Drug eruptions

INTRODUCTION — Classic and less common clinical presentations of cutaneous adverse reactions to drugs will be reviewed here [1]. Drug allergy, noncutaneous hypersensitivity reactions, infusion reactions, and cutaneous adverse reactions to antineoplastic drugs are discussed elsewhere.

●Drug hypersensitivity reactions

•(See "Drug hypersensitivity: Classification and clinical features".)

•(See "Hypersensitivity reactions to macrolides, aminoglycosides, tetracyclines, clindamycin, and metronidazole".)

•(See "Hypersensitivity reactions to fluoroquinolones".)

•(See "Hypersensitivity reactions to clopidogrel".)

•(See "Vancomycin hypersensitivity".)

•(See "Progestogen hypersensitivity".)

•(See "Hypersensitivity reactions to systemic glucocorticoids".)

•(See "Hypersensitivity reactions to insulins".)

●Infusion reactions

•(See "Infusion reactions to systemic chemotherapy".)

•(See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)

●Cutaneous adverse reactions to antineoplastic agents

•(See "Cutaneous adverse effects of conventional chemotherapy agents".)

•(See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

•(See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors".)

•(See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

•(See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)

EPIDEMIOLOGY — Adverse cutaneous reactions to drugs are common, affecting 2 to 3 percent of hospitalized patients, and are a significant cause of outpatient morbidity [2]. It is estimated that 1 in 1000 hospitalized patients has a serious cutaneous drug reaction. Drug-induced exanthems, also called morbilliform eruptions, are the most common cutaneous reactions, responsible for approximately 90 percent of all drug rashes.

APPROACH TO THE DIAGNOSIS — The diagnosis of drug eruptions is primarily clinical, based on the clinical and medication history, timing of initial drug administration and onset of symptoms, and assessment of the type and distribution of the rash. The clinical manifestations of drug hypersensitivity reactions are summarized in the table (table 1).

However, the diagnosis may be difficult, due to overlapping clinical feature and multiple differential diagnoses. An approach to the evaluation and clinical diagnosis of the most important, localized and generalized drug eruptions is illustrated in the algorithms (algorithm 1A-B).

CLASSIC DRUG REACTION PATTERNS

Exanthematous drug eruptions — Drug-induced exanthems are the most common cutaneous reactions to drugs, responsible for approximately 90 percent of all drug rashes [3]. The rashes are referred to as exanthematous, morbilliform, and maculopapular eruptions (picture 1A-D) [4]. Commonly prescribed medications (eg, antibiotics, sulfonamides) are implicated in most cases.

The diagnosis and management of exanthematous drug eruptions are discussed in detail separately. (See "Exanthematous (maculopapular) drug eruption".)

Lichenoid drug eruption (drug-induced lichen planus) — Lichen planus typically presents with flat-topped, violaceous or hyperpigmented, pruritic papules that typically affect the ankles and the volar surface of the wrists (picture 2A-B). The drug-induced form of this disorder usually develops insidiously, months or up to a year or more after drug initiation, and can affect any area of the body surface (picture 3A-B). Beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, methyldopa, penicillamine, quinidine, antimalarials, and thiazide diuretics are most frequently implicated [5]. Cases induced by tumor necrosis factor (TNF)-alpha inhibitors and the tyrosine kinase inhibitor imatinib have also been reported [6,7]. Oral lichenoid drug eruptions are rare and share clinical features with oral lichen planus, including reticular or erosive lesions (picture 4).

The diagnosis and management of lichenoid drug eruptions and oral lichen planus are discussed in detail separately. (See "Lichenoid drug eruption (drug-induced lichen planus)" and "Oral lichen planus: Pathogenesis, clinical features, and diagnosis".)

