics, penicillins, phenacetin, psoralen plus UV-A, salicylazosulfapyridine, sirolimus, sulfasalazine, and terbinafine. ^[20]

Dermatomyositislike ^[21]

Causative agents include bacille Calmette-Guérin (BCG) vaccine, hydroxyurea (most common ^[22] ), lovastatin, omeprazole, penicillamine, simvastatin, and tegafur.

DRESS syndrome

The most common causative agents include aromatic anticonvulsants (phenytoin, phenobarbital [phenobarbitone], carbamazepine, lamotrigine, leviteracetam), sulfonamides, and antimicrobials (dapsone, TMP-SMX, piperacillin-tazobactam, vancomycin, abacavir, nevirapine, minocycline, and doxycycline). ^{[23, 24]}

Erythema nodosum

Causative agents include echinacea, halogens, oral contraceptives (most common), penicillin, sulfonamides, and tetracycline.

Erythroderma

Causative agents include 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

Causative agents include acetaminophen, ampicillin, anticonvulsants, aspirin/NSAIDs, barbiturates, benzodiazepines, butalbital, cetirizine, ciprofloxacin, clarithromycin, dapsone, dextromethorphan, doxycycline, fluconazole, hydroxyzine, lamotrigine, loratadine, metronidazole, oral contraceptives, penicillins, phenacetin, phenolphthalein, phenytoin, piperacillin-tazobactam, ^[25] piroxicam, saquinavir, sulfonamides, tetracyclines, ticlopidine, tolmetin, vancomycin, and zolmitriptan.

Hypersensitivity syndrome

Causative agents include allopurinol, amitriptyline, carbamazepine, dapsone, lamotrigine, minocycline, NSAIDs, olanzapine, oxcarbazepine, phenobarbital, phenytoin, saquinavir, spironolactone, sulfonamides, zalcitabine, and zidovudine.

Lichenoid

Causative agents include amlodipine, antimalarials, beta blockers, captopril, diflunisal, diltiazem, enalapril, furosemide, glimepiride, gold, leflunomide, levamisole, L-thyroxine, orlistat, penicillamine, phenothiazine, pravastatin, proton pump inhibitors (PPIs), rofecoxib, salsalate, sildenafil, tetracycline, thiazides, and ursodeoxycholic acid. ^[26]

Linear IgA dermatosis

Causative agents include atorvastatin, captopril, carbamazepine, diclofenac, glibenclamide, lithium, phenytoin, and vancomycin. ^[27]

Lupus erythematosus

Drug-induced systemic lupus erythematosus (SLE) is most commonly associated with hydralazine, procainamide, and minocycline. ^[28] Beta blockers, chlorpromazine, cimetidine, clonidine, estrogens, isoniazid, lithium, lovastatin, methyldopa, oral contraceptives, quinidine, sulfonamides, tetracyclines, and tumor necrosis factor (TNF)-α inhibitors have been reported. Drug-induced subacute cutaneous lupus erythematosus (SCLE) is most commonly associated with hydrochlorothiazide. Calcium-channel blockers, cimetidine, griseofulvin, leflunomide, terbinafine, and TNF-α inhibitors have been reported.

Morbilliform (exanthematous)

Causative agents include ACE inhibitors, allopurinol, amoxicillin, ampicillin, anticonvulsants, barbiturates, carbamazepine, cetirizine, ginkgo biloba, hydroxyzine, isoniazid, nelfinavir, NSAIDs, phenothiazine, phenytoin, quinolones, sulfonamides, thalidomide, thiazides, TMP-SMX, and zalcitabine.

Pemphigus

Causative agents include thiols and nonthiols. ^[29] 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 rifampin.

Photosensitivity

Causative agents include ACE inhibitors, amiodarone, amlodipine, celecoxib, chlorpromazine, diltiazem, furosemide, griseofulvin, lovastatin, nifedipine, phenothiazine, piroxicam, quinolones, sulfonamides, tetracycline, and thiazide.

