ACP medicine, 3rd Edition

Dermatology

Cutaneous Adverse Drug Reactions

Neil H. Shear MD1

Professor of Medicine, Pharmacology, Pediatrics, and Pharmacy

Sandra Knowles BSC PHM2

Pharmacist

Lori Shapiro MD3

Assistant Professor

1University Director of Dermatology, and Director of the Drug Safety Research Group, University of Toronto Faculty of Medicine, Director of Dermatology, Sunnybrook and Women's College Health Science Centre

2Drug Safety Clinic, Sunnybrook and Women's College Health Science Centre

3Department of Medicine, University of Toronto Faculty of Medicine, Physician, Drug Safety Clinic, Sunnybrook and Women's College Health Science Centre

Neil H. Shear, M.D., has received grants for clinical research or educational purposes and served as advisor for Roche, Galderma SA, Genesoft Co. Ltd., GlaxoSmithKline, Novartis AG, and Fujisawa Healthcare Inc.

Sandra Knowles, B.Sc. Phm., and Lori Shapiro, M.D., have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

October 2006

An adverse drug reaction (ADR) is defined as any noxious, unintended, and undesired effect of a drug that occurs at doses used in humans for prophylaxis, diagnosis, or therapy.1 An ADR may range from a cutaneous eruption to severe syndromes (e.g., drug hypersensitivity syndrome, Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN], and serum sickness-like reaction). Over the past 25 years, a dramatic shift has occurred in the understanding of drug-induced cutaneous eruptions. It is now believed that many severe cutaneous adverse drug reactions are caused by the formation of reactive oxidative metabolites and perhaps the formation of antibodies to drug-protein complexes and skin proteins, or both. The predisposition to drug-induced eruptions may be genetic, and family counseling and in vitro testing are being used in certain centers to manage patients and their families. This chapter reviews the pathophysiology and clinical manifestations that are important for correct diagnosis and treatment of cutaneous ADRs.

Epidemiology

Epidemiologic studies have shown that ADRs occur in 6.7% of all hospitalized patients,2 and 3% to 6% of all hospital admissions are the result of ADRs.3 In the Boston Collaborative Drug Surveillance Program,4 the prevalence of cutaneous ADRs in hospitalized patients was 2.2%. Antibiotics were responsible for 75% of detected reactions. In the Harvard Medical Practice Study, approximately 14% of ADRs in hospital patients were cutaneous or allergic in nature.5 The cost of drug-related morbidity and mortality has been estimated at $30 billion a year,6 and ADRs are thought to be between the fourth and sixth leading cause of death in the United States.2,6

Etiology

Cutaneous reactions to drugs often occur in complicated clinical scenarios that may include exposure to multiple agents. New drugs started within the preceding 6 weeks are potential causative agents, as are drugs that have been used intermittently, including over-the-counter preparations and herbal and naturopathic remedies.

Diagnosis

Clinical Manifestations

The morphology of cutaneous eruptions may be exanthematous, urticarial, blistering, or pustular. The extent of the reaction is variable. For example, once the morphology of the reaction has been documented, a specific diagnosis (e.g., fixed drug eruption or acute generalized exanthematous pustulosis) can be made. The reaction may also present as a syndrome (e.g., serum sickness-like reaction or hypersensitivity syndrome reaction). Fever is associated with the more serious cutaneous ADRs.

Differential Diagnosis

Differential diagnoses can include viral exanthems (e.g., infectious mononucleosis and parvovirus B19 infection), bacterial infections, Kawasaki syndrome, collagen vascular disease, and neoplasia.

Laboratory Tests

Penicillin skin testing with major and minor determinants is useful for confirmation of an IgE-mediated immediate hypersensitivity reaction to penicillin. Skin tests are performed 6 weeks to 6 months after complete healing of the cutaneous drug reaction.7 Oral rechallenges may be useful in the diagnosis of ADRs; however, they should not be used in patients who experienced a serious reaction, such as SJS or TEN. Patch testing may be helpful in the diagnosis of fixed drug eruptions or contact dermatitis.8

Exanthematous Eruptions

Simple Eruptions

Exanthematous eruptions, also known as morbilliform, maculopapular, or scarlatiniform eruptions, are the most common cutaneous ADRs.4Simple exanthems are erythematous changes in the skin without blistering or pustulation.