Exfoliative dermatitis/erythroderma — Exfoliative dermatitis/erythroderma is a severe and potentially life-threatening condition characterized by diffuse erythema and scaling involving ≥90 percent of the body surface area (picture 5). Drugs are the second most common cause of erythroderma, accounting for approximately 10 to 20 percent of all erythrodermas [8]. Allopurinol, ACE inhibitors, penicillins, sulfonamides, carbamazepine, phenytoin, barbiturates, and other drugs have been associated with exfoliative dermatitis (table 2).

The diagnosis and management of erythroderma are discussed in detail elsewhere. (See "Erythroderma in adults".)

Urticaria/angioedema — Urticaria (hives) and angioedema may be manifestations of drug hypersensitivity reactions that may be immunoglobulin E (IgE)-mediated (type I hypersensitivity (table 3)) or due to direct mast cell activation through non-IgE-mediated mechanisms [9]. Reactions involving urticaria/angioedema can be immediate, accelerated (hours postexposure), or delayed (days postexposure). As with most drug eruptions, these reactions are more common during the first weeks of therapy but can happen at any time (see "New-onset urticaria" and "An overview of angioedema: Pathogenesis and causes"):

●Clinical features:

•Urticaria is characterized by an intensely pruritic, circumscribed, raised, and erythematous eruption, often with central pallor (picture 6A-B). Individual lesions may enlarge, coalesce with other lesions (picture 7), and typically disappear over a few hours. (See "New-onset urticaria", section on 'Clinical manifestations'.)

•Angioedema is swelling of the deeper dermis and subcutaneous tissues that may coexist with urticaria in as many as 50 percent of cases. Angioedema may be disfiguring if it involves the face and lips or life threatening if airway obstruction occurs from laryngeal edema or tongue swelling. (See "An overview of angioedema: Clinical features, diagnosis, and management".)

●Common causative drugs:

•Antibiotics – Antibiotics (especially penicillins, cephalosporins, and sulfonamides) are common causes of IgE-mediated drug allergy. IgE-mediated drug reactions tend to become more severe and progress toward anaphylaxis upon re-exposure to the causative agent. (See "New-onset urticaria" and "Penicillin allergy: Immediate reactions".)

•Opiate analgesics – Other drugs may cause urticaria due to direct mast cell activation by a non-IgE-mediated mechanism. The most frequently implicated are the opiate analgesics morphine and codeine. The concomitant use of opiates and vancomycin may increase the risk of vancomycin hypersensitivity reaction, the so-called "red man syndrome" seen after rapid vancomycin infusion, which is also due to direct mast cell activation and may have accompanying urticaria. (See "New-onset urticaria", section on 'Direct mast cell activation' and "Vancomycin hypersensitivity".)

•NSAIDs – Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause acute urticaria/angioedema through direct mast cell activation or by nonmast cell-mediated mechanisms. The latter include abnormalities of the complement cascade (inherited and acquired abnormalities of complement metabolism) and increased activity of vasodilatory kinin pathways (table 4). (See "An overview of angioedema: Pathogenesis and causes", section on 'Aspirin and NSAIDs'.)

●ACE inhibitors – Angioedema (in the absence of urticaria) occurs in 2 to 10 per 10,000 new users of angiotensin-converting enzyme (ACE) inhibitors and usually affects the mouth or tongue (picture 8) [10]. Impaired bradykinin degradation by ACE, leading to elevated blood levels of the vasoactive peptide bradykinin, is thought to be the underlying mechanism. ACE inhibitor-induced angioedema can arise many months after starting ACE inhibitor treatment and can take months to resolve. (See "ACE inhibitor-induced angioedema".)

Anaphylaxis — Drugs are the second or third most common cause of anaphylaxis, the most severe and potentially life-threatening form of immediate type I hypersensitivity [11,12]. Symptoms include pruritus, urticaria, angioedema, laryngeal edema, wheezing, nausea, vomiting, tachycardia, sense of impending doom, and, occasionally, shock. (See "Anaphylaxis: Confirming the diagnosis and determining the cause(s)".)

