NONIMMUNE CUTANEOUS REACTIONS
Exacerbation or Induction of Dermatologic Diseases
A variety of drugs can exacerbate preexisting diseases or induce—or unmask—a disease that may or may not disappear after withdrawal of the inducing medication. For example, NSAIDs, lithium, beta blockers, tumor necrosis factor (TNF) antagonists, interferon (IFN) α, and angiotensin-converting enzyme (ACE) inhibitors can exacerbate plaque psoriasis, whereas antimalarials and withdrawal of systemic glucocorticoids can worsen pustular psoriasis. The situation of TNF-α inhibitors is unusual, as this class of medications is used to treat psoriasis; however, they may induce psoriasis (especially palmoplantar) in patients being treated for other conditions. Acne may be induced by glucocorticoids, androgens, lithium, and antidepressants. Follicular papular or pustular eruptions of the face and trunk resembling acne frequently occur with epidermal growth factor receptor (EGFR) antagonists. The severity of the eruption correlates with a better anticancer effect. This rash is typically responsive to and prevented by tetracycline antibiotics.
Several medications induce or exacerbate autoimmune disease. Interleukin (IL) 2, IFN-α, and anti-TNF-α are associated with new-onset systemic lupus erythematosus (SLE). Drug-induced lupus is classically marked by antinuclear and antihistone antibodies and, in some cases, anti-double-stranded DNA (D-penicillamine, anti-TNF-α) or perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) (minocycline) antibodies. Subacute lupus erythematosus (SCLE) can be induced by a growing list of drugs, including thiazide diuretics, TNF-inhibitors, terbinafine, and minocycline. IFN and TNF-inhibitors can induce granulomatous disease and sarcoidosis. Autoimmune blistering diseases may be drug induced as well: pemphigus by D-penicillamine and ACE inhibitors, bullous pemphigoid by furosemide and PD-1 inhibitors, and linear IgA bullous dermatosis by vancomycin. Other medications may cause highly specific cutaneous reactions. Gadolinium contrast has been associated with nephrogenic systemic fibrosis, a condition of sclerosing skin with rare internal organ involvement; advanced renal compromise may be an important risk factor. Granulocyte colony-stimulating factor, azacitidine, all-trans retinoic acid, and the FLT3-inhibitor class of drugs may induce neutrophilic dermatoses. In this setting, the hypothesis that a drug may be responsible should always be considered, even after the treatment is complete. In addition, reactions may develop in cases of long-term medication therapy due to small changes in dosing or host metabolism. Resolution of the cutaneous reaction may be delayed upon discontinuation of the medication.
Photosensitivity eruptions are usually most marked in sun-exposed areas, but they may extend to sun-protected areas. The mechanism is almost always phototoxicity. Phototoxic reactions resemble sunburn and can occur with first exposure to a drug. Blistering may occur in drug-related pseudoporphyria, most commonly with NSAIDs. The severity of the reaction depends on the tissue level of the drug, its efficiency as a photosensitizer, and the extent of exposure to the activating wavelengths of ultraviolet (UV) light (Chap. 57).
Common orally administered photosensitizing drugs include fluoroquinolones, tetracycline antibiotics, and trimethoprim/sulfamethoxazole. Other drugs less frequently implicated are chlorpromazine, thiazides, NSAIDs, and BRAF inhibitors. Voriconazole may result in severe photosensitivity, accelerated photoaging, and cutaneous carcinogenesis.
Because UV-A and visible light, which trigger these reactions, are not easily absorbed by nonopaque sunscreens and are transmitted through window glass, photosensitivity reactions may be difficult to block. Photosensitivity reactions abate with removal of either the drug or UV radiation, use of sunscreens that block UV-A light, and treatment of the reaction as one would a sunburn. Rarely, individuals develop persistent reactivity to light, necessitating long-term avoidance of sun exposure. Some chemotherapeutic agents, such as methotrexate, can induce a UV-recall reaction characterized by an erythematous, slightly scaly eruption at sites of prior severe sun exposure.
