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PATTERNS OF DRUG ERUPTION

Urticaria, angioedema, and anaphylaxis

Numerous drugs may cause acute urticaria or anaphylaxis (Table 18.2). In many cases, the eruption is IgE-mediated and lasts less than 24 h, usually occurring rapidly after the second exposure to the causative agent. It should, however, be stressed that anaphylaxis due to drugs is rare; a UK study of anaphylaxis identied less than one case per 10000 person years, 10% needing urgent treatment, and only 30% of these were due to drugs.

    The risk of severe urticarial or anaphylactic reactions is greatest with intravenous administration. Penicillins, NSAIDs, contrast media, and serum products or desensitizing agents are the most frequent cause of acute reactions. Vaccines may cause transient urticaria (Fig.18.11). Reactions to anesthetics are difcult to interpret sometimes (see later discussion of local anesthetic reactions). Intravenous immunoglobulin and monoclonal antibodies are an increasingly common cause of immediate urticarial or angioedema reactions of relevance in dermatologic usage, but the cause is generally readily apparent.

    Aspirin and angiotensin-converting enzyme (ACE) inhibitors are relatively common and underdiagnosed causes of intermittent urticaria or angioedema (Fig.18.12); aspirin is often taken without medical prescription, and related salicylates are also present in numerous foods. NSAIDs may also trigger or aggravate chronic urticaria. Such reactions have non-immunologic (‘pseudoallergic') mechanisms, for example due to overproduction of cysteinyl leukotrienes in NSAID-aggravated chronic urticaria. Angioedema due to ACE inhibitors occurs in an older population than does most idiopathic angioedema, although there may be a higher frequency of previous angioedema than in the average population, and onset may be delayed. As with NSAIDs, the mechanism is non-immunologic, in this case increased bradykinin activity due to reduced degradation. In these non-immunologic triggers of urticaria, the problem is likely to occur with other drugs of the same type.

Figure 18.11  Rashes due to vaccines and related agents are often of urticarial pattern. In this case, the presumed cause was an influenza vaccination some days previously

Figure 18.12  Angiotensin-converting enzyme inhibitors all cause angioedema in a small proportion of patients. This appears to be most common in older patients, often with mild preceding angioedema problems. This patient has swelling of the right side of the lower lip.

    Postoperative opiates are common non-immunologic causes of urticaria. Their ability to non-specically cause mast cell degranulation is a particular concern in mastocytosis, discussed earlier. A reaction that appears to relate specically to rapid infusion is the ‘red man' syndrome due to vancomycin, which may be associated with severe hypotension.

    Treatment of drug-induced urticaria or anaphylaxis is the same as for other triggers, such as foods, insect stings, or blood products, and is discussed in Chapter 9.

^aIncludes some drugs that are less commonly used but that commonly cause this pattern of eruption

Exanthem or maculopapular pattern

This is the most common pattern of eruption (Table 18.3) and usually occurs within 2 weeks of exposure to the causative drug. It is important to recognize that the rash may therefore start or worsen after the causative drug has been discontinued, especially after short courses of antibiotics, which are the most frequent cause of this reaction pattern (Fig. 18.13). Maculopapular eruptions occur particularly with ampicillin derivatives if used in the context of a viral infection (Figs 18.3 and 18.4). Cross-reactions (e.g. between penicillins and cephalosporins, or between the sulfa drugs including sulfonamides, sulfonylureas, and thiazides) are common with this pattern of eruption.

    The skin involvement is usually generalized but often initially apparent on the trunk. Pressure areas under clothing, and flexures, are sometimes spared. Lips may be affected, facial swelling may be a feature, diffuse erythema of palms and soles may occur, and a purpuric component on
the lower legs (Fig.18.4) is common, especially if there is associated dependent edema.

    Most such reactions settle within a week or so of withdrawal, but some may be complicated (e.g. the pityriasis rosea-like eruption due to captopril may become lichenoid in appearance and last for several weeks), and a few may progress to a more generalized form or may be associated with systemic hypersensitivity symptoms (see discussion in the section on anticonvulsants, the commonest cause of this progression). In uncomplicated cases, a topical steroid is generally much the most effective therapy; as symptoms in most eruptions of this type are self-limiting over days, a potent or moderately potent agent can be used safely.

    A specic pattern of maculopapular eruption that is rare but distinctive is the ‘baboon syndrome', in which a systemic contact dermatitis affects the buttocks and flexures (also termed an inverse pattern of exanthem, Fig.18.7). Mercury is the best documented trigger, although other metals, such as nickel, are also relevant; triggering by drugs may occur with antibiotics (especially ampicillin and derivatives), aminophylline, pseudoephedrine, heparin, and terbinane.

Figure 18.13  Antibiotics are the most common cause of maculopapular drug eruptions, usually with an interval of several days before the eruption develops. This rash was due to penicillin.

PRACTICE POINTS

Eczematous pattern

Other than predictable dry skin with eczematous change with oral retinoid drugs, eczematous drug eruptions are not very common. However, this pattern (Table 18.4) is a particular cause of diagnostic difculty, as it may be gradual in onset and may be difcult to distinguish from endogenous eczema; for example, infliximab may cause a pattern that resembles atopic dermatitis, and interferon-alpha a rash similar to discoid eczema. Some of the systemic agents that cause an eczematous drug eruption are also known to cause eczematous reactions due to external contact (allergic contact dermatitis); in some cases where there is a history of preceding contact hypersensitivity to the same agent, the eruption will affect previous sites of external contact reactions. Penicillins and sulfonamides are of particular importance, as both were used topically for many years; older patients and some senior nursing staff who have handled topical penicillins or sulfonamides are at particular risk. Patch tests are positive in such individuals.

Erythroderma

Drug reactions account for about 5–15% of cases of erythroderma (Figs 18.14 and 18.15, Table 18.5). When it occurs, it has all the implications of erythroderma due to a primary skin disease (Ch.7). It often overlaps with exfoliative patterns, as generalized peeling may occur in the resolution phase.

