RECENT ADVANCES IN THE PATHOLOGY OF CUTANEOUS DRUG ERUPTIONS

doi:10.1016/S0733-8635(05)70106-6

Dermatologic Clinics

Volume 17, Issue 3, 1 July 1999, Pages 537-560

https://doi.org/10.1016/S0733-8635(05)70106-6 Get rights and content

Roughly 2% of adult¹⁸ and 4% of pediatric⁴⁷ hospital admissions relate to adverse reactions to drug therapy, one hallmark of which is the development of a cutaneous eruption. It is important that the dermatologist and pathologist be familiar with the clinical and histologic spectra of cutaneous reactions to drug therapy and have some understanding of the commonly implicated drug classes, which differ in the inpatient and ambulatory care settings.³⁵ Drug reactions may be of either immunologic or nonimmunologic etiology. Immune mechanisms operative in drug reactions include immediate hypersensitivity reactions (type 1), reactions in which drug hapten binds to endogenous cellular elements evoking an antibody-mediated response to a complete antigen (type 2), immune complex–based reactions (type 3), and reactions of either delayed-type or cellular cytotoxic subtypes (type 4). Nonimmunologic reactions fall primarily in the category of drug toxicity and include anaphylactic reactions to agents that degranulate mast cells or impair arachadonic acid metabolism. Such reactions are idiosyncratic, unpredictable, and uncommon. Other forms of drug toxicity reflect adverse reactions when excessive quantities of a particular agent are given. In this era of polypharmacy, synergistic and cumulative effects of drugs may also provoke cutaneous and systemic adverse reactions.⁴⁰ In general, drug interactions reflect either pharmacokinetic or pharmacodynamic interactions, the latter occurring when one drug induces a change in another without altering its serum level.³ In pharmacokinetic interactions, the type most commonly encountered in dermatology, one drug changes the effective serum concentration of another by interfering with its hepatic metabolism (usually via the cytochrome p450 isoenzyme system), its absorption, its distribution from binding sites, or its excretion.³ In order to attribute a given reaction to a drug, one should ideally establish that the drug in question has the established adverse effect, that an alternate explanation for the eruption is unlikely, that the onset of the eruption is temporally linked to drug ingestion, that the eruption resolves after drug therapy is stopped, and that it recurs following rechallenge.56, 63 Confirmatory drug rechallenge by an oral route is not without risk, but patch testing is generally well tolerated.⁵⁵ In vitro tests for drug hypersensitivity include radioallergosorben (RAST) testing, assay of drug-specific antibodies, and lymphocyte transformation assays,⁵⁵ all of which either are of limited availability to clinicians or are hampered by low sensitivity. This article discusses the most common forms of drug reactions and recent advances in their pathobiology and clinicopathologic expression.

Section snippets

Clinical Features

Exanthematous (morbilliform) drug eruptions, the most common form of drug eruptions, present as red to salmon-colored macular or papular eruptions that start on the trunk and spread peripherally in a symmetric fashion. Lesions mimic a viral exanthem but clear rapidly following withdrawal of the implicated agent and may progress to a generalized exfoliative dermatitis if use of the drug is not discontinued. Constitutional symptoms may be present. Commonly implicated drugs include those from the

Clinical Features

Lichenoid drug eruptions resemble lichen planus clinically by virtue of a violaceous papular eruption with or without oral involvement. The eruptions, often extensive, involve the extremities and trunk and develop weeks to months following commencement of the drug, indicative of a role for delayed-type hypersensitivity in the pathogenesis. When treatment with the implicated drug is stopped, the resolution is slow, and postinflammatory hyperpigmentation may be pronounced, particularly in black

Clinical Features/Pathogenesis

Fixed drug eruptions (FDEs) clasically manifest clinically as sharply circumscribed round to oval patches with violaceous or dusky erythema, which recur in the same location(s) following rechallenge with the causative agent or another drug with which it cross-reacts, and showing a propensity to involve the genitalia and acral skin. Other clinical presentations include nonpigmenting erythema, urticaria, dermatitis, or periorbital or generalized hypermelanosis.⁴⁶ Bullous FDEs, such as those

Clinical Features/Pathogenesis

Photosensitivity eruptions represent roughly 8% of all adverse cutaneous drug reactions.⁶² Some drugs absorb ultraviolet light in either the UVA (320 to 400 nm) or the UVB (290 to 320 nm) range to become immunologically active compounds. Hence, the photoallergic drug reaction occurs preferentially in sun-exposed areas of the skin, sparing the submental and retroauricular areas and upper eyelids. In a minority of cases, however, the photoallergic eruption can become generalized and involve