Drugs, either systemic or topical, may cause a variety of pigmentary changes in the skin by triggering melanocyte production of melanin (as in the case of oral contraceptives causing melasma) or due to deposition of drug or drug metabolites. Long-term minocycline and amiodarone may cause blue-gray pigmentation. Phenothiazine, gold, and bismuth result in gray-brown pigmentation of sun-exposed areas. Numerous cancer chemotherapeutic agents may be associated with characteristic patterns of pigmentation (e.g., bleomycin, busulfan, daunorubicin, cyclophosphamide, hydroxyurea, fluorouracil, and methotrexate). Clofazimine causes a drug-induced lipofuscinosis with characteristic red-brown coloration. Hyperpigmentation of the face, mucous membranes, and pretibial and subungual areas occurs with antimalarials. Quinacrine causes generalized yellow discoloration. Pigmentation changes may also occur in mucous membranes (busulfan, bismuth), conjunctiva (chlorpromazine, thioridazine, imipramine, clomipramine), nails (zidovudine, doxorubicin, cyclophosphamide, bleomycin, fluorouracil, hydroxyurea), hair, and teeth (tetracyclines).
Warfarin Necrosis of Skin
This rare reaction (0.01–0.1%) usually occurs between the third and tenth days of therapy with warfarin, usually in women. Common sites are breasts, thighs, and buttocks (Fig. 56-1). Lesions are sharply demarcated, erythematous, or purpuric, and may progress to form large, hemorrhagic bullae with necrosis and eschar formation.
Warfarin necrosis involving the breasts.
Warfarin anticoagulation in protein C or S deficiency causes an additional reduction in already low circulating levels of endogenous anticoagulants, permitting hypercoagulability and thrombosis in the cutaneous microvasculature, with consequent areas of necrosis. Heparin-induced necrosis may have clinically similar features but is probably due to heparin-induced platelet aggregation with subsequent occlusion of blood vessels; it can affect areas adjacent to the injection site or more distant sites if infused.
Warfarin-induced cutaneous necrosis is treated with vitamin K, heparin, surgical debridement, and intensive wound care. Treatment with protein C concentrates may also be helpful. Newer anticoagulants such as dabigatran etexilate may avoid warfarin necrosis in high-risk patients.
Drug-Induced Hair Disorders • DRUG-INDUCED HAIR LOSS
Medications may affect hair follicles at two different phases of their growth cycle: anagen (growth) or telogen (resting). Anagen effluvium occurs within days of drug administration, especially with antimetabolite or other chemotherapeutic drugs. In contrast, in telogen effluvium, the delay is 2–4 months following initiation of a new medication. Both present as diffuse, nonscarring alopecia most often reversible after discontinuation of the responsible agent.
A considerable number of drugs have been associated with hair loss. These include antineoplastic agents (alkylating agents, bleomycin, vinca alkaloids, platinum compounds), anticonvulsants (carbamazepine, valproate), beta blockers, antidepressants, antithyroid drugs, IFNs, oral contraceptives, and cholesterol-lowering agents.
Medications may also cause hair growth. Hirsutism is an excessive growth of terminal hair with masculine hair growth pattern in a female, most often on the face and trunk, due to androgenic stimulation of hormone-sensitive hair follicles (anabolic steroids, oral contraceptives, testosterone, corticotropin). Hypertrichosis is a distinct pattern of hair growth, not in a masculine pattern, typically located on the forehead and temporal regions of the face. Drugs responsible for hypertrichosis include anti-inflammatory drugs, glucocorticoids, vasodilators (diazoxide, minoxidil), diuretics (acetazolamide), anticonvulsants (phenytoin), immunosuppressive agents (cyclosporine A), psoralens, and zidovudine.
Changes in hair color or structure are uncommon adverse effects from medications. Hair discoloration may occur with chloroquine, IFN-α, chemotherapeutic agents, and tyrosine kinase inhibitors. Changes in hair structure have been observed in patients given EGFR inhibitors, BRAF inhibitors, tyrosine kinase inhibitors, and acitretin.
Drug-Induced Nail Disorders
Drug-related nail disorders usually involve all 20 nails and need months to resolve after withdrawal of the medication. The pathogenesis is most often toxic. Drug-induced nail changes include Beau’s line (transverse depression of the nail plate), onycholysis (detachment of the distal part of the nail plate), onychomadesis (detachment of the proximal part of the nail plate), pigmentation, and paronychia (inflammation of periungual skin).
Onycholysis occurs with tetracyclines, fluoroquinolones, retinoids, NSAIDs, and others, including many chemotherapeutic agents, and may be triggered by exposure to sunlight.