Many drugs can cause exanthematous eruptions, including the penicillins, sulfonamides, barbiturates, antiepileptic medications, nonnucleoside reverse transcriptase inhibitors (e.g., nevirapine), and antimalarials.4 Exanthematous eruptions occur in 3% to 7% of patients receiving such aminopenicillins as ampicillin and amoxicillin. However, these eruptions may occur in 60% to 100% of patients taking ampicillin or amoxicillin who are receiving concurrent allopurinol therapy or who have concomitant lymphocytic leukemia, infectious mononucleosis, cytomegalovirus infection, or hyperuricemia.9

Studies suggest that some exanthematous eruptions represent cell-mediated hypersensitivity.10 The etiology of the ampicillin rash concurrent with a viral infection is unknown, but the rash does not appear to be IgE mediated, and patients can tolerate all β-lactam antibiotics, including ampicillin, once the infectious process has resolved. Similar reactions are seen in 50% of HIV-infected patients exposed to sulfonamide antibiotics.11 Drug-specific T cells play a major role in exanthematous, bullous, and pustular drug reactions.12

Simple exanthems are symmetrical and often become generalized. Pruritus is the most frequently associated symptom. Fever is not associated with simple exanthematous eruptions. These eruptions usually occur within 1 week after the start of therapy and generally resolve within 7 to 14 days.13 A change in color of the exanthem from bright red to brownish red signifies resolution. Resolution may be followed by scaling or desquamation. Some patients with ampicillin- or amoxicillin-induced exanthematous eruptions may have a positive result on a patch test or on a delayed intradermal test.9 In general, however, skin testing is not considered helpful in the diagnosis of an exanthematous eruption.

The differential diagnosis of drug-induced exanthematous eruption includes viral exanthem (patients should be tested for mononucleosis), collagen vascular disease, bacterial infection, and rickettsial infection. Hypersensitivity syndrome should be considered in the differential diagnosis.

Table 1 Clinical Features of Hypersensitivity Syndrome Reaction and Serum Sickness-like Reaction

 

Rash

Fever

Internal Organ Involvement

Arthralgia

Lymphadenopathy

Hypersensitivity syndrome reaction

Exanthem

Present

Present

Absent

Present

Exfoliative dermatitis

Pustular eruptions

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Serum sickness-like reaction

Urticaria

Present

Absent

Present

Present

Exanthem

The treatment of simple exanthematous eruptions is generally supportive. For example, oral antihistamines used in conjunction with soothing baths may help relieve pruritus. Topical corticosteroids are indicated when antihistamines do not provide relief. Systemic corticosteroids are used only in severe cases. Discontinuance of the offending agent is recommended in most cases.

Complex Eruptions

Hypersensitivity Syndrome Reaction

Hypersensitivity syndrome reaction is a complex drug reaction that affects various organ systems. A triad of fever, skin eruption, and internal organ involvement signals this potentially life-threatening syndrome. It occurs in approximately one in 3,000 exposures to such agents as aromatic anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine), lamotrigine, sulfonamide antibiotics, dapsone, nitrofurantoin, nevirapine, minocycline, and allopurinol.

It has been suggested that the metabolism of aromatic anticonvulsants by cytochrome P-450 plays a pivotal role in the development of the hypersensitivity syndrome reaction with these drugs.14 In most people, the chemically reactive metabolites that are produced are detoxified by epoxide hydroxylases. If detoxification is defective, however, one of the metabolites may act as a hapten and initiate an immune response, stimulate apoptosis, or cause cell necrosis directly. There also appears to be an association between human herpesvirus type 6 (HHV-6) infection (either initial infection or reactivation) and severe hypersensitivity syndrome. Viral infections may act as, or generate the production of, danger signals that lead to damaging immune responses to drugs, rather than to immune tolerance.15,16

In one study, 75% of patients with hypersensitivity syndrome reactions to one aromatic anticonvulsant showed in vitro cross-reactivity to the other two aromatic anticonvulsants.14 In addition, in vitro testing has shown that there is a familial occurrence of hypersensitivity to anticonvulsants.14 Although lamotrigine is not an aromatic anticonvulsant, it too can cause a hypersensitivity syndrome reaction.17 There is no evidence that lamotrigine cross-reacts with the aromatic anticonvulsants. Lamotrigine and other anticonvulsants are also associated with more severe reactions (e.g., SJS and TEN) [see Complex Eruptions, below].

Sulfonamide antibiotics can cause hypersensitivity syndrome reactions in susceptible persons. The primary metabolic pathway for sulfonamides involves acetylation of the drug to a nontoxic metabolite and renal excretion. An alternative metabolic pathway, quantitatively more important in patients who are slow acetylators, engages the cytochrome P-450 mixed-function oxidase system. These enzymes transform the parent compound to reactive metabolites—namely, hydroxylamines and nitroso compounds, which produce cytotoxicity independently of preformed drug-specific antibody. In most people, detoxification of the metabolite occurs. However, hypersensitivity syndrome reactions may occur in patients who are unable to detoxify this metabolite (e.g., those who are glutathione deficient).18 Although the detoxification defect is present in 2% of the population, only one in 10,000 persons will manifest a hypersensitivity syndrome reaction in response to sulfonamide antibiotics. Siblings and other first-degree relatives of patients with the detoxification defect are at increased risk (perhaps one in four) for having a similar defect.