Clinical Features

One form of pustular drug eruption is characterized by diffuse total body erythema with superimposed nonfollicular pustules accompanied by constitutional symptoms, for which the appellation acute generalized exanthematous pustolosis (AGEP) is used.30, 48, 60 The most frequently implicated agents include calcium channel blockers, nonsteroidal anti-inflammatory drugs, anticonvulsants, and antimicrobials, particularly those with β-lactam and macrolide properties.6, 18, 50, 74, 76, 78 Antifungal

Clinical Features

Oral ingestion, inhalation, or the transcutaneous application of a compound to which a person has been previously sensitized by a contact exposure may elicit an eczematous drug reaction. The symptoms typically develop within 2 to 24 hours after ingestion of the implicated drug, and the affected sites correspond to those involved in the prior contact dermatitis. The term “baboon syndrome” has been used to describe a symmetric eczematous eruption involving the elbows, axilla, eyelids, and sides

BLISTERING DRUG ERUPTIONS

The blistering drug eruptions encompass erythema multiforme, bullous fixed drug eruptions, linear immunoglobulin A (IgA) bullous dermatosis, drug-induced pemphigus and pemphigoid, and pseudoporphyria cutanea tarda.

Clinical Features/Pathogenesis

Drug-induced linear IgA dermatosis manifests clinically as erythema multiforme–like lesions, as urticaria, as tense blisters on an erythematous base indistinguishable from bullous pemphigoid (BP), or as a papulovesicular eruption mimicking dermatitis herpetiformis (DH). These manifestations depend upon the antibody specificity; namely, lamina lucida localization produces BP-like lesions, whereas anchoring fibril localization causes DH-like lesions. Unlike idiopathic linear IgA bullous

Clinical Features/Pathogenesis

The idiopathic pemphigus states are autoimmune diseases characterized by the generation of antibodies directed at antigenic targets within the epidermis: a 130-kDa glycoprotein, which is complexed to an 85-kDa cytoplasmic plaque protein called plakoglobin to form the adhesion molecule desmoglein III in pemphigus vulgaris, and the partly homologous 165-kDa cell adhesion molecule desmoglein I in pemphigus foliaceus.¹⁰ The latter antigen is prominent in the buccal mucosa, scalp, and lower torso,

Clinical Features/Pathogenesis

Bullous pemphigoid is an autoimmune blistering dermatosis, usually seen in the elderly, in which IgG antibodies are directed at antigenic targets of 230 and 180 kDa molecular weight, localized to the lamina lucida of the basement membrane zone, which are components of the hemidesmosome.4, 10 Circulating antibodies are identified in most cases. The characteristic manifestation is the formation of tense blisters on an erythematous or urticarial base involving the trunk, extremities, and

Clinical Features

Pseudoporphyria cutanea tarda (pseudo-PCT) resembles PCT at a clinical, light microscopic, and direct immunofluorescent level. Porphyrin metabolism, however, is normal, and a temporal association appears to link the onset of the blisters to the commencement of a drug and resolution of the eruption to its cessation. Clinically, discrete blisters develop on the face and the dorsa of the hands and can heal with milia. Among the drugs associated with pseudo-PCT are nonsteroidal anti-inflammatory

Clinical Features

Drug-induced lupus erythematosus (LE) is suspected in patients who develop antinuclear antibodies and one or more stigmata of LE while ingesting a drug and in whom symptoms abate following its discontinuance.²⁰ Skin disease is less frequent, and pulmonary manifestations more common in drug-induced LE than in idiopathic LE; a systemic LE-like syndrome is characteristic. Drug-induced discoid LE is distinctly uncommon. Drug-induced subacute cutaneous lupus erythematosus (SCLE) is a recently

Clinical Features

The concept of the lymphomatoid drug eruption, or so-called drug-associated pseudomycosis fungoides, was introduced decades ago when phenytoin (Dilantin) ingestion was linked to lesions which clinically resembled mycosis fungoides.⁵⁸ Subsequent reports in the literature described similar lesions clinically in association with other drugs including phenothiazines, barbiturates, β-blockers, and angiotensin-converting enzyme inhibitors.14, 41, 57 Although the prototypic reaction pattern for the

Clinical Features

Drugs that induce sclerodermoid tissue alterations can be divided into those that provoke systemic fibrosing disorders and those whose reactions are confined to the skin. The former include serotonin, methysergide and other ergot alkaloids, practolol, and hydralazine, while the latter include bromocriptine, lithium, valproate, hydantoins, and l-tryptophan.6, 18, 74, 76, 78 Sclerodermoid tissue alterations localized to injection sites are associated with the use of steroids, heparin, vitamin K,

OTHER ALTERATIONS OF COLLAGEN AND ELASTIC FIBERS

Drugs can provoke cutis laxa, anetoderma, elastosis perforans serpiginosa, and pseudoxanthoma elasticum. The causative agents are listed in Table 8.