Cutaneous small vessel vasculitis — Cutaneous small vessel vasculitis (CSVV; also called hypersensitivity vasculitis, cutaneous leukocytoclastic vasculitis, serum sickness or serum sickness-like reaction, and allergic vasculitis) is a single-organ vasculitis caused in most cases by drugs (table 5) [13-15]. (See "Overview of cutaneous small vessel vasculitis".)

Hydralazine, minocycline, propylthiouracil, and levamisole-adulterated cocaine are most often reported as causes of CSVV [16]. Penicillins, cephalosporins, sulfonamides (including most loop and thiazide-type diuretics), phenytoin, and allopurinol have also been implicated [17-20].

CSVV typically presents with palpable purpura and/or petechiae (picture 9A-B); additional clinical findings include fever, urticaria, arthralgias, lymphadenopathy, low serum complement levels, and an elevated erythrocyte sedimentation rate. In most patients, the clinical manifestations begin 7 to 10 days after exposure to the offending drug [17]. However, the latent period may be as short as two to seven days with a secondary exposure or longer than two weeks with a long-acting drug, such as penicillin G benzathine [18].

Discontinuation of the offending drug should lead to resolution of the signs and symptoms within a period of days to a few weeks. Patients with more severe reactions may require NSAIDs or corticosteroids.

UNCOMMON DRUG REACTION PATTERNS

Severe cutaneous reactions

Stevens-Johnson syndrome/toxic epidermal necrolysis — Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe mucocutaneous eruption that is frequently triggered by medications. Allopurinol, certain antiepileptics, antibacterial sulfonamides, and oxicam nonsteroidal anti-inflammatory drugs (NSAIDs) are most frequently implicated (table 6). This disorder is characterized by epidermal necrosis and sloughing of the mucous membranes and skin (picture 10A-E). The amount of skin detachment related to the body surface area is used to distinguish SJS from TEN; detachment affects less than 10 percent of the body surface in SJS and more than 30 percent in TEN.

The diagnosis and management of SJS and TEN are discussed in detail elsewhere. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

Drug reaction with eosinophilia and systemic symptoms — Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) is a severe idiosyncratic reaction characterized by fever (38 to 40°C [100.4 to 104°F]), malaise, lymphadenopathy, and skin eruption (picture 11A-C) [21]. Additional systemic symptoms may be related to visceral involvement (eg, liver, kidney, lung) [22,23]. In most patients, the reaction begins two to six weeks after the initiation of the offending medication. The aromatic antiepileptic agents (carbamazepine, phenytoin, lamotrigine, oxcarbazepine, and phenobarbital), allopurinol, and antibacterial sulfonamides are the most frequent causes of this disorder (table 7). The clinical presentation, diagnosis, and management of DRESS are discussed in detail separately. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Acute generalized exanthematous pustulosis — Acute generalized exanthematous pustulosis (AGEP) is a rare disorder characterized by the appearance of superficial pustules after drug ingestion or infection [24,25]. AGEP is remarkable for its short time to onset (24 hours) after the administration of the suspected drug, although in some cases, the onset of symptoms may be delayed for up to three weeks [26].

The cutaneous eruption begins on the face or intertriginous areas and disseminates within a few hours. Nonfollicular, small pustules arise on edematous erythema with burning and/or itching (picture 12A-B). Antibiotics, particularly penicillins and macrolides, are thought to play a role in 80 percent of cases [25,27]. The clinical manifestations, diagnosis, and management of AGEP are discussed separately. (See "Acute generalized exanthematous pustulosis (AGEP)".)

Fixed drug eruption — A fixed drug eruption is a distinctive reaction characterized acutely by erythematous and edematous plaques with a grayish center or frank bullae and characterized chronically by a dark, postinflammatory pigmentation (picture 13A-B). Favored sites include the mouth (lips and tongue), genitalia, face, and acral areas [4]. The defining features of this eruption include postinflammatory hyperpigmentation and recurrence of lesions at exactly the same sites with drug re-exposure [4]. Patients with generalized bullous fixed drug eruption (GBFDE) can be misdiagnosed as having SJS/TEN. However, in GBFDE, mucosal involvement is usually absent or mild, and the clinical course is favorable, with rapid resolution in 7 to 14 days after drug discontinuation [28]. The drugs commonly involved include NSAIDs (acetylsalicylic acid, ibuprofen, naproxen, mefenamic acid), antibacterial agents (trimethoprim-sulfamethoxazole, tetracyclines, penicillins, quinolones, dapsone), barbiturates, acetaminophen (paracetamol), metamizole, and antimalarials [4,28-31].

