Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology, Seventh Edition

SECTION 23

Adverse Cutaneous Drug Reactions1

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Adverse Cutaneous Drug Reactions

ICD-9: 995.2 imageICD:10: T88.7 image

Image Adverse cutaneous drug reactions (ACDRs) are common in hospitalized (2–3%) as well as in ambulatory patients (>1%).

Image Most reactions are mild, accompanied by pruritus, and resolve promptly after the offending drug is discontinued.

Image Severe, life-threatening ACDRs do occur and are unpredictable.

Image Drug eruptions can mimic virtually all the morphologic expressions in dermatology and must be the first consideration in the differential diagnosis of a suddenly appearing eruption

Image Drug eruptions are caused by immunologic or nonimmunologic mechanisms and are provoked by systemic or topical administration of a drug.

Image The majority are based on a hypersensitivity mechanism and are thus immunologic and may be of types I, II, III, or IV.

Classification

Immunologically Mediated ACDR (see Table 23-1). It should be noted, however, that classification of immunologically mediated ACDR according to the Gell and Coombs classification is an oversimplification because in most reactions both cellular and humoral immune reactions are involved. Nonimmunologic reactions are summarized in Table 23-2.

TABLE 23-1 IMMUNOLOGICALLY MEDIATED ADVERSE CUTANEOUS DRUG REACTIONS*

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TABLE 23-2 NONIMMUNOLOGIC DRUG REACTIONS

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Guidelines for Assessment of Possible ACDRs

• Exclude alternative causes, especially infections, in that many infections (especially viral) are difficult to distinguish clinically from the adverse effects of drugs used to treat infections.

• Examine interval between introduction of a drug and onset of the reaction.

• Note any improvement after drug withdrawal.

• Determine whether similar reactions have been associated with the same compound.

• Note any reaction on readministration of the drug.

Findings Indicating Possible Life-Threatening ACDR

• Skin pain

• Confluent erythema

• Facial edema or central facial involvement

• Palmar/plantar painful erythema

• Concomitant erosive mucous membrane involvement

• Blisters of epidermal detachment

• Positive Nikolsky sign

• Mucous membrane erosions

• Urticaria

• Swelling of the tongue

• High fever (temperature >40°C)

• Enlarged lymph nodes

• Arthralgia

• Shortness of breath, wheezing, hypotension

• Palpable purpura

• Skin necrosis

Clinical Types of Adverse Drug Reactions

ACDRs can be exanthematous and can manifest as urticaria/angioedema, anaphylaxis, and anaphylactoid reactions, or serum sickness; they can mimic other dermatoses; they can present as cutaneous necrosis, pigmentation, alopecia, hypertrichosis; and they can induce nail changes. An overview is presented in Tables 23-3 and 23-4.

TABLE 23-3 TYPES OF CLINICAL ACDRs

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TABLE 23-4 ACDR MIMICRY OF OTHER DERMATOSES

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Exanthematous Drug Reactions ICD-9: 995.2 imageICD-10: T88.7 image

Image An exanthematous drug reaction (EDR) (eruption) is an adverse hypersensitivity reaction to an ingested or parenterally administered drug.

Image Most common type of cutaneous drug reaction.

Image Cutaneous eruption that mimics a measles-like viral exanthem.

Image Systemic involvement is low.

Image Drugs with a high probability of reaction (3–5%): penicillin and related antibiotics, carbamazepine, allopurinol, gold salts (10–20%). Medium probability, sulfonamides (bacteriostatic, antidiabetic, diuretic), nonsteroidal anti-inflammatory drugs (NSAIDs), hydantoin derivatives, isoniazid, chloramphenicol, erythromycin, streptomycin. Low probability (<1%): barbiturates, benzodiazepines, phenothiazines, and tetracyclines.

Image Exact mechanism unknown. Probably delayed hypersensitivity.

Image Prior Drug Sensitization. Patients with prior history of exanthematous drug eruption will most likely develop a similar reaction if rechallenged with same drug.

Image Sensitization occurs during administration or after completing course of drug; peak incidence at ninth day after administration. However, EDR may occur at any time between the first day and 3 weeks after the beginning of treatment. Reaction to penicillin can begin ≥2 weeks after drug is discontinued. In previously sensitized patient, eruption starts within 2 or 3 days after readministration of drug.