Table 18.4 CAUSES OF ECZEMATOUS DRUG ERUPTION

Category	Drug(s)
Antibiotics	Penicillins, cephalosporins, sulfonamides
Diuretics	Thiazides
Antihypertensives	Methyldopa, beta-blockers
Hypoglycemics	Sulfonylureas
Anticonvulsants	Phenytoin, carbamazepine, lamotrigine
Psychiatry	Chlorpromazine
Other	Quinine, quinidine, gold, bleomycin, isotretinoin, statins (ichthyosis), infliximab, interferon-alpha

 

Figure 18.14  Erythrodermic drug reactions may cause severe symptoms, and may be difficult to distinguish from other causes of erythroderma. An underestimated feature of erythroderma that may cause diagnostic concern is the eruption of multiple tiny acanthomas resembling seborrheic keratoses. This case was due to phenytoin.

 

Figure 18.15  Ectropion is common in erythroderma, in this case due to a thiazide diuretic. It resolves as the skin settles but may need treatment with lubricant or antibiotic eye ointments.

Table 18.5 CAUSES OF ERYTHRODERMIC DRUG REACTIONS

Category	Drug(s)
Anticonvulsants	Phenytoin, carbamazepine
Antiinflammatory	Gold, allopurinol, phenylbutazone and other pyrazolones, chloroquine, hydroxychloroquine, thalidomide
Psychiatry	Chlorpromazine, lithium
Antiinfective	Sulfonamides, nitrofurantoin, penicillins, antituberculous drugs, pristinamycin
Miscellaneous	Cimetidine, quinine, captopril

Erythema multiforme and toxic epidermal necrolysis

These patterns are considered together, because some patients may progress from erythema multiforme (EM) lesions to toxic epidermal necrolysis (TEN), although others are rmly at one end of the spectrum from the outset. The intermediate picture has given rise to terms such as acute disseminated epidermal necrolysis ( ADEN ), but such terms have currently been discarded. Blistering may also occur in xed drug eruptions, mimicking immunobullous disease, at pressure sites in drug-induced coma, in pseudoporphyria, and in eczematous drug reactions.

    Erythema multiforme is most commonly due to herpes simplex infection (discussed in Ch.11); drug-induced EM (Figs 18.16 and 18.17, Table 18.6) generally produces rather more variable and less well-dened ‘target lesions'. In cases due to antibiotics, it is often difcult to condently distinguish between EM due to the drug or due to the underlying infection. Mucous membrane involvement (Stevens–Johnson syndrome) may occur, but pure mucous membrane involvement is more likely to be due to mycoplasma infection than to drugs. The xed lesions of EM should be distinguished from the much rarer, slowly migrating, annular erythema that may occur due to H2 antagonists, penicillins, thiazides, chloroquine, and estrogens.

    In TEN (Figs 18.18 and 18.19, Table 18.7), there is much more widespread supercial blistering, with mucous membrane involvement and signicant malaise. The cause is usually a drug, but rare cases of adult staphylococcal scalded skin syndrome (SSSS) need to be excluded; in this condition, the blistering is subcorneal rather than a full-thickness epidermal cell death. Many patients have some areas of EM-like lesions (sometimes termed TEN with spots); these strongly suggest the diagnosis of TEN, as they are not a feature of SSSS. Other differential diagnoses include extensive drug-induced linear IgA disease (see later) and, if the condition occurs in the right hematologic context, graft-versus-host disease. The commonest causes are probably antibiotics, anticonvulsants, and allopurinol. Among the NSAIDs that may provoke TEN, there is some evidence that it may be commonest with oxicams; there are also several recent reports of TEN due to celecoxib.

Figure 18.16  Erythema multiforme on the palm of the hand, due to sulfasalazine. Note the typical grayish center of the target lesions, due to epidermal necrosis.

Figure 18.17  Erythema multiforme on the leg of a child, due to amoxicillin. Herpes simplex should always be excluded as a cause of this reaction pattern. Remember that the cause may be the underlying infection rather than the drug used to treat it.

Table 18.6 DRUG CAUSES OF ERYTHEMA MULTIFORME

Category	Drug(s)
Antimicrobials	Sulfonamides, penicillins, tetracyclines, thiabendazole, isoniazid, didanosine
Anticonvulsants	Phenytoin, carbamazepine, barbiturates
Analgesics and rheumatology	Aspirin, codeine, non-steroidal antiinflammatory
Diuretics	Furosemide, thiazides
Others	Phenothiazines, quinine, sulfonylureas, progestogens, omeprazole

    For prognostic purposes and to allow comparison between different interventional studies, it is helpful to record the following.   

    Toxic epidermal necrolysis is a rare condition but can be fatal due to the problems of toxemia, electrolyte control, and secondary infection of denuded areas of skin. Intensive care similar to that for burns is required. The earlier a suspect drug is withdrawn, then the better the overall outcome, but this is also influenced by the half-life of the causative agent (there is higher mortality if drug persistence is longer). Treatment has been the subject of much argument, but demonstration of abnormality of Fas and its ligand has generated interest in approaches that influence this. In two of three recent studies, high-dose intravenous immunoglobulin was benecial; there is also some support for use of ciclosporin.

Figure 18.18  Examples of toxic epidermal necrolysis. In (a), the eruption was due to allopurinol, one of the more common causes of this reaction; no cause could be identified in (b). Note the semiconfluent, rather erythema multiforme–like, annular areas (‘atypical target lesions') with central epidermal necrosis, most apparent in (a); these areas of necrosis should be counted as blisters when evaluating the extent of the eruption.

Figure 18.19  Atypical target lesions are shown in this patient with carbamazepine-induced erythema multiforme, in whom there were also areas of blistering.