The diagnosis and management of fixed drug eruption are discussed in detail separately. (See "Fixed drug eruption".)

Erythema multiforme — Erythema multiforme (EM) is an acute, immune-mediated eruption characterized by distinctive target-like skin lesions that tend to affect the distal extremities, including the palms and soles (picture 14) [2,32,33]. Erythema multiforme major describes EM with mucosal involvement; in severe cases, fever and malaise may be associated symptoms. Although in the past EM major has often been misdiagnosed as SJS/TEN, the two conditions are considered to be different entities, with different clinical presentations and etiologies [32,34,35].

EM is most commonly induced by infection (typically herpes simplex virus or Mycoplasma pneumoniae), but in approximately 10 percent of cases, it is caused by drugs, including antibiotics, NSAIDs, sulfonamides, and antiepileptics.

The diagnosis and management of EM are discussed in detail elsewhere. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)

Photosensitivity reactions — There are two basic types of photosensitivity reactions, phototoxic and photoallergic, which differ in clinical appearance and pathogenesis. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity' and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.)

Phototoxic eruptions — Phototoxic eruptions are by far the most common drug-induced photo eruptions. They typically present as an exaggerated sunburn, often with blisters, or bluish-gray discoloration of the skin (picture 15A-B). NSAIDs, quinolones, tetracyclines, amiodarone, and the phenothiazines are the most frequent causes of phototoxicity [36-38]. Phototoxic reactions have also been reported with multitargeted tyrosine kinase inhibitors (eg, imatinib) and BRAF inhibitors (eg, vemurafenib) [39,40].

The pathogenetic mechanism involves the absorption of ultraviolet light by the causative drug, which releases energy and damages cells. Ultraviolet A (UVA) light is the most common wavelength implicated. Ultraviolet B (UVB) light and visible light can elicit reactions with some drugs. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity' and "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

Photoallergic eruptions — Photoallergic eruptions are characterized by widespread eczema in the photoexposed areas, such as the face, upper chest, and back of hands (picture 15C). Most photoallergic reactions are caused by topical agents, including biocides added to soaps (halogenated phenolic compounds) and fragrances, such as musk ambrette and 6-methylcoumarin [41]. Systemic photoallergens, such as the phenothiazines, chlorpromazine, sulfa products, and NSAIDs, can produce photoallergic reactions, although most of their photosensitive reactions are phototoxic [41,42].

Photoallergy is a lymphocyte-mediated reaction caused by exposure to UVA. It is postulated that the absorbed radiation converts the drug into an immunologically active compound that is then presented to lymphocytes by Langerhans cells, causing a spongiotic dermatitis (eczema). (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.)

Bullous eruptions

Pemphigus — Pemphigus is a rare autoimmune bullous disease presenting with widespread mucocutaneous blisters and erosions (picture 16A-B). It may be induced or precipitated by drugs, most commonly thiol (SH) compounds (eg, penicillamine, captopril) or NSAIDs that are metabolized to thiols (eg, piroxicam) [43,44]. Penicillin and its derivatives, but not cephalosporins, have also been implicated (table 8).

The pathogenesis, clinical presentation, and management of pemphigus are discussed in detail elsewhere. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus" and "Initial management of pemphigus vulgaris and pemphigus foliaceus".)