Image Usually quite pruritic. Painful skin lesions suggest development of a more serious ACDR, such as toxic epidermal necrolysis (TEN).

Image Systems Review. ± Fever, chills.

Image Skin Lesions. Macules and/or papules, a few millimeters to 1 cm in size (Fig. 23-1). Bright or “drug” red. Resolving lesions have hues of tan and purple. In time, lesions become confluent forming large macules, polycyclic/gyrate erythema, reticular eruptions, sheet-like erythema (Fig. 23-1), erythroderma; also erythema multiforme-like. Purpura may be seen in lesions of lower legs. In individuals with thrombocytopenia, exanthematous eruptions can mimic vasculitis because of intralesional hemorrhage. Scaling and/or desquamation may occur with healing.

Image Distribution. Symmetric (Fig. 23-1). Almost always on trunk and extremities. Confluent lesions in intertriginous areas, i.e., axilla, groin, inframammary area. Palms and soles variably involved. In children, may be limited to face and extremities.

Image Mucous Membranes. Enanthem on buccal mucosa.

Image Laboratory. Peripheral eosinophilia. Dermatopathology: Perivascular lymphocytes and eosinophils.

Image Differential diagnosis includes all exanthematous eruptions: Viral exanthem, secondary syphilis, atypical pityriasis rosea, and early widespread allergic contact dermatitis.

Image After discontinuation of drug, rash usually fades; however, it may worsen for a few days. The eruption may also begin after the drug has been discontinued. Eruption usually recurs with rechallenge, although not always.

Image The definitive step in management is to identify the offending drug and discontinue it. Oral antihistamine to alleviate pruritus. Glucocorticoids. Potent Topical Preparation May help speed resolution of eruption. Oral or IVProvides symptomatic relief. If offending drug cannot be substituted or omitted, systemic glucocorticoids can be administered to treat the ACDR. Prevention. Patients must be aware of their specific drug hypersensitivity and that other drugs of the same class can cross-react. Wearing a medical alert bracelet is advised.

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Figure 23-1. Exanthematous drug eruption: ampiciMin Symmetrically arranged, brightly erythematous macules and papules, discrete in some areas, and confluent in others, on the trunk and the extremities.

Reactions to Specific Drugs (Selected)

Allopurinol. Incidence: 5%. Begins on face, spreads rapidly to all areas; may occur in photodistribution. Onset: 2–3 weeks after initiation of therapy. Associated findings: facial edema; systemic vasculitis, especially involving kidneys. Rash may fade in spite of continued administration.

Ampicillin, Amoxicillin. In up to 100% of patients with EBV or CMV mononucleosis syndrome. Increased incidence of EDR to penicillins in patients taking allopurinol. Ten percent cross-react with cephalosporins.

Barbiturates. Site: face, trunk. Onset: few days after initiation of therapy. Cross-reactivity with other barbiturates: not universal.

Benzodiazepines. Rare. Onset: few days after initiation of therapy. Rechallenge: frequently rash does not occur.

Carbamazepine. Morphology: diffuse erythema; severe erythroderma may follow. Site: begins on face, spreads rapidly to all areas; may occur in photodistribution. Onset: 2 weeks after initiation of therapy. Associated findings: facial edema.

Gold Salts. Incidence: 10–20% of patients; dose-related. Morphology: diffuse erythema; exfoliative dermatitis, lichenoid, hemorrhagic, bullous, or pityriasis rosea-like eruptions may follow.

Hydantoin Derivatives. Macular → confluent erythema. Begins on face, spreads to trunk and extremities. Onset: 2 weeks after initiation of therapy. Associated findings: fever, peripheral eosinophilia; facial edema; lymphadenopathy (can mimic lymphoma histologically).

Isoniazid. May evolve to exfoliative dermatitis. Associated findings: fever and hepatitis.

Phenothiazines. Begins on face, spreads to trunk (mainly back), and extremities. Onset: between second and third weeks after initiation of therapy. Associated findings: periorbital edema. Rechallenge: rash may not occur. Cross-reactivity: common.