Figure 18.20  This eruption appears to be typical lichen planus in a scar, but was due to captopril. It started as a pityriasis rosea–like pattern on the trunk, with evolution to a more lichen planus–like morphology over 2 weeks, and resolved after withdrawal of the trigger.

Erythema nodosum

Most cases of erythema nodosum (mainly discussed in Ch.22) are due to systemic diseases such as streptococcal infection, inflammatory bowel disease, or acute sarcoidosis, but it may also be caused by drugs such as penicillins, sulfonamides, dapsone, gold, codeine, NSAIDs, sulfonylureas, amiodarone, thiouracils, halogens, and oral contraceptives.

Lichenoid drug eruption

Lichenoid drug eruptions (Figs 18.20 and 18.21, Table 18.8) are often difcult to diagnose, for the following reasons.

    Histologic examination of a skin biopsy may show typical lichen planus, but usually there is a more mixed cellular inltrate with some prominence of eosinophils, and inltrate around sweat glands.

    External agents that cause a lichenoid reaction, and localized causes such as tattoo pigments, are discussed in Chapter 8.

Fixed drug eruption

Fixed drug eruption (FDE) is an uncommon and usually characteristic pattern of drug reaction (Figs 18.22–18.25, Table 18.9). The acute lesion is a well-demarcated erythematous plaque, sometimes with blistering (Fig.18.22), and usually a few centimeters in diameter. Brown staining may be prominent as it resolves, particularly after repeated episodes, as the eruption recurs at the same site on reexposure. Lesions are usually solitary but may be multiple initially, or may increase in number with several episodes (Fig.18.23). Distal limbs or the glans penis (Figs 18.24 and 18.25) are favored sites; the latter is particularly linked with FDE due to co-trimoxazole. FDE on the face or lip has been linked with naproxen as a likely cause. HLA associations of FDE were discussed earlier in this chapter.

    Rarer variants include non-pigmented FDE (typically a pattern seen with ephedrine or pseudoephedrine), ‘wandering' FDE, periorbital FDE, bilateral symmetric FDE, urticarial or eczematous FDE, linear or extensive sheets of FDE, and mucous membrane FDE.

Table 18.7 SOME CAUSES OF TOXIC EPIDERMAL NECROLYSIS

Category	Drugs
Antibiotics	Penicillins, sulfonamides, tetracyclines, chloramphenicol, macrolides, nitrofurantoin, ciprofloxacin, metronidazole, vancomycin
Antiretrovirals	Nevirapine, foscarnet
Anticonvulsants and psychiatry	Phenytoin, carbamazepine, lamotrigine, barbiturates, valproate, fluoxetine,
Rheumatologic and analgesics opiates, acetaminophen	Allopurinol, gold, non-steroidal antiinflammatory drugs and aspirin, celecoxib,
Antimalarials	Sulfadoxine or pyrimethamine, mefloquine, hydroxychloroquine
Antidiabetic	Sulfonylureas
Cytotoxics	Cyclophosphamide, methotrexate, cytosine arabinoside, docetaxel, gemcitabine, Adriamycin (doxorubicin), mithramycin, amifostine, interleukin-2
Radiology	Iohexidol, iopamidol
Cardiology	Quinidine, captopril
Others	Vaccines (various), thalidomide

Figure 18.21  Spectrum of lichenoid drug eruption due to quinine (a) on the dorsum of the hand, and (b) mimicking dermatomyositis on the eyelids. Lichenoid eruptions often have the purple color of idiopathic lichen planus, but are usually broader and less discrete lesions, without the typical Wickham's striae of the idiopathic pattern (Ch. 8). (Panel b courtesy of Dr. L. Barco.)

Figure 18.22  (a) A discrete plaque with central blistering due to fixed drug eruption (FDE). (b) In some cases, blistering may be the dominant feature of FDE, in this case due to ibuprofen. (Panel b courtesy of Dr. G. Dawn.)

Table 18.8 SYSTEMATCALLY ADMINSTERED DRUGS THAT MAY CAUSE A LICHENOID REACTION

Category	Drugs
Cardiology	Beta-blockers, methyldopa a , captopril and other angiotensin-converting converting enzyme inhibitors a,b , nifedipine, quinidine c , thiazides c , furosemide b,c , spironolactone, simvastatin, pravastatin, diazoxide c , hydralazine, acetylsalicylic acid, clopidogrel
Antimicrobials	Isoniazid, p -aminosalicylic acid, ethambutol c , isoniazid, tetracyclines c , interferon or ribavirin, zidovudine a , hepatitis B vaccine a , dapsone, ketoconazole a , terbinafine
Antimalarials	Mepacrine, chloroquine, hydroxychloroquine
Rheumatologic	Gold a , penicillamine a , non-steroidal antiinflammatory drugs a , allopurinol a , leflunomide and anti-tumor necrosis factor agents
Hematologic and cytotoxic	Hydroxycarbamide, bleomycin, 5-fluorouracil c , imatinib a , granulocyte-colony stimulating factor (localized to injection site)
Anticonvulsants	Carbamazepine c , phenytoin, valproate
Psychiatry	Phenothiazines, especially chlorpromazine c ; chloral hydrate; lithium carbonate
Gastroenterology	Ursodeoxycholic acid, histamine H2 antagonists, proton pump inhibitors
Heavy metals	Bismuth, mercury, arsenicals
Others	Sulfonylureas a , iodides, quinine c , cyanamide (= carbimide) a , cinnarizine b , infliximab, , thalidomide a , isotretinoin, sildenafi

Figure 18.23  Residual pigmentation is common in fixed drug eruption, especially after multiple episodes; in this patient, the cause was mefenamic acid taken for premenstrual symptoms.

Figure 18.24  Multiple lesions of fixed drug eruption are less common than a solitary lesion, and may cause greater diagnostic problems. The typical discoid morphology is apparent in (a); the acral pattern in (b), due to a sulfonamide, is more unusual. (Panel b courtesy of Dr. G. Dawn.)