Onychomadesis is caused by temporary arrest of nail matrix mitotic activity. Common drugs reported to induce onychomadesis include carbamazepine, lithium, retinoids, and chemotherapeutic agents.
Paronychia and multiple pyogenic granuloma with progressive and painful periungual abscess of fingers and toes are side effects of systemic retinoids, lamivudine, indinavir, and anti-EGFR monoclonal antibodies.
Some drugs—including anthracyclines, taxanes, fluorouracil, psoralens, and zidovudine—may induce nail bed hyperpigmentation through melanocyte stimulation. It appears to be reversible and dose dependent.
Toxic Erythema of Chemotherapy and Other Chemotherapy Reactions
Because many agents used in cancer chemotherapy inhibit cell division, rapidly proliferating elements of the skin, including hair, mucous membranes, and appendages, are sensitive to their effects. A broad spectrum of chemotherapy-related skin toxicities have been reported, including neutrophilic eccrine hidradenitis, sterile cellulitis, exfoliative dermatitis, and flexural erythema; recent nomenclature classifies these under the unifying diagnosis of toxic erythema of chemotherapy (TEC) (Fig. 56-2). Acral erythema is marked by dysesthesia and an erythematous, edematous eruption of the palms and soles. Common causes include cytarabine, doxorubicin, methotrexate, hydroxyurea, fluorouracil, and capecitabine.
Toxic erythema of chemotherapy.
The recent introduction of many new monoclonal antibody and small molecular signaling inhibitors for the treatment of cancer has been accompanied by numerous reports of skin and hair toxicity; only the most common of these are mentioned here. EGFR antagonists induce follicular eruptions and nail toxicity after a mean interval of 10 days in a majority of patients. Xerosis, eczematous eruptions, acneiform eruptions, and pruritus are common. Erlotinib is associated with marked hair textural changes. Sorafenib, a tyrosine kinase inhibitor, may result in follicular eruptions and focal bullous eruptions at palmoplantar, flexural sites or areas of frictional pressure. BRAF inhibitors are associated with photosensitivity, palmoplantar hyperkeratosis, hair curling, dyskeratotic (Grover’s-like) rash, hyperkeratotic benign cutaneous neoplasms, and keratoacanthoma-like squamous cell carcinomas. Rash, pruritus, and vitiliginous depigmentation have been reported in association with ipilimumab (anti-CTLA4) treatment. Up to 50% of patients experience immune-mediated skin eruptions, including granulomatous reactions, dermatomyositis, panniculitis, and vasculitis.
IMMUNE CUTANEOUS REACTIONS: COMMON
Morbilliform or maculopapular eruptions (Fig. 56-3) are the most common of all drug-induced reactions, often start on the trunk or intertriginous areas, and consist of blanching erythematous macules and papules that are symmetric and confluent. Nonblanching, dusky, or bright-red macules should raise concern for a more severe reaction. Involvement of mucous membranes is rare and should prompt consideration of SJS. Facial involvement in morbilliform eruptions is also uncommon, and the presence of extensive facial lesions with facial edema suggests DIHS. Diagnosis of morbilliform eruptions is rarely assisted by laboratory testing. Skin biopsy often shows nonspecific inflammatory changes.
Morbilliform drug eruption.
Morbilliform eruptions may be associated with moderate to severe pruritus and fever. A viral exanthem is another differential diagnostic consideration, especially in children, and graft-versus-host disease is also a consideration in the proper clinical setting. Absence of enanthems; absence of ear, nose, throat, and upper respiratory tract symptoms; and polymorphism of the skin lesions support a drug rather than a viral eruption. Common offenders include aminopenicillins, cephalosporins, antibacterial sulfonamides, allopurinol, and antiepileptic drugs. Beta blockers, calcium channel blockers, and ACE inhibitors are rarely the culprit; however, any drug can cause a morbilliform exanthem. Certain medications carry very high rates of morbilliform eruption, including nevirapine and lamotrigine, even in the absence of DIHS reactions. Lamotrigine morbilliform rash is associated with higher starting doses, rapid dose escalation, concomitant use of valproate (which increases lamotrigine levels and half-life), and use in children.
Maculopapular reactions usually develop within 1 week of initiation of therapy and last less than 2 weeks. Occasionally, these eruptions resolve despite continued use of the responsible drug. Because the eruption may also worsen, the suspect drug should be discontinued unless it is essential. It is important to note that the rash may continue to progress for a few days up to 1 week following medication discontinuation. Oral antihistamines and emollients may help relieve pruritus. Short courses of potent topical glucocorticoids can reduce inflammation and symptoms. Systemic glucocorticoid treatment is rarely indicated.