Sulfonamides. Occurs in up to 50–60% of HIV/AIDS-infected patients (trimethoprim sulfamethoxazole). Patients sensitized to one sulfa-based drug may cross-react with another sulfa drug in 20%.

Pustular Eruptions ICD-9: 995.2 image ICD-10: T88.7 Image

Image Acute generalized exanthematous pustulosis (AGEP) is an acute febrile eruption that is often associated with leukocytosis (Fig. 23-2). After drug administration, it may take 1–3 weeks before skin lesions appear; however, in previously sensitized patients, the skin symptoms may occur within 2–3 days.

Image The estimated incidence is approximately 1–5 cases per million per year.

Image Onset is acute, most often following drug intake, but viral infections can also trigger the disease.

Image AGEP typically presents with nonfollicular sterile pustules occurring on a diffuse, edematous erythema (Fig. 23-2).

Image May be irregularly dispersed (Fig. 23-2) or grouped (Fig. 23-3), usually starting in the folds and/or the face.

Image Fever and elevated blood neutrophils are common.

Image Histopathology typically shows spongiform subcorneal and/or intraepidermal pustules; a marked edema of the papillary dermis; and eventually vasculitis, eosinophils, and/or focal necrosis of keratinocytes.

Image Pustules resolve spontaneously in <15 days and generalized desquamation occurs approximately 2 weeks later.

Image Differential diagnosis includes pustular psoriasis, the hypersensitivity syndrome reaction with pustulation, subcorneal pustular dermatosis (Sneddon–Wilkinson disease), and pustular vasculitis.

Image Acneiform pustular eruptions (see Section 1) are associated with iodides, bromides, adrenocorticotropic hormone (ACTH), glucocorticoids, isoniazid, androgens, lithium, actinomycin D, and phenytoin. The EGFR tyrosine kinase inhibitors erlotinib, gefitinib, cetuximab, panitumumab produce pustules that are not acneiform and erupt in the face (Fig. 23-4) but can erupt also in atypical areas, such as on the arms and legs, and are most often monomorphous. Comedones are usually absent.

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Figure 23-2. Pustular drug eruption: acute generalized exanthematous pustulosis (AGEP) Multiple tiny nonfollicular pustules against the background of diffuse erythema that first appeared in the large folds and then covered the entire trunk and the face.

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Figure 23-3. Pustular drug eruption: AGEP Multiple sterile pustules surrounded by fiery-red erythema in a 58-year-old female who had fever and leukocytosis. In contrast to the disseminated pustules in Fig. 23-2, here the pustules show a tendency for grouping and confluence. Differential diagnosis of von Zumbusch pustular psoriasis (compare with Fig. 3-13).

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Figure 23-4. Pustular drug eruption: erlotinib This pustular eruption occurred in a patient who had received an anti-EGR monoclonal antibody for cancer of the colon localized to face. Differential diagnosis to acne and rosacea.

Drug-Induced Acute Urticaria, Angioedema, Edema,

and Anaphylaxis
 (see also Section 14Image

Image Drug-induced urticaria and angioedema occur due to a variety of mechanisms (see Table 22-1) and are characterized clinically by transient wheals and angioedema.

Image In some cases, cutaneous urticaria/angioedema is associated with systemic anaphylaxis, which is manifested by respiratory distress, vascular collapse, and/or shock.

Image Drugs causing urticaria/angioedema and anaphylaxis are listed in Table 23-5.

Image Urticaria/angioedema ACDRs are classified as immune-mediated; IgE-mediated (penicillin); complement- and immune complex-mediated (penicillin, immunoglobulins, whole blood); nonallergic urticarial ACDR; cyclooxygenase inhibition/block in prostaglandin synthesis by analgesics/NSAIDs; radio contrast media; ACE inhibitors: inhibition of kinin metabolism; calcium channel blockers; drugs releasing histamine.

Image Time from Initial Drug Exposure to Appearance of Urticaria

Image IgE-Mediated. Initial sensitization, usually 7–14 days. In previously sensitized individuals, usually within minutes or hours.

Image Immune Complex-Mediated. Initial sensitization, usually 7–10 days, but as long as 28 days; in previously sensitized individuals 12–36 h.

Image Analgesics/Anti-Inflammatory Drugs. 20–30 min (up to 4 h).