Other aromatic amines, such as procainamide, dapsone, and acebutolol, are also metabolized to chemically reactive compounds. We recommend that patients who develop symptoms compatible with a sulfonamide hypersensitivity syndrome reaction avoid these aromatic amines, because the potential exists for cross-reactivity. However, cross-reactivity should not occur between sulfonamides and drugs that are not aromatic amines (e.g., sulfonylureas, thiazide diuretics, furosemide, and acetazolamide).19

Allopurinol is associated with the development of serious drug reactions, including hypersensitivity syndrome reaction. In a review of 13 patients with allopurinol adverse reactions, fever and rash were the most common presenting symptoms. Other associated abnormalities included leukocytosis (62%), eosinophilia (54%), renal impairment (54%), and liver dysfunction (69%).20 Reactivation of HHV-6 infection has been reported in a patient who developed an allopurinol-induced hypersensitivity syndrome reaction with hepatitis, as documented by polymerase chain reaction analysis showing HHV-6 DNA in his blood; HHV-6 DNA was also detected in the cerebrospinal fluid.21

Allopurinol-induced adverse reactions, including hypersensitivity syndrome reaction, SJS, and TEN, have been strongly associated with a genetic predisposition in Han Chinese; the HLA-B*5801 allele is an important genetic risk factor.22 Susceptibility to nevirapine hypersensitivity may be enhanced by the presence of the HLA-DRB1*0101 allele but inhibited by low CD4+ T cell counts.23 Abacavir is also associated with a potentially life-threatening adverse reaction in approximately 8% of patients given this drug. Studies have shown a strong predictive association between abacavir hypersensitivity syndrome reaction and HLA-B*5701.24

Hypersensitivity syndrome reaction occurs most frequently on first exposure to the drug, with initial symptoms starting 1 to 6 weeks after exposure [see Table 1]. Fever and malaise, which can be accompanied by pharyngitis and cervical lymphadenopathy, are the presenting symptoms in most patients. This is often followed by edema and swelling of the face, especially upon rising in the morning. Atypical lymphocytosis, with subsequent eosinophilia, may occur during the initial phases of the reaction in some patients. A cutaneous eruption, which occurs in approximately 85% of patients, can range from an exanthematous eruption [see Figure 1] to the more serious SJS or TEN. The liver is often involved, resulting in hepatitis, although other internal organs may be affected, such as the kidney (e.g., interstitial nephritis and vasculitis), the central nervous system (e.g., encephalitis and aseptic meningitis), and the lungs (e.g., interstitial pneumonitis, respiratory distress syndrome, and vasculitis). A subgroup of patients may become hypothyroid as part of an autoimmune thyroiditis within 2 months after the initiation of symptoms.25 This condition is characterized by a low thyroxine level, an elevated level of thyroid-stimulating hormone, and the presence of thyroid autoantibodies, including antimicrosomal antibodies.

After the occurrence of a hypersensitivity syndrome reaction has been recognized from the symptom complex of fever, rash, and lymphadenopathy, some laboratory tests can be used to evaluate internal organ involvement, which may be asymptomatic. A complete blood count, urinalysis, and measurements of liver transaminase and serum creatinine levels should be performed. In addition, the clinician should be guided by symptoms that may suggest specific internal organ involvement (e.g., respiratory symptoms). Thyroid function should be evaluated on presentation of hypersensitivity syndrome reaction and then 2 to 3 months after presentation. A skin biopsy may help confirm the diagnosis when the patient has a blistering or a pustular eruption. Unfortunately, diagnostic or confirmatory tests are not readily available. An in vitro test employing a mouse hepatic microsomal system is used for research purposes to characterize patients who develop hypersensitivity syndrome reaction.14,26 Because of the severity of the reaction, oral rechallenges are not recommended. In fact, in patients with a history of hypersensitivity syndrome reaction, reexposure to the offending agent may cause the development of symptoms within 1 day.

 

Figure 1. Hypersensitivity Syndrome

This 35-year-old woman developed hypersensitivity syndrome reaction, characterized by fever, rash, and hepatitis, 14 days after starting trimethoprim-sulfamethoxazole therapy. The rash is an extensive, symmetrical, red edematous eruption.