Figure 18.25  The glans penis is a disproportionately common site for fixed drug eruption (FDE) (a). Residual pigmentation (b) is a common feature of FDE, especially after repeated episodes and especially on the penis. This case was probably due to sulfamethoxazole some years previously.

Table 18.9 SOME CAUSES OF FIXED ERUPTION

Category	Drugs
Antimicrobials	Sulfonamides, trimethoprim, tetracyclines, metronidazole, quinolones, , macrolides, rifampin, terbinafine, fluconazole, nystatin, saquinavir, aciclovir, interferon-alpha with ribavirin, influenza vaccine
Rheumatologic and analgesics	Non-steroidal antiinflammatory drugs including cyclooxygenase-2 agents and acetylsalicylic acid, acetaminophen, opiates, allopurinol
Anticonvulsants and psychiatry	Phenytoin, barbiturates, carbamazepine, lamotrigine, chloral hydrate, disulfiram, chlordiazepoxide, imipramine, oxazepam
Antiallergy preparations and steroids	Ephedrine, pseudoephedrine, atropine, diphenhydramine, cetirizine, hydroxyzine, loratadine, betahistine, triamcinolone
Gastroenterology	Cimetidine, omeprazole, sulfasalazine
Cytotoxics and immunosuppressives	Paclitaxel, hydroxycarbamide, interferon-alpha
Others	Phenolphthalein, quinine, quinidine, dapsone, radiocontrast media, lidocaine (lignocaine)

    Some cases of clinically typical FDE may be caused by food additives and colorings (e.g. tartrazine), drinks (e.g. tonic water), or herbal preparations; many are due to non-prescribed medications such as acetaminophen or agents for upper respiratory tract infections. Drugs that may be used to treat skin conditions may be the cause, notably antihistamines (especially cetirizine and chemically related antihistamines). Intraarticular steroid injections have been reported as a cause, as has injected botulinum toxin and influenza vaccine, although most cases are due to orally administered agents. The cause may not therefore be immediately apparent even if FDE is correctly suspected. In some instances, FDE may occur due to cross-reacting drugs, especially between NSAIDs and between tetracyclines. Several drugs have been reported to cross-react with sulfonamides, causing FDE, including indapamide and rofecoxib. Some cases are due to excipients rather than the active drug, and a type of ‘compound' allergy may occur in which two drugs have to be present together to cause the reaction.

    Patch tests to the suspect drug may be positive on the lesional skin (but usually not on unaffected skin) between episodes.

Cytotoxic drug reactions

Cytotoxic agents may cause a variety of skin and systemic reactions (Figs 18.26–18.30, Table 18.10). Some reactions are common to many of the drugs used and are not listed in the table. Most cause some degree of stomatitis and alopecia due to effects on rapidly dividing cells of the gastrointestinal tract and hair follicles, respectively. The alopecia (anagen effluvium) may be prevented by local cooling of the scalp during administration, but this may be uncomfortable and is usually reserved for drugs that exhibit this effect strongly, such as doxorubicin. Other non-specic effects include Beau lines, onycholysis, and multiple parallel transverse white bands in the nails, which are due to cycles of therapy (Fig.18.28). Local extravasation and injection site reactions are a particular problem with drugs used in leukemia treatment. Urticarial or angioedematous hypersensitivity reactions are a feature of some monoclonal biologicals, although they also occur with other drugs, such as docetaxel.

Figure 18.26  Pigmentation is a potential side effect of several chemotherapeutic drugs. (a) Pigmentation due to bleomycin often has a streaky pattern, termed a flagellate pattern of eruption. (b) A more unusual pattern of pigmentation, caused by systemic 5-fluorouracil. (Panel a courtesy of Michael O. Murphy, M.D., panel b courtesy of Dr. G. Dawn.)

Figure 18.27  Local reaction due to chemotherapy extravasation from a subcutaneous subclavian line. This type of reaction is less common than it used to be, due to better methods of long-term venous access and specific extravasation regimens for many cytotoxic agents.

Figure 18.28  Multiple white bands in the nails, representing periods of growth arrest, in this case due to cycles of treatment with 5-fluorouracil.

Figure 18.29  Neutrophilic eccrine hidradenitis (NEH). Acral erythema is a common effect of cytotoxic drugs and occasionally other drugs. In some cases, this is related to inflammatory changes affecting sweat ducts, known as NEH. This biopsy-proven case was due to an amoxicillin product.

    Pigmentation may affect the skin (a streaky pattern is typical of bleomycin especially, Fig. 18.26), nails, or oral mucosa. Radiation recall (inflammation in the skin over a radiotherapy eld), and occasionally sunburn reactivation, may also be followed by hyperpigmentation. Thiotepa may cause pigmentation where the skin is occluded, possibly due to secretion in sweat.

    Neutrophilic eccrine hidradenitis (NEH) is a relatively recently described reaction of papules and plaques that last for several days, affecting areas where sweating occurs, such as the hands. It is characterized by neutrophilic inflammation around the eccrine glands, with necrosis of the secretory epithelium. Chemotherapeutic agents, especially cytosine arabinoside, are most commonly implicated, but it can occur due to other drugs (Fig.18.29). Eccrine squamous syringometaplasia is associated with high-dose chemotherapy (such as pre-marrow transplant) and presents as erythematous plaques in the axillae and groins, often with localized areas of painful palmoplantar erythema.

Figure 18.30  (a) Palmoplantar syndrome due to continuous infusion of 5-fluorouracil for bowel cancer. This reaction occurs in about 30% of patients, and has a typical sharp demarcation, as shown here. Associated nail changes are seen in some cases, but symptoms are relatively mild in most. (b) By contrast, ulceration due to 5-fluorouracil is rare. (Panel b courtesy of Dr. G. Dawn.)