Image Prior Drug Exposure Radiographic Contrast Media. 25–35% probability of repeat reaction in individuals with history of prior reaction to contrast media.

Image Skin Symptoms. Pruritus, burning of palms, and soles with airway edema difficulties breathing.

Image Constitutional Symptoms. IgE-mediated: flushing, sudden fatigue, yawning, headache, weakness, dizziness; numbness of tongue, sneezing, bronchospasm, substernal pressure, palpitations; nausea, vomiting, crampy abdominal pain, diarrhea, may have arthralgia.

Image Skin Lesions. As described in Section 14Urticaria Large wheals (see Fig. 14-6). Angioedema: Extensive tissue swelling with involvement of deep dermal and subcutaneous tissues. Often pronounced on face (Fig. 23-5A) or mucous membranes (tongue, Fig. 23-5B).

Image General Findings IgE-Mediated Reactions. Hypotension. Bronchospasm, laryngeal edema.

TABLE 23-5 DRUGS CAUSING URTICARIA/ANGIOEDEMA/ANAPHYLAXIS

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Figure 23-5. Drug-induced angioedema: penicillin (A) Angioedema has led to closure of right eye. (B) Sublingual angioedema in another patient interfered with breathing, talking, and eating and caused great concern.

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Figure 23-6. Fixed drug eruption (A) Tetracycline. Two well-defined periorbital plaques with edema. This was the second such episode following ingestion of a tetracycline. No other lesions were present. (B) Tylenol. A large oval violaceous lesion with blistering in the center. Erosive mouth lesions were also present.

Drug-induced urticaria/angioedema usually resolves within hours to days to weeks after the causative drug is withdrawn.

Management. Identify and withdraw offending drugs. Antihistamines H1 blockers or H2 blockers or combination. Systemic Glucocorticoids Intravenous. Hydrocortisone or methylprednisolone for severe symptoms. Oral.Prednisone, 70 mg, tapering by 10 or 5 mg daily over 1–2 weeks, is usually adequate. In Acute Severe Urticaria/Anaphylaxis Epinephrine 0.3–0.5 mL of a 1:1000 dilution subcutaneously, repeated in 15–20 min. Maintain airway. Intravenous access. Radiographic Contrast Media. Avoid use of contrast media known to have caused prior reaction. If not possible, pretreat patient with antihistamine and prednisone (1 mg/kg) 30–60 min before contrast media exposure.

Fixed Drug Eruption ICD-9: 995.2 image ICD-10: T88.7 Image

Image A fixed drug eruption (FDE) is an adverse cutaneous reaction to an ingested drug, characterized by the formation of a solitary (but at times multiple) erythematous patch or plaque. The most commonly implicated agents are listed in Table 23-6

Image If the patient is rechallenged with the offending drug, the FDE occurs repeatedly at the identical skin site (i.e., fixed) within hours of ingestion.

Image Skin symptoms: Usually asymptomatic. May be pruritic, painful, or burning. Time to onset of lesion(s): Occur from 30 min to 8 h after ingestion of drug in previously sensitized individual. Duration of lesion(s): Lesions persist if drug is continued. Resolve days to few weeks after drug is discontinued.

Image Skin Lesions. A sharply demarcated macule, round or oval in shape, occurring within hours after ingestion of the offending drug. Initially erythema, then dusky red to violaceous (Fig. 23-6A). Most commonly, lesions are solitary and can spread to become quite large, but they may be multiple (Fig. 23-7) with random distribution. Lesions may evolve to become a bulla (Fig. 23-6B) and then an erosion. Eroded lesions, especially on genitals or oral mucosa, are quite painful. After healing, dark brown with violet hue postinflammatory hyperpigmentation. Genital skin (see Section 34) is frequently involved site, but any site may be involved; perioral, periorbital (Fig. 23-6A). Occur in conjunctivae, oropharynx.

Image Dermatopathology. Similar to findings in erythema multiforme and/or TEN.

Image Patch Test. Suspected drug can be placed as a patch test at a previously involved site; an inflammatory response occurs in only 30% of cases.

Image FDE resolves within a few weeks of withdrawing the drug. Recurs within hours after ingestion of a single dose of the drug.