Although the role of corticosteroids is controversial, most clinicians begin a regimen of prednisone at a dosage of 1 to 2 mg/kg/day when symptoms are severe. There are reports of successful treatment with cyclosporine27 or intravenous immunoglobulin (IVIg).28 Antihistamines, topical corticosteroids, or both can be used to alleviate symptoms. Because the risk of hypersensitivity syndrome reaction in first-degree relatives of patients who have had reactions is substantially higher than in the general population, family members should receive counseling about their risk of hypersensitivity syndrome reaction.

Urticarial Eruptions

Simple Eruptions

Urticaria and Angioedema

Urticaria is characterized by pruritic red wheals of varying sizes that can occur with any medication. When deep dermal and subcutaneous tissues are also swollen, the reaction is known as angioedema29 [see 6:XIII Urticaria, Angioedema, and Anaphylaxis]. Urticaria and angioedema usually result from a type I immediate hypersensitivity reaction. This mechanism is typified by immediate reactions to penicillin and other antibiotics. Binding of the drug or its metabolite to IgE bound to the surfaces of cutaneous mast cells leads to activation, degranulation, and release of vasoactive mediators such as histamine, leukotrienes, and prostaglandins.30

Urticarial reactions may also result from nonimmunologic activation of inflammatory mediators. Drugs such as acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs),31 radiocontrast media, and narcotic analgesics may directly cause the release of histamine from mast cells, independently of IgE. Angiotensin-converting enzyme (ACE) 2inhibitors are frequent causes of angioedema.32 The mechanism of this reaction is unclear but may relate to the accumulation of bradykinin or activation of the complement system.

Although medications tend to cause urticaria, angioedema, or both, other causal agents are food [see 6:XVI Food Allergies], physical factors (e.g., dermatographism and cholinergic urticaria) [see 6:XIII Urticaria, Angioedema, and Anaphylaxis], and idiopathic factors. Certain foods containing proteins that can cross-react with latex proteins, such as bananas, kiwifruit, avocados, and chestnuts, can cause oral itching and swelling, hives, or wheezing after ingestion. The risk of latex allergy is especially high in children with spina bifida and health care workers.33,34 Latex allergy can present as contact urticaria at sites of latex exposure; such reactions include lip swelling in a person who has blown up a balloon or in an infant who has sucked on a pacifier. Contact with aerosolized powder from latex gloves to which the latex protein has adhered may cause mucosal symptoms, such as itchy, swollen eyes; runny nose; sneezing; or wheezing. Anaphylaxis may also occur.

Signs and symptoms of IgE-mediated allergic reactions are typically pruritus, urticaria, cutaneous flushing, angioedema, nausea, vomiting, diarrhea, abdominal pain, nasal congestion, rhinorrhea, laryngeal edema, and bronchospasm or hypotension or both. Fever is not associated with urticaria or angioedema reactions. In general, individual lesions of urticaria last for less than 24 hours, although new lesions can continually develop. Adverse reactions to ACE inhibitors usually begin within hours of starting the drug but can occur as late as 1 week to several months into therapy.35 With treatment, the resulting angioedema usually resolves within 48 hours.

Skin testing may be helpful in cases of IgE-mediated urticaria. For example, penicillin skin testing with the major and minor determinants identifies approximately 99% of patients who have had an IgE-mediated reaction to penicillin. A latex skin test is a sensitive indicator of IgE sensitization. Positive immediate skin-test reactions identify patients at risk for IgE-mediated reactions from large-molecular-weight agents, such as insulin, neutral protamine Hagedorn (NPH) insulin,36 and egg-containing vaccines.

Withdrawal of the causative agent is recommended. When angioedema or anaphylaxis occurs, immediate therapy with epinephrine and systemic steroids may be needed. Symptomatic relief can generally be achieved with antihistamines (H1 receptor blockers). The safety of angiotensin II receptor antagonists in patients with a history of angioedema with ACE inhibitors is not yet known.37

Differential diagnosis

Allergic urticaria must be differentiated from urticaria caused by physical factors. Cold urticaria, for example, is precipitated by exposure to cold, occurring within minutes after immersion of hands or body in cold water or after exposure to cold air. In severe cases, patients may experience systemic symptoms, including wheezing and syncope. A rare familial form of cold urticaria that is autosomal dominant has been linked to chromosome 1q44.38

Cold urticaria can be differentiated from other forms of urticaria by eliciting an urticarial reaction with an ice cube applied to the skin for 5 to 10 minutes. Other physical urticarias also have distinguishing causes or features. Solar urticaria occurs within minutes of exposure to sunlight and can be produced by exposing limited areas of skin to sunlight or to appropriate wavelengths of ultraviolet light in a phototherapy response to physical pressure. Cholinergic urticaria, which is characterized by small urticarial papules, can be induced by exposure to heat or by exercise.