Clinical Features

Drugs can evoke a vasculitic response in the skin, manifested clinically as palpable purpura or a purpuric maculopapular rash. Virtually any drug can evoke vasculitis in a predisposed host; it seems likely that patients who develop vasculitis as a sequela of drug therapy may have an underlying endogenous immune dysregulatory state, such as collagen vascular disease. The drugs implicated in the provocation of cutaneous vasculitis are listed in Table 9.¹⁸

Histopathology

The prototypic reaction pattern for

Clinical Features

The classes of drugs that can provoke an ichthyosiform tissue reaction are listed in Table 10.

Histopathology

The histopathology resembles ichthyosis vulgaris, manifesting laminated orthohyperkeratosis with a diminished or absent granular cell layer and, in some cases, the presence of eosinophils.¹⁸

HALOGENODERMAS

Vegetative pustular and ulcerative lesions can be induced through the ingestion of iodides, bromides, and fluorides (Table 11). A pustular facial rash typifies the eruption seen in the setting of iodine ingestion; verrucous ulcerating plaques on the lower extremities typify that of bromide ingestion. Iododerma is, on rare occasions, associated with the administration of radio-opaque contrast media.⁹ The pathophysiology of halogenodermas is not well understood.

Clinical Features

Patients may develop diffuse erythema involving the entire body surface in association with drug therapy. It is important to distinguish drug-induced erythroderma from other causes of erythroderma, such as pityriasis rubra pilaris, psoriasis, seborrheic dermatitis, and cutaneous T-cell lymphoma. The drugs that have been most frequently implicated in erythrodermic states are listed in Table 12.

Histopathology

Skin biopsies show variable psoriasiform hyperplasia, typically with loss of the granular cell layer

Clinical Features/Pathogenesis/Histopathology

A variety of drugs may cause increased cutaneous pigmentation (Table 13) by provoking an increased production of melanin, by causing pigment incontinence through damage to the basal layer epidermal keratinocytes or basal layer melanocytes or both, by deposition of the drug or some elemental component of it, or by deposition of drug complexes. The use of antimalarial agents such as quinacrine is associated with a yellowish pigmentation or with a slate-gray pretibial pigmentation; biopsies show

PSORIASIFORM DRUG REACTIONS

Drugs of several classes are associated with a psoriasiform eruption and/or with the induction or exacerbation of psoriasis (Table 14).6, 18, 26, 73, 74, 76, 78

Clinical Features

Erythema multiforme, a distinctive clinicopathologic entity with a wide variety of underlying causes, manifests clinically as targetoid lesions with a peripheral rim of erythema and a central zone of pallor and sometimes as dusky or violaceous macules or blisters. As the pathogenetic basis of erythema multiforme is that of a type 4 cellular cytotoxic reaction, the sites of predilection are those where antigenic processing is maximal, which include the palms and soles. However, the lesions can

Clinical Features/Pathogenesis

Drug therapy may be associated with erythematous to violaceous, nonpruritic plaques in an annular pattern, involving inner aspects of the arms, medial thighs, and intertriginous areas, associated with a histomorphology comprising interstitial histiocytic infiltrates accompanied by collagen and elastic fiber degeneration mimicking early lesions of granuloma annulare (GA). Lesions clinically mimic cutaneous T-cell lymphoma, erythema annulare centrifigum, GA, and LE. Implicated drug classes

Clinical Features/Pathogenesis

The authors have encountered a few patients who developed eruptions temporally related to intake of antihypertensive medications, which resembled pityriasis rubra pilaris (PRP),³⁹ an idiopathic disorder of keratinization. Specifically, the patients had circumscribed follicular keratosis, palmoplantar keratoderma, and desquamating yellow-orange–hued erythematous papulosquamous eruptions that followed a cephalocaudal progression to erythroderma with islands of sparing. The implicated agents are

CUTANEOUS REACTIONS TO CYTOKINE THERAPY

The recent commercial availability of cytokines for clinical use, made possible in large part by recombinant DNA technology, has resulted in the recognition of a variety of cutaneous reaction patterns in patients undergoing therapy for cancer and autoimmune disease. This article briefly considers some recently described reactions to injection of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and interferon.

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Histologically, in morbilliform drug eruptions, there is focal interface vacuolar dermatitis with dyskeratotic cells at the dermoepidermal junction, dermal edema, and a superficial perivascular lymphocytic infiltrate. Hemorrhage into skin and absence of tissue eosinophilia may support a diagnosis of viral exanthem over drug eruption.26 Ultimately, differentiating the two entities may not be possible until rechallenge of the drug after the child is both unmedicated and healthy; however, this is rarely done.25
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: Address reprint requests to A. N. Crowson, MD, St. John Medical Center, 1923 S. Utica Avenue, Tulsa, OK 74104–6502

^*: Central Medical Laboratories and the Department of Laboratories, Misericordia General Hospital, Winnipeg, Manitoba, Canada (ANC); and Ameripath Cutaneous Pathology and Immunofluorescence Laboratory, Beachwood, Ohio (CMM)

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