Image Management. Withhold offending drug. Noneroded lesions: potent topical glucocorticoid ointment. Eroded lesions: antimicrobial ointment. For widespread, generalized, and highly painful mucosal lesions, oral prednisone 1 mg/kg body weight tapered over a course of 2 weeks.

TABLE 23-6 MOST COMMONLY IMPLICATED AGENTS IN FIXED DRUG ERUPTIONS

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Figure 23-7. Fixed drug eruption Doxycycline. Multiple lesions. Similar violaceous plaques were also on the anterior and posterior trunk.

Drug Hypersensitivity Syndrome

ICD-9: 995.2 image ICD.0: I88.7 image

Image Drug hypersensitivity syndrome is an idiosyncratic adverse drug reaction that begins acutely in the first 2 months after initiation of drug and is characterized by fever, malaise, and facial edema or an exfoliative dermatitis. Synonym: Drug rash with eosinophilia and systemic symptoms (DRESS).

Image Etiology. Most commonly: antiepileptic drugs (phenytoin, carbamazepine, phenobarbital; cross-sensitivity among the three drugs is common) and sulfonamides (antimicrobial agents, dapsone, sulfasalazine). Less commonly: allopurinol, gold salts, sorbinil, minocycline, zalcitabine, calcium-channel blockers, ranitidine, thalidomide, mexiletine.

Image Some patients have a genetically determined inability to detoxify the toxic arene oxide metabolic products of anticonvulsant agents. Slow N-acetylation of sulfonamide and increased susceptibility of leukocytes to toxic hydroxylamine metabolites are associated with higher risk of hypersensitivity syndrome.

Image Onset. 2–6 weeks after drug is initially used, and later than most other serious skin reactions.

Image Symptoms: Fever → rash → malaise.

Image Skin Lesions. Early: morbilliform eruption (Fig. 23-8) on face, upper trunk, upper extremities; cannot be distinguished from exanthematous drug eruption. May progress to generalized exfoliative dermatitis/erythroderma, especially if drug is not discontinued. Eruption becomes infiltrated with edematous follicular accentuation. Facial edema (especially periorbitally) is characteristic, may result in blister formation. Sterile pustules may occur. Eruption may become purpuric on legs. Scaling and/or desquamation may occur with healing.

Image Distribution. Symmetric. Almost always on trunk and extremities. Lesions may become confluent and generalized.

Image Mucous Membranes. Cheilitis, erosions, erythematous pharynx, enlarged tonsils.

Image General Examination. Elevated temperature (drug fever).

Image Lymph Nodes. Lymphadenopathy frequent ± tender; usually due to benign lymphoid hyperplasia.

Image Involvement of liver, heart, lungs, joints, muscles, thyroid, brain also occurs.

Image Eosinophilia (30% of cases). Leukocytosis. Mononucleosis-like atypical lymphocytes. Signs of hepatitis and nephritis. Histology Skin. Lymphocyte infiltrate, dense and diffuse or superficial and perivascular. ± Eosinophils or dermal edema. In some cases, bandlike infiltrate of atypical lymphocytes with epidermotropism, simulating cutaneous T cell lymphoma. Lymph Nodes. Benign lymphoid hyperplasia. Uncommonly atypical lymphoid hyperplasia, pseudolymphoma. Liver. Eosinophilic infiltrate or granulomas. Kidney. Interstitial nephritis.

Image Proposed Diagnostic Criteria. (1) Cutaneous drug eruption, (2) hematologic abnormalities (eosinophilia ≥ 1500/μL or atypical lymphocytes), and (3) systemic involvement [adenopathies ≥ 2 cm in diameter or hepatitis (SGOT ≥ 2 N) or interstitial nephritis or interstitial pneumonitis or carditis]. Diagnosis is confirmed if three criteria are present.

Image Course and prognosis: Rash and hepatitis may persist for weeks after drug is discontinued. In patients treated with systemic glucocorticoids, rash and hepatitis may recur as glucocorticoids are tapered. Lymphadenopathy usually resolves when drug is withdrawn; however, rare progression to lymphoma has been reported. Patients may die from systemic hypersensitivity such as with eosinophilic myocarditis (10%). Clinical findings recur if drug is given again.