Histologically, all the urticarias are characterized by an increase in mast cells in the dermis. Edema, vascular changes, and mononuclear infiltrates are more striking in the dermis of patients with cold urticaria. Mononuclear infiltrates are also more prominent in the deep dermis of patients with delayed pressure urticaria.39

As with drug-induced urticaria, first-line therapy of most urticarias consists of oral antihistamines and avoidance of precipitating factors. Psoralen plus ultraviolet A (PUVA) has been used successfully to treat patients with solar urticaria. Montelukast has been used successfully to treat delayed pressure urticaria,40 and cyclosporine is promising for cases of severe refractory chronic urticaria.41

Complex Eruptions

Serum Sickness-like Reactions

Serum sickness-like reactions are defined by fever, rash (usually urticarial), and arthralgias occurring 1 to 3 weeks after drug initiation. Other symptoms, such as lymphadenopathy and eosinophilia, may also be present. In contrast to true serum sickness, serum sickness-like reactions are without immune complexes, hypocomplementemia, vasculitis, and renal lesions [see Table 1].

Epidemiologic studies in children suggest that the risk of serum sickness-like reactions is greater with cefaclor than with other antibiotics, including other cephalosporins.42,43 The overall incidence of cefaclor serum sickness-like reactions has been estimated to be 0.024% to 0.2% per course of cefaclor.

Although the pathogenesis is unknown, it has been postulated that in genetically susceptible hosts, metabolism of cefaclor produces a reactive metabolite that may bind to tissue proteins and elicit an inflammatory response that manifests as a serum sickness-like reaction.43

Other drugs that have been implicated in serum sickness-like reactions are cefprozil,44 bupropion,45 minocycline,46 rituximab,47 and infliximab.48 The incidence of serum sickness-like reactions caused by these drugs is unknown.

Discontinuance of the culprit drug and symptomatic treatment with antihistamines and topical corticosteroids are recommended for patients with serum sickness-like reactions. A short course of oral corticosteroids may be required for patients with more severe symptoms. The drug that caused the serum sickness-like reaction should be avoided. For cefaclor and cefprozil, the risk of cross-reaction with β-lactam antibiotics is small, and the administration of another cephalosporin is usually well tolerated.49 However, some clinicians recommend that patients who experience serum sickness-like reactions from cefaclor avoid all β-lactam drugs.50

Blistering Eruptions

Simple Eruptions

Fixed Drug Eruptions

Fixed drug eruptions usually appear as solitary pruritic, erythematous, bright-red or dusky-red macules that may evolve into an edematous plaque [see Figure 2]. In some patients, multiple lesions may be present. Blistering and erosion may occur on mucosal surfaces. Fixed drug eruptions recur in the same skin area after readministration of the causative medication.

 

Figure 2. Fixed Drug Eruption

This 28-year-old man taking tetracycline for acne vulgaris developed a fixed drug eruption.

Many drugs have been implicated in fixed drug eruptions, including phenolphthalein, naproxen, ibuprofen, sulfonamides, tetracyclines, and barbiturates.51 The pathogenesis of fixed drug eruptions has not been fully elucidated. A haplotype linkage in the setting of trimethoprim-sulfamethoxazole-induced fixed drug eruptions has been documented.52

Fixed drug eruptions are most common on the genitalia and in the perianal area, although they can occur anywhere on the skin surface. The onset of a fixed drug eruption can be sudden, developing within 30 minutes to 8 to 16 hours after ingestion of the medication. In patients who continue to take the offending drug, the number of eruption sites may gradually increase.52

After the initial acute phase, which lasts days to weeks, residual hyperpigmentation develops. Some patients may complain of burning or stinging on the affected skin sites. Systemic manifestations, which are present in approximately 25% of cases, can include fever, malaise, and abdominal symptoms.52

No conclusive diagnostic tests are available, but a challenge or provocation test with the suspected drug may be useful in confirming the diagnosis. Patch testing at the site of a previous lesion yields a positive response in up to 43% of patients. Prick and intradermal skin tests are reported to yield positive reactions in 24% and 67% of patients, respectively, but results vary with different drugs and reaction patterns. Patients with maculopapular rashes are more likely to have positive patch tests than patients with urticarial rashes.53

Treatment includes discontinuance of the causative agent and symptomatic therapy (e.g., topical corticosteroids).