Pruritus is associated with almost all drug eruptions and, in some cases, may represent the only symptom of the adverse cutaneous reaction. It may be alleviated by antihistamines such as hydroxyzine or diphenhydramine. Pruritus stemming from specific medications may require distinct treatment, such as selective opiate antagonists for opiate-related pruritus.
Urticaria, the second most frequent type of cutaneous reaction to drugs, is characterized by pruritic, red wheals of varying size rarely lasting more than 24 hours. It has been observed in association with nearly all drugs, most frequently ACE inhibitors, aspirin, NSAIDs, penicillin, and blood products. However, medications account for no more than 10–20% of acute urticaria cases. Deep edema within dermal and subcutaneous tissues is known as angioedema and may involve respiratory and gastrointestinal mucous membranes. Urticaria and angioedema may be part of a life-threatening anaphylactic reaction.
Drug-induced urticaria may be caused by three mechanisms: an IgE-dependent mechanism, circulating immune complexes (serum sickness), and nonimmunologic activation of effector pathways. IgE-dependent urticarial reactions usually occur within 36 hours of drug exposure but can occur within minutes. Immune complex–induced urticaria associated with serum sickness–like reactions usually occur 6–12 days after first exposure. In this syndrome, the urticarial eruption (typically polycyclic plaques over distal joints) may be accompanied by fever, hematuria, arthralgias, hepatic dysfunction, and neurologic symptoms. Certain drugs, such as NSAIDs, ACE inhibitors, angiotensin II antagonists, radiographic dye, and opiates, may induce urticarial reactions, angioedema, and anaphylaxis in the absence of drug-specific antibodies through direct mast-cell degranulation.
Radiocontrast agents are a common cause of urticaria and, in rare cases, can cause anaphylaxis. High-osmolality radiocontrast media are about five times more likely to induce urticaria (1%) or anaphylaxis than are newer low-osmolality media. About one-third of those with mild reactions to previous exposure react on reexposure. Pretreatment with prednisone and diphenhydramine reduces reaction rates.
The treatment of urticaria or angioedema depends on the severity of the reaction. In severe cases with respiratory or cardiovascular compromise, epinephrine and intravenous glucocorticoids are the mainstay of therapy. For patients with urticaria without symptoms of angioedema or anaphylaxis, drug withdrawal and oral antihistamines are usually sufficient. Future drug avoidance is recommended; rechallenge, especially in individuals with severe reactions, should only occur in an intensive care setting.
Vancomycin is associated with red man syndrome, a histamine-related anaphylactoid reaction characterized by flushing, diffuse maculopapular eruption, and hypotension. In rare cases, cardiac arrest may be associated with rapid IV infusion of the medication.
Irritant/Allergic Contact Dermatitis
Patients using topical medications may develop an irritant or allergic contact dermatitis to the medication itself or to a preservative or other component of the formulation. Reactions to neomycin sulfate, bacitracin, and polymyxin B are common. Contact dermatitis may be seen to adhesive tapes, leading to irritation or blisters around ports and IV sites (Fig. 56-4). Harsh disinfectant skin cleansers may lead to localized irritant dermatitis.
Allergic contact dermatitis (bullous) due to adhesive tape.
These less common reactions are characterized by one or more sharply demarcated, dull red to brown lesions, sometimes with central dusky violaceous erythema and central bulla (Fig. 56-5). Hyperpigmentation often results after resolution of the acute inflammation. With rechallenge, the process recurs in the same (fixed) location but may spread to new areas as well. Lesions often involve the lips, hands, legs, face, genitalia, and oral mucosa, and cause a burning sensation. Most patients have multiple lesions. Fixed drug eruptions have been associated with pseudoephedrine (frequently a nonpigmenting reaction), phenolphthalein (in laxatives), sulfonamides, tetracyclines, NSAIDs, barbiturates, and others.