Image Management: Identify and discontinue the offending drug. Systemic. Prednisone (0.5 mg/kg per day) usually results in rapid improvement of symptoms and laboratory parameters.

Image Prevention. The individual must be aware of his or her specific drug hypersensitivity and that other drugs of the same class can cross-react. These drugs must never be readministered. Patient should wear a medical alert bracelet.

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Figure 23-8. Drug hypersensitivity syndrome: phenytoin Symmetric, bright red, exanthematous eruption, confluent in some sites; the patient had associated lymphadenopathy and fever.

Drug-Induced Pigmentation

ICD-9: 995.2 image ICD-10: T88.7 image

Image Drug-induced alterations in pigmentation are relatively common.

Image They result from the deposition of a variety of endogenous and exogenous pigments in the skin.

Image Can be of significant cosmetic concern to the patient.

Image Drugs most commonly causing hyperpigmentation:

Image Antiarrhythmetic: amiodarone

Image Antimalarial: chloroquine, hydroxychloroquine, quinacrine, quinine

Image Antimicrobial: minocycline, clofazimine, zidovudine

Image Antiseizure: hydantoins

Image Cytostatic: bleomycin, cyclophosphamide, doxorubicin, daunorubicin, busulfan, 5-fluorouracil, dactinomycin

Image Metals: silver, gold, iron

Image Hormones: ACTH estrogen/progesterone

Image Psychiatric: chlorpromazine

Image Dietary: β-carotene

Clinical Manifestation

Amiodarone. More than 75% of patients after 40-g cumulative dose after >4 months of therapy. More common in skin phototypes I and II. Low-grade or minimal photosensitivity; phototoxic erythema limited to the light-exposed areas in a small proportion (8%) of patients. Dusky-red erythema and, later, blue-gray dermal melanosis (Fig. 23-9) in exposed areas (face and hands). Lipofuscin-type pigment deposited in macrophages and endothelial cells.

Antimalarials. Cloroquíne, hydroxyckloroquine. Occurs in 25% of individuals who take the drug for >4 months. Brownish, gray-brown, and/or blue-black discoloration due to melanin, hemosiderin. Over shins; face, nape of neck; hard palate (sharp line of demarcation at soft palate); under finger- and toenails (see Section 34); may also occur in cornea and retina; Quinacrine: yellow, yellow-green skin, and sclerae (resembling icterus); yellow-green fluorescence of nail bed with Wood lamp.

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Figure 23-9. Drug-induced pigmentation: amiodarone A striking mix of a slate gray and brown pigmentation in the face. The bluish color is due to the deposition of melanin and lipofuscin contained in macrophages and endothelial cells in the dermis. The brown color is due to melanin. The pigmentation is reversible, but it may take up to a year or more to complete resolution. In this patient, it took 16 months for the pigmentation to disappear.

Minocycline. Onset delayed, usually after total dose of >50 g, but may occur after a small dose. Not melanin but an iron-containing brown pigment, located in the dermal macrophages; stippled or diffuse. Blue-gray or slate-gray pigmentation (Fig. 23-10). Distributed on extensor legs, ankles, dorsa of feet, face, especially around eyes; sites of trauma or inflammation such as acne scars, contusions, abrasions; hard palate, teeth; nails. Clofazimine. Orange, reddish brown (range, pink to black) discoloration, ill-defined on light-exposed areas; conjunctivae; accompanied by red sweat, urine, feces. Subcutaneous fat is orange. Zidovudine. Brown macules on lips or oral mucosa; longitudinal brown bands in nails.

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Figure 23-10. Drug-induced pigmentation: minocycline Striking, blue-gray pigmentation on the lower legs. This 75-year-old woman had been treated with minocycline for >1 year because of nontuberculous mycobacterial infection.

Phenytoin. High dose over a long period of time (>1 year). Discoloration is spotty, resembling melasma, in light-exposed areas and is due to melanin.

Bleomycin. Tan to brown to black and due to increase in epidermal melanin at sites of minor inflammation, i.e., parallel linear streaks at sites of exoriations due to scratching (“flagellate” pigmentation), most commonly on the back, elbows, small joints, and nails. Cyclophosphamide. Brown. Diffuse or discrete macules on elbows; palms with Addisonian-like pigmentation (see Fig. 15-11) and macules.