Pseudoporphyria

Pseudoporphyria is a cutaneous phototoxic disorder that can resemble either porphyria cutanea tarda (PCT) or erythropoietic protoporphyria (EPP). Tetracycline, furosemide, and naproxen have been implicated in PCT- and EPP-pseudoporphyria.54 The eruption may begin within 1 day after initiation of therapy or may be delayed for as long as 1 year. PCT-pseudoporphyria is characterized by skin fragility, blister formation, and scarring in areas exposed to sunlight; it occurs with normal porphyrin metabolism. The second clinical pattern mimics EPP and presents as cutaneous burning, erythema, vesiculation, angular scars, and waxy thickening of the skin.

Because of the risk of permanent facial scarring, the implicated drug should be discontinued when skin fragility, blistering, or scarring occurs. In addition, broad-spectrum sunscreen and protective clothing should be recommended to the patient.

Complex Eruptions

Drug-Induced Linear IgA Disease

Linear IgA disease is an autoimmune bullous dermatosis that is identified on the basis of the linear deposition of IgA at the basement membrane zone.55 This disease can be induced by such drugs as vancomycin, lithium, diclofenac, and amiodarone. The drug-induced disease probably represents an immunologic response to the offending drug.

Drug-induced linear IgA disease is heterogeneous in clinical presentation. Cases have shown morphologies resembling erythema multiforme, bullous pemphigoid, and dermatitis herpetiformis. Drug-induced disease cannot be distinguished from the idiopathic variety either clinically, histologically, or immunologically; however, the clinical courses of these presentations differ. In drug-induced disease, spontaneous remission occurs once the offending agent is withdrawn; in idiopathic linear IgA disease, immune deposits disappear from the skin once the lesions resolve. Steroids and dapsone do not influence the healing process in drug-induced disease, whereas these agents have proved effective in the treatment of idiopathic linear IgA disease.56

Drug-Induced Pemphigus

Pemphigus may be drug induced or drug triggered (i.e., the latent disease is unmasked by the drug exposure).

Drugs that cause pemphigus are penicillin, rifampin, phenylbutazone, propranolol, progesterone, piroxicam, interferon beta, interleukin-2, and levodopa.53 An active amide group found in masked thiol drugs such as penicillin and cephalosporins and in nonthiol drugs such as enalapril may contribute to the pathogenesis of pemphigus.57,58 Pemphigus foliaceus [see Figure 3] caused by penicillamine and other thiol drugs tends to resolve spontaneously in 35% to 50% of cases.57 The average interval to onset is 1 year. Antinuclear antibodies are detected in 25% of affected patients.

 

Figure 3. Pemphigus Foliaceus

Pemphigus foliaceus developed in this 64-year-old man taking enalapril.

Nonthiol drug-induced pemphigus manifests clinical, histologic, immunologic, and evolutionary aspects similar to those of idiopathic pemphigus vulgaris [see Figure 4]. Drug-induced pemphigus is associated with mucosal involvement. Spontaneous recovery after drug withdrawal occurs in 15% of affected patients.

 

Figure 4. Pemphigus Vulgaris

Pemphigus vulgaris developed in this 59-year-old woman who took penicillamine as treatment for rheumatoid arthritis.

Treatment of drug-induced pemphigus begins with drug withdrawal. Systemic corticosteroids are often required until all symptoms of active disease disappear. Vigilant follow-up is required after remission for an early relapse to be detected. The patient's serum should be monitored regularly for autoantibodies.57

Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis

The eruptions of erythema multiforme (EM), SJS, and TEN may represent variants of the same disease process. Reactions encompass a spectrum ranging from the less serious eruptions seen in EM to more serious reactions seen in SJS and TEN [see Figure 5].

 

Figure 5. Toxic Epidermal Necrolysis

This 50-year-old woman developed toxic epidermal necrolysis 17 days after starting phenytoin therapy.

A large percentage of EM and SJS cases are not drug related; these disorders may develop after a variety of predisposing factors, including infections, neoplasia, and autoimmune diseases. The drugs most frequently cited as causes of EM, SJS, and TEN are anticonvulsants, antibiotics (e.g., sulfonamides), allopurinol, and NSAIDs (e.g., piroxicam).59 With anticonvulsants, risk appears to be greatest during the first 8 weeks of therapy.60