Pseudoporphyria

Causative agents include amiodarone, bumetanide, chlorthalidone, cyclosporine, dapsone, etretinate, 5-fluorouracil (FU), flutamide, furosemide, hydrochlorothiazide/triamterene, isotretinoin, NSAIDs (including nalidixic acid and naproxen), oral contraceptive pills, and tetracycline

Psoriasis

Causative agents include 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. ^{[30, 31, 32]}

Serum sickness

Causative agents include antithymocyte globulin for bone marrow failure, human rabies vaccine, penicillin, pneumococcal vaccine (in AIDS patients), and vaccines containing horse serum derivatives. ^[33]

Serum sickness–like

Causative agents include beta-lactam antibiotics, ^[34] cefaclor (most common), minocycline, propranolol, streptokinase, sulfonamides, and NSAIDs.

Stevens-Johnson syndrome

Causative agents include 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 TMP-SMX. ^{[35, 36, 37]}

Sweet syndrome

Causative agents include all-trans-retinoic acid, celecoxib, granulocyte colony-stimulating factor (G-CSF), nitrofurantoin, oral contraceptives, tetracyclines, and TMP-SMX.

Toxic epidermal necrolysis

Causative agents include alfuzosin, allopurinol, anticonvulsants, aspirin/NSAIDs, sulfadoxine-pyrimethamine, isoniazid, lamotrigine, lansoprazole, letrozole, penicillins, phenytoin, prazosin, sulfonamides, tetracyclines, thalidomide, TMP-SMX, and vancomycin.

Urticaria

Causative agents include ACE inhibitors, alendronate, aspirin/NSAIDs, blood products, cephalosporins, cetirizine, clopidogrel, dextran, didanosine, infliximab, inhaled steroids, nelfinavir, opiates, penicillin, peptide hormones, polymyxin, PPIs, radiologic contrast material, ranitidine, tetracycline, vaccines, and zidovudine.

Vasculitis

Causative agents include adalimumab, allopurinol, aspirin/NSAIDs, cimetidine, gold, hydralazine, indinavir, leflunomide, levofloxacin, minocycline, montelukast, penicillin, phenytoin, propylthiouracil, PPIs, quinolones, ramipril, sulfonamide, tetracycline, thiazides, and thioridazine.

Vesiculobullous (other)

Causative agents include 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 (SCC) ^[38] and melanoma. ^[39]  Studies have shown a dose-dependent increased risk for SCC: 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 of 28% for SCC.

Psychotropic drugs associated with specific cutaneous reactions

Psychotropic agents associated with particular morphologic patterns include the following ^[40] :

• 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 drugs associated with specific cutaneous reactions

The following is a list of chemotherapeutic agents associated with particular morphologic patterns of cutaneous reactions.

Acneiform

Associated agents include cetuximab, ^[41] dactinomycin, erlotinib, ^[41] fluoxymesterone, gefitinib, medroxyprogesterone, and vinblastine. ^[42]

Acral erythema (erythrodysesthesia)

Associated agents include capecitabine, cisplatin, clofarabine, cyclophosphamide, cytarabine, docetaxel, doxorubicin, fluorouracil, gemcitabine, MTX, tegafur, and vinorelbine.

Alopecia

All classes of chemotherapeutic agents are associated with alopecia (see the first image below). Commonly associations include alkylating agents, anthracyclines, bleomycin, doxorubicin, hydroxyurea, MTX, mitomycin, mitoxantrone, vinblastine, and vincristine. Coadministration of busulfan and cyclophosphamide can cause permanent hair loss. Nilotinib is a potent and selective bcr-abl kinase inhibitor used to treat imatinib-resistant chronic myeloid leukemia. Clinically, pink/fleshy perifollicular papules with diffuse alopecia may be seen (see the second image below), without follicular dropout. Histologically, it can demonstrate scarring or nonscarring alopecia with mixed features (see the third image below). ^{[43, 44]}

Erythema multiforme

Associated agents include busulfan, chlorambucil, cyclophosphamide, diethylstilbestrol (DES), etoposide, hydroxyurea, mechlorethamine, MTX, mitomycin C, mitotane, paclitaxel, and suramin.

Erythema nodosum

Associated agents include busulfan, DES, and imatinib.

Fixed drug eruptions

Associated agents include dacarbazine, hydroxyurea, paclitaxel, and procarbazine.