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Figure 23-11. Pseudoporphyria: nonsteroidal anti-inflammatory agents In this 20-year-old male, blisters appeared on the dorsa of both hands that led to erosions, crusting, and were clinically indistinguishable from porphyria cutanea tarda. However, there was no urinary fluorescence, and porphyrin studies were negative. The patient had taken an NSAID for arthritis and had impaired kidney function.

Busulfan. Occurs in 5% of treated patients. Addisonian-like pigmentation. Face, axillae, chest, abdomen, and oral mucous membranes.

Gold (Chrysiasis). Source: Organic colloidal gold preparations used in therapy of rheumatoid arthritis. 5–25% of all treated patients. Dose-dependent. In high-dose therapy, appears in a short time; with lower dose, occurs after months. Blue-gray to purple discoloration of light-exposed areas; sclerae. Persists long after drug is discontinued.

ACTH. Addisonian pigmentation of skin and oral mucosa. First 13 amino acids of ACTH are identical to α-melanocyte-stimulating hormone (MSH) (see Fig. 15-11). Estrogens/Progesterone Caused by endogenous and exogenous estrogen combined with progesterone, i.e., during pregnancy or with oral contraceptive therapy. Sunlight causes marked darkening of pigmentation. Tan/brown. Melasma (see Fig. 13-10).

Chlorpromazine and Other Phenothiazines. Occurs after long-term (>6 months), high-dose (>500 mg/d) therapy. Phototoxic reaction. Slate-gray, blue-gray, or brownish in areas exposed to light, i.e., chin and cheeks.

Silver (Argyria or Argyrosis). Source: Silver nitrate nose drops; silver sulfadiazine applied as an ointment. Silver sulfide (silver nitrate converted into silver sulfide by light, as in photographic film). Blue-gray discoloration. Primarily areas exposed to light, i.e., face, dorsa of hands, nails, conjunctiva; also diffuse. Iron. Source: IM iron injections; multiple blood transfusions. Brown or blue-gray discoloration. Generalized; also, local deposits at site of injection.

Carotene. Ingestion of large quantities of β-carotene-containing vegetables; β-carotene tablets. Yellow-orange discoloration. Most apparent on palms and soles.

Pseudoporphyria ICD-9: 277.1 image ICD-10: E80.25 Image

Image Pseudoporphyria is a condition that clinically presents with cutaneous manifestations of porphyria cutanea tarda (PCT) (see Section 10) without the characteristic abnormal porphyrin excretion.

Image It is a bullous drug-induced photosensitivity reaction.

Image Drugs causing pseudoporphyria are naproxen, nabumetone, oxaprozin, diflunisal, celecoxib, tetracyclines, ketoprofen, mefenamic acid, tiaprofenic acid, nalidixic acid, amiodarone, and furosemide.

Image Develops on the dorsa of hands and feet with characteristic tense bullae that rupture and leave erosions (Fig. 23-11) and heal with scars and milia formation.

Image It is characterized by subepidermal blistering with little or no dermal inflammation and, in contrast to true PCT, little or no deposition of immunoreactants around upper dermal blood vessels and capillary walls.

Image A bullous dermatosis that is morphologically and histologically indistinguishable from pseudoporphyria also occurs in patients with chronic renal failure receiving maintenance hemodialysis (see Section 18).

ACDR-Related Necrosis ICD-9: 995.2 image ICD-10: T88.7 Image

Image Drugs can cause cutaneous necrosis when given orally or at sites of injection.

Image Warfarin-induced cutaneous necrosis is a rare reaction with onset between the third and fifth days of anticoagulation therapy with the warfarin derivatives and indandione compounds, manifested by cutaneous infarction.

Image Risk factors: Higher initial dosing, obesity, female sex; individuals with hereditary deficiency of protein C, protein S, or antithrombin III deficiency.

Image Lesions vary with severity of reaction: petechiae to ecchymoses to tender hemorrhagic infarcts to extensive necrosis: well demarcated, deep purple to black (Fig. 22-12). Deep tissue sloughing and ulceration if lesions are not debrided and grafted. Often single; may present as two lesions. Distribution: areas of abundant subcutaneous fat: breasts (Fig. 23-12), buttocks, abdomen, thighs, calves; acral areas are spared.