The pathogenesis of severe cutaneous ADRs is unknown, although a metabolic basis has been hypothesized.61 Sulfonamides and anticonvulsants, the two groups of drugs most frequently associated with SJS and TEN, are metabolized to toxic metabolites that are subsequently detoxified in most persons. However, in predisposed patients with a genetic defect, the metabolite may bind covalently to proteins. In some of these patients, the metabolite-protein adducts may trigger an immune response that leads to a cutaneous ADR.62 In addition, the detection of drug-specific T cell proliferation provides evidence that T cells are involved in severe skin rashes. Drug-specific major histocompatibility complex (MHC) class I-restricted perforin- and granzyme-mediated cytotoxicity may have a primary role in the development of TEN.63 Clinically, the reaction patterns of EM, SJS, and TEN are characterized by the triad of mucous membrane erosions, target lesions, and epidermal necrosis with skin detachment. SJS is characterized by mucous membrane erosions and blisters on less than 10% of the total body surface area, whereas TEN involves more than 30% of the total body surface area.64 The more severe the reaction, the more likely it is that it was drug-induced. Cases of severe cutaneous ADRs to lamotrigine (e.g., SJS and TEN) have been reported.65 The prevalence of severe cutaneous ADRs associated with lamotrigine has been reported to be as high as one in 1,000 in adults and higher in children. The risk is increased in the presence of valproic acid.

Complete blood counts, liver enzyme measurements, and chest x-rays should be performed to rule out concurrent internal organ involvement.

Treatment of EM, SJS, and TEN includes discontinuance of a suspected drug and such supportive measures as careful wound care, hydration, and nutritional support.66 The use of cortico-steroids in SJS and TEN is controversial.67 IVIg (0.4 to 1.0 g/kg/day for 2 to 4 days), which contains naturally occurring Fas ligand (FasL)-blocking antibodies, has been shown in most reports to halt progression of TEN, especially when IVIg is started early.68 However, other studies did not find an improved outcome in patients with TEN who were treated with IVIg.69Patients who have developed a severe cutaneous ADR (i.e., EM, SJS, or TEN) should not be rechallenged with the drug or undergo desensitization with the medication.

Pustular Eruptions

Simple Eruptions

Acneiform Eruptions

Eruptions morphologically mimicking acne vulgaris may be associated with drug ingestion. Iodides, bromides, adrenocorticotropic hormone, corticosteroids, isoniazid, androgens, lithium, dactinomycin, and phenytoin are reported to induce acnelike lesions.70 Acne fulminans was induced by testosterone in 1% to 2% of adolescent boys who were treated for excessively tall stature.71

Drug-induced acne often appears on the face and back, but it may appear in atypical areas, such as arms and legs, and is usually monomorphous. Comedones are usually absent. Fever is absent. Acneiform eruptions do not affect prepubertal children, indicating that previous hormonal priming is a prerequisite. Topical tretinoin may be useful when the drug cannot be stopped.

Complex Eruptions

Acute Generalized Exanthematous Pustulosis

Acute generalized exanthematous pustulosis is characterized by acute onset, fever, and a cutaneous eruption with nonfollicular sterile pustules on an edematous erythema, generally starting within days of drug ingestion72 [see Figure 6]; leukocytosis is another common finding. Generalized desquamation occurs 2 weeks later. Differential diagnosis includes pustular psoriasis, subcorneal pustular dermatosis (Sneddon-Wilkinson disease), hypersensitivity syndrome reaction with pustulation, and pustular eruptions of infancy.

 

Figure 6. Exanthematous Pustulosis

Acute generalized exanthematous pustulosis (small nonfollicular pustules on a red base) in a 70-year-old man who took cloxacillin as treatment for cellulitis.

 

Figure 7. Coumarin-induced Skin Necrosis

Coumarin-induced skin necrosis in a 57-year-old woman who was given coumarin as treatment for atrial fibrillation.

Acute generalized exanthematous pustulosis is most commonly associated with β-lactam and macrolide antibiotic usage. Many other drugs have been implicated, however, including calcium channel blockers and analgesics. The estimated incidence is approximately one to five cases per million patients per year.73 Discontinuance of therapy is usually the extent of treatment necessary in most patients, although some patients may require the use of corticosteroids. Patch testing to the putative drug is often positive, resulting in a localized pustular reaction. Positive patch tests and lymphocyte transformation tests suggest involvement of T cells in acute generalized exanthematous pustulosis. Drug-specific CD4+ and CD8+ T cells have been isolated from patch test sites and blood from patients with a history of this disorder.74

Other Eruptions

Anticoagulant-Induced Skin Necrosis

Anticoagulant drugs may induce hypercoagulable states with subsequent vascular infarction and cutaneous necrosis [see Figure 7]. Both coumarin and heparin (unfractionated and low-molecular-weight) can induce skin necrosis. Clinical pearls that can help differentiate these reactions involve the location, timing, platelet count, and primary diagnosis [see Table 2].