Table 18.10 SOME CUTANEOUS SIDE EFFECTS OT CYTOTOXIC DRUGS

Side effect	Drug(s)
Urticaria	Asparaginase, cisplatin, melphalan (intravenous)
Radiation recall	Dactinomycin, doxorubicin, bleomycin, 5-fluorouracil (may follow veins), hydroxyurea (nails)
Pigmentation	Bleomycin (may be flagellate pattern), cyclophosphamide, busulfan, doxorubicin, 5-fluorouracil
Photosensitivity	Dacarbazine, vinblastine, mitomycin, 5-fluorouracil
Acral erythema	5-fluorouracil, cytosine arabinoside, doxorubicin
Neutrophilic eccrine hidradenitis	Cytosine arabinoside, bleomycin, docetaxel
Dermatomyositis-like (acral)	Hydroxyurea (long term)
Dermatitis	Mitomycin (intravesical)
Toxic epidermal necrolysis	See Table 18.7
Acute generalized eruptive pustulosis	Cytosine arabinoside
Scleroderma-like reaction	Paclitaxel

Palmar erythema

Palmar erythema is seen as part of several exanthematous drug eruptions. Palmar crease purpura is a feature of drug-induced vasculitis in some patients and may occur in TEN.

    Isolated palmar erythema may occur due to several non-drug causes, such as in pregnancy, liver disease, and acutely in the purpuric gloves and stocking pattern of parvovirus B19 infection.

    Erythromelalgia is a palmoplantar disorder consisting of erythema and burning pain, which may be relieved in some patients by immersing the affected sites in cold water or walking on a cold floor. It may be idiopathic, but may also be due to drugs; nifedipine and nicardipine have been particularly implicated. It may respond to aspirin and drug withdrawal, but can be very resistant to treatment.

    Some cytotoxic agents commonly cause palmoplantar erythema. The most consistent is 5-fluorouracil given by continuous infusion for bowel carcinomas, about 30% of patients developing ‘palmoplantar syndrome' with this regimen (Fig.18.30). This reaction takes a few months to develop, may affect the face and nails as well as the palms and soles, and is relatively asymptomatic but can be reduced in degree by treatment with oral pyridoxine. A more acute palmoplantar erythema and desquamation may occur due to doxorubicin, daunorubicin, cytosine arabinoside, and others.

Anticonvulsant rashes and drug hypersensitivity syndrome

Anticonvulsant reactions (Figs 18.2, 18.31 and 18.32) are important as:

Figure 18.31  An eczematous pattern of drug eruption as part of the anticonvulsant hypersensitivity syndrome.

Figure 18.32  Chest radiograph of a patient with a severe carbamazepine reaction. She had extensive rash, lymphadenopathy, fever, hepatitis, and eosinophilia.

    The usual cutaneous reaction pattern to anticonvulsants is exanthematous or maculopapular, but may be urticarial, EM, TEN, FDE, and others. Facial edema is common in the more severe cases. The anticonvulsant syndrome, which occurs in up to 1% of patients on aromatic anticonvulsants, especially phenytoin, consists of fever, headache, sore throat, arthralgia, hepatitis, pneumonitis (Fig.18.32), nephritis, and lymphadenopathy. Laboratory features include leukocytosis with eosinophilia and atypical lymphocytes, presence of cold agglutinins, positive rheumatoid factor or antinuclear antibody, and increased polyclonal hypergammaglobulinemia. It may take several weeks to develop after the drug is started. In cases where carbamazepine is suspected to be the cause, patch testing is useful to conrm the diagnosis, but is retrospective. Less severe, usually morbilliform, skin reactions occur in a further 2% of patients but can be difcult to distinguish from the hypersensitivity syndrome, as rash and fever are usually the initial features of the more severe reactions. There is extensive cross-reaction between anticonvulsants due to common arene oxide metabolites.

    Lamotrigine, a more recently introduced drug, has also been increasingly implicated as a cause of severe skin rash with fever, multiorgan dysfunction, and sometimes disseminated intravascular coagulation; this severe reaction is more frequent in children and may be more likely if valproate is given concurrently (as it increases plasma lamotrigine levels). However, valproate in isolation is a rare cause of signicant rash and, as it has a different structure to the cross-reacting aromatic anticonvulsants, is the usual substitute in patients with severe drug reactions.

    Severe reactions of this type with systemic features are also termed the drug hypersensitivity syndrome (DHS) or drug reaction with eosinophilia and systemic symptoms (DRESS). Anticonvulsants account for most cases, but this pattern of hypersensitivity may also occur with sulfonamides, allopurinol, gold, dapsone, minocycline, nitrofurantoin, terbinane, abacavir, diltiazem, and many others less commonly.

    A pseudolymphoma picture, with lymphadenopathy and variable skin plaques or nodules resembling B-cell lymphoma or mycosis fungoides, may occur with phenytoin. This is occasionally fatal due to agranulocytosis or neutropenia, and the incidence of true lymphoma is increased.

PRACTICE POINTS

Severe drug eruptions are important! Don't forget the following points.

Drug-induced pigmentation

Pigmentation due to postinflammatory pigmentary incontinence may be a feature of any lichenoid reaction, and is usual in FDE. There are many other patterns of drug-induced pigmentation (Table18.11), involving a variety of mechanisms, the most frequent being:

    Some drugs seem to have an association with particular patterns or site combinations of pigmentation, which may strongly suggest a certain drug or group of agents as being responsible. Examples include the following.

Figure 18.33  Pigmentation due to long-term administration of minocycline for rosacea. In this case, the pattern is a diffuse blue-gray pigmentation affecting the face and nail beds.

Figure 18.34  Pigmentation due to long-term administration of minocycline. In this instance, the pigment is localized to old scars on the lower legs. The same process may occur in facial acne scars. See also examples in Figure 4.3.