Bullous pemphigoid — Bullous pemphigoid (BP) is an autoimmune bullous disease that presents with tense vesicles and bullae with an inflammatory base distributed on the arms, legs, and trunk of older patients. BP has been associated with a large number of drugs, including penicillamine, furosemide, captopril, penicillin and its derivatives, sulfasalazine, phenacetin, nalidixic acid, and tumor necrosis factor (TNF)-alpha inhibitors, including adalimumab and etanercept (table 9) [45-48]. Multiple studies have found an association between BP and dipeptidyl-peptidase 4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus [49-52].

Drug-induced BP may be an acute, self-limited illness that resolves after drug withdrawal or a chronic type that appears to be merely precipitated by the drug and follows the course of classic BP. (See "Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Infections and drugs'.)

Linear IgA bullous dermatosis — Linear IgA bullous dermatosis is an idiopathic subepidermal blistering disease characterized histologically by the linear deposition of immunoglobulin A (IgA) antibodies at the basement membrane zone. A spectrum of clinical features has been described. Patients with drug-induced disease may have EM-type lesions, BP-like lesions, or dermatitis herpetiformis-like lesions [53]. Mucosal or conjunctival lesions are not present in drug-induced disease but are common in the idiopathic form.

Vancomycin is most commonly implicated; lithium, cefamandole, captopril, and diclofenac have also been associated with this illness. Spontaneous remission occurs in drug-induced disease once the offending agent is discontinued. (See "Linear IgA bullous dermatosis".)

Pseudoporphyria — Pseudoporphyria is an uncommon bullous photodermatosis with clinical and histologic features similar to porphyria cutanea tarda that can be induced by several drugs, including antibiotics, NSAIDs, diuretics, and retinoids (table 10). It has been reported in over 10 percent of children treated with naproxen for early-onset pauciarticular arthritis [54]. Pseudoporphyria presents with bullae and vesicles typically localized on sun-exposed areas (eg, face, dorsum of the hands (picture 17), forearms).

The diagnosis and management of pseudoporphyria are discussed in detail elsewhere. (See "Pseudoporphyria" and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis" and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis".)

Drug-induced lupus — Drug-induced lupus presents with a phenotype similar to that of idiopathic systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus (SCLE), or, rarely, chronic cutaneous lupus erythematosus (CCLE). However, some clinical and immunologic features may be different [55]. A variety of drugs can induce a lupus-like syndrome, particularly those agents that are metabolized by acetylation, such as procainamide and hydralazine [56]. Other drugs implicated in the development of SLE include minocycline, isoniazid, rifampin, phenytoin, penicillamine, quinidine, phenytoin, methyldopa, chlorpromazine, carbamazepine, ethosuximide, propylthiouracil, and sulfasalazine [57]. Anti-TNF agents, such as infliximab, etanercept, and adalimumab, can induce SLE. Checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab, have also been associated with SCLE [58,59].

The cutaneous and noncutaneous manifestations of drug-induced lupus are discussed in detail elsewhere. SLE, SCLE, and CCLE are also discussed separately. (See "Drug-induced lupus" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Overview of cutaneous lupus erythematosus".)

Drug-induced Sweet syndrome — Sweet syndrome (acute febrile neutrophilic dermatosis) is an uncommon reaction to multiple drugs, including targeted anticancer drugs (table 11) [60]. It usually develops approximately two weeks after drug exposure in patients who lack a prior history of exposure to the inciting drug. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis", section on 'Drug-induced Sweet syndrome'.)

Symmetrical drug-related intertriginous and flexural exanthema — Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE; intertriginous drug eruption, baboon syndrome) is an infrequent type of drug-induced eruption [61]. SDRIFE occurs a few hours to a few days after the administration of the offending drug. The rash presents as a sharply demarcated, V-shaped erythema in the gluteal/perianal or inguinal/perigenital areas, often with involvement of at least one other flexural or intertriginous fold, in the absence of systemic symptoms (picture 18) [62]. Amoxicillin, ceftriaxone, penicillin, clindamycin, and erythromycin are thought to be implied in approximately 50 percent of cases [62]. Iodinate contrast media, pseudoephedrine, acetyl salicylic acid, mitomycin, phenothiazines, valacyclovir, and many other drugs have also been implicated [63]. Treatment includes discontinuing the suspected drug and the use of topical or systemic corticosteroids. (See "Exanthematous (maculopapular) drug eruption", section on 'Intertriginous and flexural reaction pattern'.)