Table 2 Clinical Pearls to Identify Antocoagulant-Induced Skin Necrosis

 

Interval to Onset

Location

Other

Coumarin-induced skin necrosis

3–5 days

Adipose-rich sites

 

Heparin-induced thrombocytopenia and thrombosis

4–14 days

Extremities

Thrombocytopenia occurs concurrently

Purple-toe syndrome

3–8 wk

Acral location

Often occurs after angiography

The pathogenesis of coumarin-induced skin necrosis is the paradoxical development of occlusive thrombi in cutaneous and subcutaneous venules caused by a transient hypercoagulable state. This condition results from the suppression of the natural anticoagulant protein C at a greater rate than natural procoagulant factors. Coumarin-induced skin necrosis is associated with protein C and protein S deficiency, but pretreatment screening is not warranted. An association with heterozygosity for the factor V Leiden mutation has been reported.75

It is estimated that one in 10,000 persons who take coumarin are at risk for this adverse event.76 The prevalence is four times higher in women than in men. In both sexes, the peak incidence occurs in the sixth and seventh decades of life. Afflicted patients tend to be obese.

Coumarin-induced skin necrosis begins 3 to 5 days after initiation of treatment. Painful red plaques develop in adipose-rich sites such as breasts, buttocks, and hips. These plaques may blister, ulcerate, or develop into necrotic areas. An accompanying infection, such as pneumonia, viral infection, or erysipelas, may occur in as many as 25% of patients. Purple-toe syndrome occurs 3 to 8 weeks after initiation of coumarin therapy.

Treatment entails the discontinuance of coumarin, administration of vitamin K, and infusion of heparin at therapeutic doses. Fresh frozen plasma and purified protein C concentrates have been used.77 Supportive measures for the skin are recommended. Plastic surgery for remediation is necessary in 60% of affected patients.

Drug-Induced Lichenoid Eruptions

The lesions of drug-induced lichen planus are clinically and histologically indistinguishable from those of idiopathic lichen planus. Many drugs, including beta blockers, penicillamine, NSAIDs, gold, and ACE inhibitors, especially captopril, have been reported to produce this reaction.

The latent period between the start of administration of the drug and appearance of the eruption is variable. The mean latent period is between 2 months and 3 years for penicillamine, approximately 1 year for beta blockers, and 3 to 6 months for ACE inhibitors. The latent period may be shorter if the patient was previously exposed to the drug.78 In general, resolution usually occurs within 2 to 4 months.

Rechallenge with the culprit drug has been attempted in a few patients, with reactivation of symptoms within 4 to 15 days.79 Patch testing has not proved helpful in most cases of drug-induced lichen planus. However, results of patch tests performed with contact inducers of lichen drug eruptions (e.g., color-film developers and dental restorative materials) are usually positive.78

Drug-Induced Vasculitis

Drug-induced vasculitis represents approximately 10% of the acute cutaneous vasculitides; it usually affects small vessels [see Figure 8].80Drug-induced vasculitis should be considered in any patient with small vessel vasculitis that is confined to the skin.81 Drugs that are most frequently associated with vasculitis include propylthiouracil, hydralazine, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), allopurinol, cefaclor, minocycline, penicillamine, phenytoin, and isotretinoin.79 The average interval to onset of drug-induced vasculitis is 7 to 21 days.82

 

Figure 8. Leukocytoclastic Vasculitis

Leukocytoclastic vasculitis developed in this 47-year-old woman taking hydrochlorothiazide.

The clinical hallmark of cutaneous vasculitis is palpable purpura, classically found on the lower extremities, although any cutaneous site may be affected. Urticaria can be a manifestation of small vessel vasculitis. Unlike nonvasculitic allergic urticaria, vasculitic urticaria lasts longer than 1 day, may evolve into purpuric lesions, and may be accompanied by hypocomplementemia.83 Other features are hemorrhagic bullae, urticaria, ulcers, nodules, Raynaud disease, and digital necrosis. The same vasculitic process may also affect internal organs, such as the liver, kidney, gut, and CNS, and is potentially life-threatening.84

Histologically, the small blood vessels of the dermis display fibrinoid necrosis, polymorphonuclear infiltration into the blood vessel wall, extravasation of red blood cells, and nuclear dust. Direct immunofluorescence may show deposits of IgM and C3 in the blood vessel walls. Therefore, these reactions are immune complex-dependent drug reactions. The immune complexes may be composed of antibodies directed against drug-related haptens, but this has not been proved.

Drug-induced vasculitis can be difficult to diagnose, and diagnosis is often one of exclusion. Alternative causes of cutaneous vasculitis, such as infection or autoimmune disease, must be eliminated. Tissue eosinophilia may be an indicator of drug induction in cutaneous small vessel vasculitis.85

Treatment consists of drug withdrawal. Therapy for patients with severe manifestations includes hemodialysis, pulse corticosteroids, cyclophosphamide, and plasmapheresis.79

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Editors: Dale, David C.; Federman, Daniel D.