Figure 18.35  Pigmentation due to long-term administration of minocycline, showing a more bruise-like pattern on the legs in a younger patient. See also examples in Figure 4.3.

Figure 18.36  Pigmentation due to mepacrine commonly affects the palate, sclera, or nails, as shown here. The color is usually brownish or blue-gray, but skin pigmentation may be rather yellowish.

Hair changes

Alopecia is frequently considered to be a side effect of drugs but in many instances is not well substantiated; drugs perhaps account for about 5% of cases of diffuse alopecia. Some potential causes are listed in Table 18.12. Mechanisms vary; in some cases, such as alopecia due to cytotoxic agents, the cause is well understood (see anagen effluvium, Ch.28). Poisons such as thallium may do the same. Some drugs may cause other patterns of hair change, such as the generalized curliness or marginal ‘acquired progressive kinking' that can occur in some patients taking systemic retinoids.

    Hypertrichosis due to drugs is mainly due to a small number of agents, including corticosteroids, androgenic steroids, ciclosporin, diazoxide, and minoxidil.

Anticoagulant drug eruptions and vitamin K

Any anticoagulant may predispose to bruising (Fig.18.37), which may be localized (e.g. to areas of heparin injection) or more widespread.

    Heparin may also cause local allergic reactions (Fig.18.38); some of these are due to preservatives such as chlorocresol in the vehicle, but others are true allergy to heparin, which causes local eczematous plaques at injection sites. Change to a heparin of different molecular weight usually resolves the problem. Local heparin-induced necrosis at injection sites is very rare, and is due to a heparin-dependent platelet-activating IgG, which may also cause thrombocytopenia and paradoxical thrombosis.

Figure 18.37  Bruising on the shoulder and upper trunk in a patient taking an excessive dose of warfarin (coumarin) anticoagulant.

Figure 18.38  Local allergy to subcutaneous heparin injections, in this case in a pregnant patient with high risk of thromboembolism, caused multiple erythematous or eczematous plaques at the injection sites on the anterior thighs.

Figure 18.39  Coumarin necrosis affecting the feet, in a patient with paraneoplastic venous thrombosis who received anticoagulation with standard doses.

    Coumarins such as warfarin may rarely cause a severe reaction known as coumarin necrosis, in which erythematous and bruised areas progress
to blistering and necrosis (Fig.18.39). This usually starts on about the third day of anticoagulation, and is fairly symmetric over fatty areas or sometimes at the extremities. It is associated with thrombophilic states, usually heterozygous protein C deciency. The condition occurs because warfarin depresses circulating levels of protein C (which has an anticoagulant function) before it decreases levels of other (procoagulant) vitamin K-dependent clotting factors; once the additional anticoagulant effect of heparin is withdrawn, there may therefore be a period of hypercoagulability. This effect is most prominent in individuals who have low levels of protein C, protein S, or antithrombin III.

    Vitamin K injections may cause prolonged local injection site macules and plaques, in a minority of cases progressing to localized scleroderma- or morphea-like changes (Texier syndrome).

Acneiform eruptions

Acneiform drug eruptions (Table 18.13) generally differ from ordinary acne by having relatively monomorphic papules and pustules, and no comedones. The commonest cause is corticosteroid therapy. However, some drugs such as lithium may aggravate ordinary acne, and some such as halides cause a more inflammatory pustular eruption in which there may also be plaques, nodules, and necrotic lesions; this may mimic pyoderma gangrenosum or Sweet disease (Ch.14).

Pustular eruptions, acute generalized exanthematous pustulosis

Pustular eruptions distinct from acneiform drug eruptions are increasingly recognized, for example eosinophilic pustular folliculitis related to carbamazepine, a pustular psoriasiform eruption due to terbinane, and provocation of true pustular psoriasis by bupropion.

    A particularly acute and severe pustular pattern of drug eruption has been described as acute generalized exanthematous pustulosis (AGEP; Figs 18.40 and 18.41, Table 18.14). In this disorder, the eruption consists of small, supercial, semiconfluent, non-follicular pustules that may resemble acute pustular psoriasis; occasionally, purpuric lesions resembling atypical target lesions may be seen. Most cases are drug-induced; a minority appear to follow viral infections (especially enteroviruses) or to occur in patients with autoimmune diseases (such as thyroid disease or ulcerative colitis). Overall, antibiotics account for about two-thirds of cases; the most common cause is penicillins (especially ampicillin and derivatives). The eruption is usually of rapid onset (typically within a day or two in antibiotic-triggered cases) with fever and malaise, and often involves flexures initially. Lymphocyte transformation tests, and sometimes patch tests to the suspect drug, may be positive. Primary skin infections, other neutrophilic dermatoses, pustular vasculitis (both Ch.14), and generalized pustular psoriasis (Ch. 7) should be excluded.

Photosensitivity

This is discussed in more detail in Chapter 17. Many drugs can cause this pattern of reaction (Fig.18.42).

Purpura, vasculitis, and serum sickness

Vasculitis and purpura are discussed in more detail in Chapter 14. Drugs that cause this reaction pattern include antibiotics (especially penicillins and sulfonamides), diuretics (especially thiazides and furosemide, Fig.18.43), NSAIDs, hydantoins, thiouracils, systemic imidazole antifungals such as itraconazole, intravenous immunoglobulins, and anti- tumor necrosis factor agents. Provocation of pigmented purpuric dermatosis is discussed later.

Figure 18.40  Acute generalized exanthematous pustulosis, showing more confluent pustules.

Figure 18.41  Acute generalized exanthematous pustulosis, showing grouped pustules.