Drug-induced hair loss — Drugs cause hair loss by two major mechanisms: inducing an abrupt cessation of mitotic activity in rapidly dividing hair matrix cells (anagen effluvium) or precipitating the follicles into premature rest (telogen effluvium) [64,65]. In the former, hair loss usually occurs within days to weeks of drug administration. In the latter, hair loss occurs two to four months after starting treatment.

Anagen effluvium is most commonly caused by antineoplastic drugs (table 12). Telogen effluvium is seen in association with many drugs, including anticoagulants, retinoids, interferons, and antihyperlipidemic drugs (table 13) [65]. (See "Alopecia related to systemic cancer therapy" and "Telogen effluvium".)

Lymphomatoid drug eruption — Lymphomatoid drug eruption, also called cutaneous pseudolymphoma, usually presents as a solitary, erythematous nodule or plaque most frequently located on the trunk or head that mimics cutaneous T cell lymphomas (picture 19) [66-69]. Anticonvulsants, antidepressants, antihypertensives, beta blockers, calcium channel blockers, diuretics, antibiotics, NSAIDs, antihistamines, and biologics have been linked to lymphomatoid drug eruptions. In most patients, the skin lesions resolve when the offending drug is discontinued. (See "Cutaneous T cell pseudolymphomas", section on 'Lymphomatoid drug reaction'.)

CUTANEOUS REACTIONS TO ANTICANCER THERAPIES

Acral erythema (hand-foot syndrome) — Acral erythema (also called hand-foot syndrome, palmar-plantar erythrodysesthesia, toxic erythema of chemotherapy) is a cutaneous eruption associated with conventional cytotoxic agents, including liposomal doxorubicin, capecitabine, cytarabine, fluorouracil, carboplatin, docetaxel, cyclophosphamide, fludarabine, methotrexate, and many others [61]. (See "Cutaneous adverse effects of conventional chemotherapy agents".)

Dysesthesia of the involved areas (eg, paresthesia, tingling, burning, painful sensation) precedes the development of the skin lesions. Acral erythema is most often characterized by a symmetric edema and erythema of the palms and soles, which may progress to blistering and necrosis (picture 20A-B). In contrast, hand-foot skin reaction is characterized by well-demarcated, bean- to coin-sized, hyperkeratotic, painful plaques with underlying erythema localized to the pressure areas of the soles (picture 21) [70].

Hand-foot skin reaction — The small molecule tyrosine kinase inhibitors sunitinib and sorafenib and others that target angiogenesis are associated with a high incidence of hand-foot skin reaction, which presents with clinical and histologic patterns different from the classic, acral erythema caused by conventional cytotoxic agents (picture 22). (See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)

Cutaneous reactions to immune checkpoint inhibitors — Immune checkpoint inhibitors, including anti-programmed cell death protein 1 (PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibodies, have shown great benefits and have been widely used in the treatment of multiple cancer types. Cutaneous immune-related adverse events (irAEs) are one of the most frequently encountered adverse events in clinical practice. Various types and presentations of cutaneous irAEs, including maculopapular eruption, pruritus, eczematous eruption, vitiligo, and neutrophilic dermatosis, have been described [60,71-73]. Vitiligo, a possible indicator for better outcome, was present in approximately 7.5 to 11 percent in nivolumab- and pembrolizumab-treated patients with melanoma and was lower in those who were treated with ipilimumab [74,75]. (See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors".)