IMMUNE CUTANEOUS REACTIONS: RARE AND SEVERE
Drug-Induced Hypersensitivity Syndrome
DIHS is a systemic drug reaction also known as DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome; since eosinophilia is not always present, the term DIHS is now preferred. Clinically, DIHS presents with a prodrome of fever and flu-like symptoms for several days, followed by the appearance of a diffuse morbilliform eruption usually involving the face (Fig. 56-6). Facial swelling and hand/foot swelling are often present. Systemic manifestations include lymphadenopathy, fever, and leukocytosis (often with eosinophilia or atypical lymphocytosis), as well as hepatitis, nephritis, pneumonitis, myositis, and gastroenteritis, in descending order. Distinct patterns of timing of onset and organ involvement may exist; for example allopurinol classically induces DIHS with renal involvement, cardiac and lung involvements are more common with minocycline, gastrointestinal involvement is almost exclusively seen with abacavir, and some medications typically lack eosinophilia (abacavir, dapsone, lamotrigine). The cutaneous reaction usually begins 2–8 weeks after the drug is started and persists after drug cessation. Signs and symptoms may continue for several weeks, especially those associated with hepatitis. The eruption recurs with rechallenge, and cross-reactions among aromatic anticonvulsants, including phenytoin, carbamazepine, and phenobarbital, are common. Other drugs causing DIHS include antibacterial sulfonamides and other antibiotics. Hypersensitivity to reactive drug metabolites, hydroxylamine for sulfamethoxazole and arene oxide for aromatic anticonvulsants, may be involved in the pathogenesis of DIHS. Reactivation of herpes viruses, in particular human herpesviruses 6 and 7, EBV, and cytomegalovirus (CMV), has been frequently reported in this syndrome, although the causal role of viral infection has been debated. Recent research suggests that inciting drugs may reactivate quiescent herpes viruses, resulting in expansion of viral-specific CD8+ T lymphocytes and subsequent end-organ damage. Viral reactivation may be associated with a worse clinical prognosis. Mortality rates as high as 10% have been reported, with most fatalities resulting from liver failure. Systemic glucocorticoids (1.5–2 mg/kg/d prednisone equivalent) should be started and tapered slowly over 8–12 weeks, during which time clinical symptoms and labs (including complete blood count with differential, basic metabolic panel, and liver function tests) should be followed carefully. A steroid-sparing agent such as mycophenolate mofetil may be indicated in cases of rapid recurrence upon steroid taper. In all cases, immediate withdrawal of the suspected culprit drug is required. Given the severe long-term complications of myocarditis, patients should undergo cardiac evaluation in cases of severe DIHS or if heart involvement is suspected due to hypotension or arrhythmia. Patients should be closely monitored for resolution of organ dysfunction and for development of late-onset autoimmune thyroiditis and diabetes (up to 6 months).
Drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (DIHS/DRESS).
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
SJS and TEN are characterized by blisters and mucosal/epidermal detachment resulting from full-thickness epidermal necrosis in the absence of substantial dermal inflammation. The term Stevens-Johnson syndrome (SJS) describes cases in which the total body surface area of blistering and eventual detachment is <10% (Fig. 56-7). The term Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap is used to describe cases with 10–30% epidermal detachment (Fig. 56-8), and TEN is used to describe cases with >30% detachment (Figs. 56-9 and 56-10).
Stevens-Johnson syndrome (SJS).
Toxic epidermal necrolysis, hand.
Toxic epidermal necrolysis.
Other blistering eruptions with concomitant mucositis may be confused with SJS/TEN. Erythema multiforme (EM) associated with herpes simplex virus is characterized by painful mucosal erosions and target lesions, typically with an acral distribution and limited skin detachment. Mycoplasma infection in children causes a clinically distinct presentation with prominent mucositis and limited cutaneous involvement. The name Mycoplasma-induced rash and mucositis has been proposed to help differentiate this clinical entity, which some believe may be the syndrome originally described by Stevens and Johnson.