 

Table 18.14 DRUG AND CHEMICAL CAUSES OF ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS(AGEP)

Category	Drugs
Antimicrobials	Penicillins (most cases), macrolides, vancomycin, sulfonamides (relatively uncommon), nystatin, fluconazole, terbinane, others
Analgesics	Non-steroidal antiinflammatory drugs, celecoxib, acetaminophen
Neurology and antidepressant	Carbamazepine, clobazam, amoxapine
Cardiac and respiratory	Calcium channel blockers, quinidine, theophyllines, furosemide
Others	Mercury, cytosine arabinoside, mesalazine, hydroxychloroquine

 

Figure 18.42  (a) Acute photosensitivity due to chlorpromazine. The diagnosis was confirmed by grossly abnormal phototest results. (b) Photoonycholysis is a less common phototoxic reaction; it was common with a non-steroidal antiinflammatory drug called benoxaprofen (withdrawn from sale for may years) and is currently seen most often due to tetracyclines, as in this case (see also Fig. 17.40).

Figure 18.43  Vasculitis of ‘palpable purpura' type (see Ch 14), due to furosemide. Some cases of vasculitis due to furosemide present months or even years after the drug has been started.

 

Figure 18.44  Serum sickness–like reaction, in this case due to amoxicillin. The acute onset in a child of inflammatory, red papulonodules that spread out into annular, urticarial plaques with dusky centers (‘purple-colored urticaria') is characteristic. Note the coalescence of some lesions.

    Serum sickness is a type III reaction with immune complex-mediated vascular damage. It presents as a vasculitis (palpable purpura, hemorrhagic blisters and ulcers, sometimes digital necrosis) with associated morbilliform and urticarial rash, arthralgia, fever, and malaise. Apart from true serum sickness due to serum products and vaccines, a serum sickness-like eruption may occur due to antibiotics (especially some cephalosporins, also ampicillin and derivatives, other b -lactam antibiotics, minocycline, and doxycycline), beta-blockers, bupropion, and streptokinase. Complement levels (C3 and C4) are reduced in true serum sickness but not in these drug-induced eruptions.

Serum sickness–like reaction

Serum sickness-like reaction is a recognizable reaction to a drug. It has occurred most frequently following cefaclor, but may occur with other cephalosporins, penicillins, or other drugs. Prior treatment with the drug is not necessary.

    The acute onset in a child of inflammatory, red papulonodules that spread out into annular, urticarial plaques with dusky centers is characteristic (it has been termed purple-colored urticaria; Fig.18.44). The onset is usually 7–10 days after the causative drug was begun. There are no true target lesions as with EM, and the lesions may expand but do not have the day-to-day fluctuation seen in urticaria. The child often has joint pains and fever. Lymphadenopathy and renal involvement usually do not occur, in contrast to true serum sickness. The causative medication should be stopped. Prednisone (e.g. 2mg/kg per day) can be dramatically helpful, if needed.

Bullous eruptions

Drug-induced blisters (Table 18.15) may occur in several ways.

Drug-induced porphyria and pseudoporphyria (Fig.18.45) are described in Chapter 17. Blistering at pressure areas due to barbiturate-induced coma is now uncommon.

    Drug eruptions that resemble immunobullous disorders are increasingly recognized (Table 18.16). Some of these occur only after months or years of treatment (e.g. penicillamine-induced pemphigus, Figs 18.46 and 18.47), but others may be relatively acute (e.g. vancomycin-induced linear IgA disease, Fig.18.48). Drug-induced pemphigus is generally of foliaceous or erythematosus type. Several cases of drug-induced linear IgA disease have been reported in which the morphology resembled TEN.

Injection site reactions

In addition to simple effects of tissue damage, such as bruising or transient tenderness, and reactions to vitamin K discussed earlier, a number of local reactions may occur related to injections, summarized in Table 18.17 (Fig.18.49). Generalized rash may also be triggered, such as urticaria due to the hepatitis B vaccine (urticarial rash is a feature of early hepatitis B infection in some cases); there are even occasional reports of TEN temporally related to vaccine administration. Occasionally, a viral exanthem that would normally be expected to be generalized will occur locally around a recent vaccination site.

Local anesthetic reactions

Local anesthetics may cause dose-related systemic toxicity due to either lidocaine (lignocaine; tinnitus, numb lips, metallic taste, nausea, diplopia, nystagmus, tremor, and convulsions) or adrenaline (epinephrine; local vasoconstriction, tachycardia, dysrhythmias, and tremor). These are most likely in children, the elderly, and those with existing heart, liver, or renal disease.

    Idiosyncratic reactions to local anesthetic agents are unpredictable and less easy to interpret. Allergy to topical esters such as benzocaine is not uncommon, but reactions to amides such as lidocaine are very rare. The vast majority of such events after skin or dental surgery are simple fainting episodes, which are unrelated to the anesthetic agent. Collapse that is not associated with injection site urticaria, facial angioedema, or respiratory symptoms, and especially if occurring after an uneventful procedure, is unlikely to be due to local anesthetic allergy. Urticaria conned to a surgical area or around the mouth may alternatively be due to other allergies, such as to latex gloves. Palpitations and sweating may be due to inadvertent injection of adrenaline (epinephrine) into a vessel.

    In a case where allergy to lidocaine appears unlikely but a degree of caution is required, prilocaine can be used (with octapressin as a vasoconstrictor if necessary). Lidocaine cross-reacts with dibucaine (cinchocaine) and mepivacaine, but reactions to prilocaine are extremely rare. In patients with a strong suspicion of lidocaine allergy, it is possible to perform testing, but this is time-consuming and requires adequate resuscitation facilities. The usual sequence is patch testing to 20% lidocaine, followed by prick testing, intradermal testing, and a gradually increasing sequence of challenge doses, but results are often not reliable; for example, patients may have a positive skin test to an agent that has been used clinically without any problem, or vice versa.

Figure 18.45  Pseudoporphyria due to (a) tetracycline and (b) naproxen. (Panel b courtesy of Dr. G. Dawn.)