Acneiform eruption induced by EGFR inhibitors — Epidermal growth factor receptor (EGFR) inhibitors and other tyrosine kinase inhibitors used to treat cancers are known to cause an inflammatory, acneiform eruption involving the face, neck, and upper trunk in the majority of patients receiving these medications (picture 23). (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

OTHER DRUGS OF SPECIAL CONCERN

Anticoagulants

Warfarin — Warfarin-induced skin necrosis typically occurs during the first several days of warfarin therapy, often in association with the administration of large loading doses [76]. The skin lesions occur on the extremities, breasts, trunk, and penis (in males) and marginate over a period of hours from an initial, central, erythematous macule (picture 24). Biopsies demonstrate fibrin thrombi within cutaneous vessels with interstitial hemorrhage.

Skin necrosis appears to be mediated by the reduction in protein C levels on the first day of therapy, which induces a transient hypercoagulable state. Approximately one-third of patients have underlying protein C deficiency, although skin necrosis is an infrequent complication of warfarin therapy among patients with protein C deficiency [77]. Case reports have also described this syndrome in association with an acquired functional deficiency of protein C, heterozygous protein S deficiency, and factor V Leiden. (See "Protein C deficiency", section on 'Warfarin-induced skin necrosis'.)

Heparin — Heparin may induce several skin reactions, including delayed-type hypersensitivity reactions and, rarely, immediate hypersensitivity reactions, skin necrosis, or bullous hemorrhagic dermatosis (BHD) [78]:

●Delayed-type hypersensitivity reactions – Delayed-type hypersensitivity reactions may occur with both unfractionated and low molecular weight heparins, generally within two weeks of heparin treatment. Delayed-type reactions present most often with localized erythema at the injection site but may progress to generalized, eczematous, or maculopapular eruption.

●Immediate hypersensitivity reactions – Immediate hypersensitivity reactions are rare and manifest as anaphylactic (IgE-mediated) or anaphylactoid (non-IgE-mediated) reactions [79]. Clinical symptoms include localized or generalized urticaria, hypotension, angioedema, allergic rhinoconjunctivitis, tachycardia, or bronchospasm.

●Skin necrosis – Skin necrosis may develop in 10 to 20 percent of patients with heparin-induced, immune-mediated thrombocytopenia, a rare and life-threatening complication of treatment with unfractionated or low molecular weight heparins [80,81]. Cutaneous necrosis is caused by intradermal microvascular thromboses occurring locally or distantly from the injection site. Lesions appear 3 to 15 days after the initiation of therapy as erythematous patches that progress to skin necrosis. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

●Bullous hemorrhagic dermatosis – Bullous hemorrhagic dermatosis (BHD) is an uncommon adverse reaction to low molecular weight heparins characterized by the acute onset of rapidly expanding, tense, hemorrhagic bullae [82-84]. Blisters appear days to weeks after heparin treatment initiation in areas distant from the injection site, most often on the extremities, and generally resolve spontaneously in a few weeks, regardless of whether heparin treatment is maintained or discontinued.

The pathophysiology of BHD remains unclear. On histopathology, there is an intraepidermal or subcorneal blister filled with erythrocytes and plasma and dermal extravasation of erythrocytes, in the absence of significant inflammatory infiltrate.

Gold — Dermatitis and stomatitis account for most adverse gold reactions. Gold rashes are highly variable and may mimic many other skin conditions. In a prospective study of 74 patients with rheumatoid arthritis, 39 patients developed a mucocutaneous reaction to gold [85]. A variety of morphologic features were noted, the bulk of which were characterized as nonspecific dermatitis. Most patients had pruritus. Gold-associated eruptions had a median duration of two months, with a range of one week to two years. Most cases resolved promptly with discontinuation of gold or with dose reduction; application of topical steroids was also helpful.

Lithium — Cutaneous side effects from lithium therapy have been reported in 3 to 34 percent of patients [86]:

●Psoriasis is one of the most common reactions. It may begin for the first time during therapy, or a mild case may be exacerbated when the patient begins the drug.