Patients with SJS/TEN initially present with fever >39°C (102.2°F); sore throat; conjunctivitis; and acute onset of painful dusky, atypical, target-like lesions (Fig. 56-11). Intestinal and upper respiratory tract involvement are associated with a poor prognosis, as are older age and greater extent of epidermal detachment. At least 10% of those with SJS and 30% of those with TEN die from the disease. Drugs that most commonly cause SJS/TEN are sulfonamides, allopurinol, antiepileptics (e.g., lamotrigine, phenytoin, carbamazepine), oxicam NSAIDs, β-lactam and other antibiotics, and nevirapine. Frozen-section skin biopsy may aid in rapid diagnosis. At this time, there is no consensus on the most effective treatment for SJS/TEN. The best outcomes stem from early diagnosis, immediate discontinuation of the suspected drug, and meticulous supportive therapy in an intensive care or burn unit. Issues such as fluid management, atraumatic wound care, infection prevention and treatment, and ophthalmologic and respiratory support are critical. Systemic glucocorticoid therapy (prednisone 1–2 mg/kg) may be useful early in disease evolution; however, long-term or late systemic glucocorticoid use has been associated with increased mortality. After initial enthusiasm for the use of intravenous immunoglobulin (IVIG) in the treatment of SJS/TEN, more recent data question whether it is beneficial. There are emerging data to support treatment with cyclosporine and etanercept. Randomized studies to evaluate potential therapies are lacking and difficult to perform.
Target-like lesion in SJS.
AGEP is a rare reaction pattern affecting 3–5 people per million per year. It is thought to be secondary to medication exposure in >90% of cases (Fig. 56-12). Patients typically present with diffuse erythema or erythroderma, as well as high spiking fevers, and leukocytosis. One to two days later, innumerable pinpoint pustules develop overlying the erythema. The pustules are most pronounced in body fold areas; however, they may become generalized and, when coalescent, can lead to superficial erosion. In such cases, differentiating the eruption from SJS in its initial stages may be difficult; in AGEP, any erosions tend to be more superficial, and prominent mucosal involvement is lacking. Skin biopsy shows collections of neutrophils and sparse necrotic keratinocytes in the upper part of the epidermis, unlike the full-thickness epidermal necrosis that characterizes SJS. Before the pustules appear, AGEP may also mimic DIHS due to the prominent fever and erythroderma.
Acute generalized exanthematous pustulosis.
The principal differential diagnosis for AGEP is acute pustular psoriasis, which has an identical clinical and histologic appearance. Many patients with AGEP have a personal or family history of psoriasis. AGEP classically begins within 24–48 hours of drug exposure, though it may occur as much as 1–2 weeks later. β-Lactam antibiotics, calcium channel blockers, macrolide antibiotics, and other inciting agents (including radiocontrast and dialysates) have been reported. Patch testing with the responsible drug often results in a localized pustular eruption.
Overlap Hypersensitivity Syndromes
An important concept in the clinical approach to severe drug eruptions is the presence of overlap syndromes, most notably DIHS with TEN-like features, DIHS with pustular eruption (AGEP-like), and AGEP with TEN-like features. In several case series of AGEP, 50% of cases had TEN-like or DRESS-like features, and 20% of cases had mucosal involvement resembling SJS/TEN. In one study, up to 20% of all severe drug eruptions had overlap features, suggesting that AGEP, DIHS, and SJS/TEN represent a clinical spectrum with some common pathophysiologic mechanisms. Designation of a single diagnosis based on cutaneous and extracutaneous involvement may not always be possible in cases of hypersensitivity; in such instances, treatment should be geared toward addressing the dominant clinical features. The timing of rash onset with respect to drug administration, which is usually much more delayed in DIHS, and the presence of systemic manifestations such as hepatitis are helpful clues to that diagnosis.
Cutaneous small-vessel vasculitis (CSVV) typically presents with purpuric papules and macules involving the lower extremities and other dependent areas (Fig. 56-13) (Chap. 356). Pustular and hemorrhagic vesicles as well as rounded ulcers also occur. Importantly, vasculitis may involve other organs, including the kidneys, joints, gastrointestinal tract, and lungs, necessitating a thorough clinical evaluation for systemic involvement. Drugs are implicated as a cause of roughly 15% of all cases of small vessel vasculitis. Antibiotics, particularly β-lactams, are commonly implicated; however, almost any drug can cause vasculitis. Vasculitis may also be idiopathic or due to underlying infection, connective tissue disease, or (rarely) malignancy.
Cutaneous small-vessel vasculitis (CSVV, leukocytoclastic vasculitis).
Rare but important types of drug-induced vasculitis include drug-induced ANCA vasculitis. Such patients commonly present with cutaneous manifestations but can develop the full range of symptoms associated with ANCA vasculitis, including crescentic glomerulonephritis and alveolar hemorrhage. Propylthiouracil, methimazole, and hydralazine are common culprits. Drug-induced polyarteritis nodosa has been associated with long-term exposure to minocycline. The presence of perivascular eosinophils on skin biopsy can be a clue to possible drug etiology.