Image Coagulation studies: Usually within normal limits.

Image Differential diagnosis: Purpura fulminans (disseminated intravascular coagulation), hematoma/ecchymosis in overly anticoagulated patient, necrotizing soft tissue infection, vasculitis, rare necrosis after vasopressin treatment, brown recluse spider bite. If area of necrosis is large in an elderly, debilitated patient, it may be life threatening. If warfarin is inadvertently readministered, reaction recurs.

Image Heparin can cause cutaneous necrosis, usually at the site of subcutaneous injection (Fig. 23-13).

Image Interferon-α can cause necrosis and ulceration at injection sites, often in the lower abdominal panniculus or thighs (Fig. 23-14).

Image Ergotism can cause necrosis. Ergotamine-containing medications lead to acral gangrene; ergotamine-containing suppositories after prolonged use cause extremely painful anal and perianal black eschars that, after having been shed, leave deep painful ulcers (Fig. 23-15).

Image Embolia cutis medicamentosa: Deep necrosis developing at the site of intramuscular injection of oily drugs inadvertently injected into an artery (Fig. 23-16).

Image Necrosis also develops in obtunded or deeply sedated patients at pressure sites (Fig. 23-17).

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Figure 23-12. ACDR-related cutaneous necrosis: warfarin Bilateral areas of cutaneous infarction with purple-to-black coloration of the breast surrounded by an area of erythema occurred on the fifth day of warfarin therapy.

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Figure 23-13. ACDR-related cutaneous necrosis: heparin Two lesions of irregular dark-red erythema with central hemorrhagic necrosis on the abdomen occurring postoperatively in a female injected with heparin.

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Figure 23-14. ACDR-related cutaneous necrosis: interferon-α An ulcer on the thigh at the site of interferon injection.

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Figure 23-15. ACDR-related cutaneous necrosis: ergotamine This 60-year-old male had used ergot-containing suppositories for pain relief over many months. Painful black necrosis followed by ulceration developed on the anus and perianally and extended into the rectum.

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Figure 23-16. ACDR-related necrosis following intramuscular injection Embolia cutis medicamentosa. The drug (an oily preparation of testosterone) had been inadvertently administered intraarterially.

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Figure 23-17. ACDR-related necrosis with hemorrhagic blistering after an overdose of barbiturates This patient had attempted suicide.

ACDR-Related to Chemotherapy ICD-9: 995.2 image ICD-10: T88.7 Image

Image Chemotherapy may induce local and systemic skin toxicity with a wide range of cutaneous manifestations from benign to life threatening.

Image The ACDR can be related to overdose, pharmacologic side effects, cumulative toxicity, delayed toxicity, or drug–drug interactions.

Image Clinical manifestations range from alopecia (see Section 31) and nail changes (see Section 32) to mucositis and acral erythema, often with sensory abnormalities: palmoplantar dysesthesia (capecitabine, cytarabine, doxorubicin, fluorouracil).

Image Chemotherapeutic agents are also responsible for inflammation and ulceration at sites of extravasation of intravenous medications, such as doxorubicin or taxol, which can be followed by skin necrosis with ulceration (Fig. 23-18A).

Image Other reactions are radiation recall or enhancement (as with methotrexate), erosion or ulceration of psoriasis due to an overdose of methotrexate, inflammation and sloughing of actinic keratosis due to 5-fluorouracil or fludarabine, or erosions due to cisplatin plus 5-fluorouracil (Fig. 23-18B).

Image Table 23-7 lists newer chemotherapeutics including “biologicals” and their ACDR.

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Figure 23-18. ACDR-related cellulitis (A) Caused by taxol infusion. Extremely painful. (B) Erosions resulting from cisplatin and 5-fluorouracil (5FU). This patient had received chemotherapy with cisplatin and 5FU. Painful erosive lesions appeared on the scrotum and there was also erosive mucositis.

TABLE 23-7 NEWER CHEMOTHERAPEUTIC AGENTS AND THEIR ACDR

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1Skin reactions or changes regularly occurring after high dose or prolonged administration of certain drugs like glucocorticoids, retinoids, cyclosporine, and others are not discussed in this section but throughout the book whenever these drugs are discussed in greater detail.