Hyperpigmentation

Associated agents include 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

Associated agents include hydroxyurea, imatinib, and tegafur.

Lupus

Associated agents include aminoglutethimide, DES, hydroxyurea, leuprolide, and tegafur.

Morbilliform (exanthematous)

Associated agents include bleomycin, carboplatin, cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum (CHIP), chlorambucil, cytarabine, docetaxel, DES, doxorubicin, etoposide, 5-FU, hydroxyurea, MTX, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, procarbazine, suramin, and thiotepa.

Toxic epidermal necrolysis

Associated agents include asparaginase, bleomycin, chlorambucil, cladribine, cytarabine, doxorubicin, 5-FU, MTX, plicamycin, procarbazine, and suramin.

Urticaria

Associated agents include amsacrine, bleomycin, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cytarabine, daunorubicin, diaziquone, didemnin, DES, docetaxel, doxorubicin, epirubicin, etoposide, 5-FU, mechlorethamine, melphalan, MTX, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, procarbazine, teniposide, thiotepa, trimetrexate, vincristine, and zinostatin. ^[45]

Vasculitis

Associated agents include busulfan, cyclophosphamide, cytarabine, hexamethylene bisacetamide (HMBA), hydroxyurea, imatinib, levamisole, 6-mercaptopurine (MP), MTX, mitoxantrone, rituximab, and tamoxifen.

Cutaneous reactions caused by targeted chemotherapy agents

The following is a list of cutaneous reactions to targeted chemotherapy agents.

Epidermal growth factor receptor inhibitors

These agents (eg, gefitinib, cetuximab, erlotinib ^[46] ) can give rise to abnormal scalp, face hair, or eyelash growth; anaphylactic infusion reaction (cetuximab); papules and annular plaques; paronychia with or without pyogenic granulomas; telangiectasias; and xerosis. ^[47]  (See the images below.)

Sorafenib

Sorafenib, a multikinase inhibitor, can cause 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. ^[48]

Vemurafenib

Vemurafenib is a systemic medication approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma. It 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 SCCs and keratoacanthomas in approximately one fourth of patients receiving the drug. The development of nonmalignant milia in a patient treated with vemurafenib has been reported. ^[49]  (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 reaction within 6-8 days after the start of treatment with vemurafenib. ^[50]

Tamoxifen

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. ^[51]

Cytokine agents causing cutaneous reactions

Cutaneous reactions to cytokine therapy include the following ^[52] :

• Erythropoietin - Abnormal hair growth, localized rash, palpebral edema, and widespread eczema
• G-CSF - Exacerbation of preexisting psoriasis, leukocytoclastic, localized erythema, localized pruritus, Sweet syndrome, and vasculitis
• Granulocyte macrophage colony-stimulating factor (GM-CSF) - 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-1α - Mucositis, phlebitis, Shwartzman reaction, and xerostomia
• IL-1β - 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-α 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 ^[53]
• IL-12 and IL-23 monoclonal antibodies ^[54] - Injection-site reactions

In the United States, drug eruptions occur in approximately 2-5% of inpatients and in more than 1% of outpatients. Internationally, drug eruptions occur in approximately 2-3% of inpatients.

Elderly patients have an increased incidence of adverse drug reactions. Adverse cutaneous reactions to drugs are more common in women than in men.

Most drug eruptions are mild and self-limited, and they typically resolve after the offending agent has been discontinued. Even after the responsible agent is discontinued, however, drug eruptions may be slow to clear or may worsen over the following few days. The degree of eosinophilia is predictive of the severity of the drug eruption. ^{[55, 56]} 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. Drug therapy complications account for roughly 19% of adverse events in hospitalized patients, making them the most common type; they account for 3% of disabling injuries during hospitalization.  ^[57] Mortality figures for EM major are significantly higher. SJS has a mortality of less than 5%, whereas the mortality 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, the patient should be advised to avoid that drug in the future. The medical record should be clearly labeled. Patients should be encouraged to carry a card or some other form of emergency identification in their wallets that lists drug allergies or intolerances, especially if they have had a severe reaction.

Patients should be educated 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.