Figure 18.46  Penicillamine-induced pemphigus, of pemphigus foliaceus type (see also Ch.16) with lesions predominantly on the face and upper trunk. This can be a prolonged and potentially serious eruption, which presents in a delayed manner.

Figure 18.47  Penicillamine-induced pemphigus affecting the hand. Intact blisters are relatively uncommon in pemphigus, and tend to rupture to produce erosions and crusting.

Figure 18.48  Vancomycin-induced linear IgA disease in a patient treated with intravenous vancomycin for an infected hip replacement wound. There was no recurrence of blistering during the following 2 years, when he was seen about an unrelated skin lesion.

PRACTICE POINTS

In considering local anesthetic reactions, the following points should be remembered.

Figure 18.49  Vaccination site granuloma due to aluminum in the vaccine; these lesions may persist for years as subcutaneous nodules.

Other patterns of eruption

A few other patterns of eruption warrant specic mention.

Figure 18.50  Hydroxycarbamide (hydroxyurea) may cause an acral lichenoid or dermatomyositis-like rash; acral or leg ulceration may also occur. Such problems may be missed, as they can occur after therapy has been used for several years. (Courtesy of Dr. G. Dawn.)

Provocation or exacerbation of preexisting skin disease

A number of drugs may occasionally provoke an apparently idiopathic dermatosis, or may aggravate an existing dermatosis; some of these are listed here (see also the earlier text on bullous drug eruptions).

Psoriasis

Drugs that may worsen psoriasis include the following.

Other drugs that may cause a psoriasiform pattern of drug eruption include captopril (Fig.18.52), methyldopa, imatinib, and interferons.

Figure 18.51  Extensive unstable and partially pustular psoriasis provoked by bupropion for smoking cessation in a patient with previously stable plaque psoriasis. (From Cox NH , et al. Br J Dermatol 2002; 146: 1061–3.)

Figure 18.52  An extensive exfoliative psoriasis pattern in a patient taking captopril.

Lupus erythematosus

Drug-induced lupus, with a list of causes, is discussed in Chapter 13. Thiazides may cause a lupus-like rash.

Porphyria cutanea tarda

A huge number of drugs may provoke the neurologic symptoms of acute intermittent porphyria or variegate porphyria, but drug induction or aggravation of porphyria cutanea tarda (PCT) is much less convincing. Alcohol is the most important trigger; of physician-prescribed medications, estrogens for prostatic neoplasia are an important trigger. Chloroquine and hydroxychloroquine can be used to treat PCT in low dose, but at higher doses may provoke symptoms. This is discussed in more detail in Chapter 17.

Dermatitis herpetiformis

Drug-induced aggravation of dermatitis herpetiformis (DH) is rare. Topical nicotinamide provokes lesions, but the potentially more severe problem is more generalized triggering of DH by iodides in radiocontrast media or in thyroid treatment (Lugol's iodine). The mechanism is probably by increasing activity of neutrophil enzymes such as myeloperoxidase.

Urticaria

The role of non-immunologic mechanisms of drug-triggering of urticaria and angioedema is discussed in the section on urticarial drug eruptions.

Rosacea

Any vasodilator may potentially aggravate the erythematous component of rosacea. Some, such as nifedipine, may cause development of telangiectasia in a photodistributed pattern. The drug trigger frequently noticed by patients is alcohol.

Sweet syndrome

Several drugs have been implicated as triggers of Sweet syndrome (acute febrile neutrophilic dermatosis; see also Ch.14). Most implicate either
all- trans -retinoic acid or granulocyte colony-stimulating factor (both agents used in hematology that induce an increase in neutrophil count) or minocycline. Other reported drug triggers include other tetracyclines, hydralazine, trimethoprim–sulfamethoxazole, nitrofurantoin, celecoxib, furosemide, lithium, isotretinoin, clonazepam, diazepam, oral contraceptives, cytosine arabinoside, and bacillus Calmette-Guérin (BCG) vaccination.

Others

Cross-reactions

Some groups of drugs exhibit important cross-reactions; a previous severe reaction with a chemically related drug is thus a reason to avoid unnecessary exposure. Some examples are given here.

Antibiotics

There are frequently cross-reactions between penicillins, and about 10% cross-reactivity between penicillins and cephalosporins. Using drug-specic T-cell clones from patients with ciprofloxacin-triggered exanthema, half demonstrated cross-reactivity with other quinolones. Cross-reactions between aminoglycosides are also very frequent, but of greater dermatologic importance during topical use.

    Cross-reactions between pristinamycin and other synergistins are particularly common, and have been proved by skin testing.

Figure 18.53  A pityriasis lichenoides–like eruption due to diclofenac.

Sulfa drugs

Sulfonamide antibiotics, sulfonylurea drugs for diabetes, and thiazide diuretics all share a similar structure. A similar spectrum of reactions is therefore seen for each of these groups; for example, they are all reasonably common causes of drug-induced photosensitivity reactions.

Anticonvulsants

The cross-reactions between aromatic anticonvulsants, due to arene metabolites that they have in common, are discussed earlier.

Local anesthetics

Cross-reactions between these agents are discussed earlier. Additionally, the para -amino agents may cross-react with topical agents (discussed later).

Cross-reactions of systemic drugs with topical allergens

Medications such as antibiotics may cause a rash when taken orally, and also cause contact sensitivity by external application or inadvertent contact (e.g. penicillins, especially in older patients who have been treated with topical penicillin or nurses who have handled such agents).

    Antabuse, for alcohol abstinence, is a thiuram chemical and may cause severe reactions in patients who are allergic to thiurams by contact sensitivity (used in rubber manufacture); flushing is part of the reaction (anticipated rather than idiosyncratic).

    Aminophylline (for asthma) is chemically related to ethylene diamine (a stabilizer in some creams) and may cross-react.

    The para -amino types of local anesthetic may cross-react with topical agents containing a similar structure, such as hair dyes.

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.