●Acne and acneiform eruptions are also common. Pustular lesions may be the result of lysosomal enzyme release and increased neutrophil chemotaxis [86]. Acneiform lesions may be seen on the forearms and legs in addition to the sites commonly involved in acne vulgaris.

●Hair loss, especially in women during the first few months of therapy, has frequently been reported.

Halogens — Ingestion of halogens, such as iodides, bromides, and fluorides, can rarely cause cutaneous reactions [87]. Iodides (such as those in seaweed, salt, amiodarone, and radiocontrast media) can cause acneiform lesions, typically on the face, as well as vesicular, pustular, hemorrhagic, urticarial, fungating, suppurative, nodular, and ulcerative lesions (picture 25). Swelling of the parotid and submandibular glands has been previously described as iodine mumps.

Iododerma due to the administration of intravenous radiocontrast media is commonly seen as an acute eruption. With oral iodine exposure, the onset is insidious [88,89]. Declining renal function may be a factor in radiocontrast-induced iododerma. (See "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography".)

Bromides can cause verrucous, ulcerating plaques, most often located on the lower extremities [87,90,91]. Discontinuation of the causative agent is sufficient in most patients, with gradual resolution of lesions expected over four to six weeks [87].

Cytokine therapy — Hematopoietic colony-stimulating factors are a heterogeneous group of cytokines that induce proliferation and differentiation of bone marrow precursor cells. They are most frequently administered in the setting of neutropenia secondary to chemotherapy (eg, recombinant human granulocyte or granulocyte-macrophage colony-stimulating factor). (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)

Serious cutaneous adverse effects of colony-stimulating factors are distinctly rare but include neutrophilic dermatoses and necrotizing vasculitis [92,93]. Upregulation of neutrophil function and secondary release of cytokines may induce these complications.

SUMMARY

●Epidemiology – Adverse cutaneous reactions to drugs are common, affecting 2 to 3 percent of hospitalized patients. Drug-induced exanthems, also called morbilliform eruptions, are the most common cutaneous reactions to drugs, responsible for approximately 90 percent of all drug rashes (picture 1C-D). Frequently prescribed medications (eg, antibiotics, sulfonamides) are implicated in most cases. (See 'Epidemiology' above.)

●Approach to the diagnosis – The diagnosis of drug eruptions is primarily clinical, based on the clinical and medication history, timing of initial drug administration and onset of symptoms, and assessment of the type and distribution of the rash (table 1). An approach to the evaluation and clinical diagnosis of the most important, localized and generalized drug eruptions is illustrated in the algorithms (algorithm 1A-B). (See 'Approach to the diagnosis' above.)

●Classic drug reaction patterns – Drug-induced exanthems are the most common drug reactions (picture 1A-D). Less frequently, drugs may cause lichenoid eruptions (picture 3A-B), exfoliative dermatitis (picture 5), urticaria/angioedema (picture 6A-B), anaphylaxis, or cutaneous small vessel vasculitis (picture 9A-B). (See 'Classic drug reaction patterns' above.)

●Uncommon drug reaction patterns – Uncommon cutaneous drug reactions include severe and potentially life-threatening reactions (eg, Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN] (picture 10A-E), drug reaction with eosinophilia and systemic symptoms [DRESS] (picture 11A-C), acute generalized exanthematous pustulosis [AGEP] (picture 12A-B)), fixed drug eruptions (picture 13B), phototoxic and photoallergic reactions (picture 15A, 15C), bullous eruptions (eg, pemphigus, bullous pemphigoid), pseudoporphyria, drug-induced lupus, and lymphomatoid eruption. (See 'Uncommon drug reaction patterns' above.)

●Cutaneous reactions to anticancer drugs – Cutaneous reactions to anticancer drugs, including hand-foot skin reaction (picture 22), acneiform eruptions to epidermal growth factor receptor (EGFR) inhibitors (picture 23), and skin reactions to immune checkpoint inhibitors, are discussed separately. (See 'Cutaneous reactions to anticancer therapies' above and "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors" and "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors" and "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors".)