Fixed Drug Eruptions Pathophysiology

Fixed Drug Eruptions 

• Author: David F Butler, MD; Chief Editor: Dirk M Elston

Background

Adverse reactions to medications are common and often manifest as a cutaneous eruption.

Drug-induced cutaneous disorders frequently display a characteristic clinical morphology such as morbilliform exanthem, urticaria, hypersensitivity syndrome, pseudolymphoma, photosensitivity, pigmentary changes, acute generalized exanthematous pustulosis, lichenoid dermatitis, vasculitis, Stevens-Johnson syndrome, or fixed drug eruption (FDE). The term fixed drug eruption describes the development of one or more annular or oval erythematous patches as a result of systemic exposure to a drug; these reactions normally resolve with hyperpigmentation and may recur at the same site with reexposure to the drug. Repeated exposure to the offending drug may cause new lesions to develop in addition to "lighting up" the older hyperpigmented lesions.

Several variants of fixed drug eruption have been described, based on their clinical features and the distribution of the lesions.^{[1, 2, 3, 4, 5, 6]} These include the following:

• Pigmenting fixed drug eruption
• Generalized or multiple fixed drug eruption
• Linear fixed drug eruption
• Wandering fixed drug eruption
• Nonpigmenting fixed drug eruption
• Bullous fixed drug eruption
• Eczematous fixed drug eruption
• Urticarial fixed drug eruption
• Erythema dyschromicum perstans–like fixed drug eruption
• Vulvitis
• Oral
• Psoriasiform
• Cellulitislike eruption^[7]

Pathophysiology

Although the exact mechanism is unknown, recent research suggests a cell-mediated process that initiates both the active and quiescent lesions. The process may involve an antibody-dependent, cell-mediated cytotoxic response.^[8] CD8⁺effector/memory T cells play an important role in reactivation of lesions with re-exposure to the offending drug.^{[9, 10]}

The offending drug is thought to function as a hapten that preferentially binds to basal keratinocytes, leading to an inflammatory response.^[11] Through liberation of cytokines such as tumor necrosis factor-alpha, keratinocytes may locally up-regulate expression of the intercellular adhesion molecule-1 (ICAM1).^[12] The up-regulated ICAM1 has been shown to help T cells (CD4 and CD8) migrate to the site of an insult.^{[13, 14]}

The newly arriving and residential CD8 cells likely perpetuate tissue damage by their production of the inflammatory cytokines interferon-gamma and tumor necrosis factor-alpha. CD8 cells isolated from active lesions have also been shown to express alpha E beta 7, a ligand for E-cadherin, which may further contribute to the lymphocyte’s ability to localize to the epidermis. Other cell surface molecules, such as CLA/alpha4beta1/CD4a, that bind E-selectin/vascular cellular adhesion molecule-2/ICAM1 help to further attract CD8 cells to the area.^[8]

Changes in cell surface markers allow vascular endothelium to select CD4 cells for migration into active lesions. These regulatory CD4 cells likely produce interleukin 10, which has been shown to help suppress immune function, resulting in a resting lesion.^[8] As the inflammatory response dissipates, interleukin 15 expression from keratinocytes is thought to help ensure the survival of CD8 cells, helping them fulfill their effector memory phenotypes. Thus, when reexposure to the drug occurs, a more rapid response develops in the exact location of any prior lesions.^[8]

Epidemiology

Frequency

United States

The prevalence of drug eruptions has been reported to range from 2-5% for inpatients and greater than 1% for outpatients.^[15] Fixed drug eruptions may account for as much as 16-21% of all cutaneous drug eruptions. The actual frequency may be higher than current estimates, owing to the availability of a variety of over-the-counter medications and nutritional supplements that are known to elicit fixed drug eruptions.

International

The international prevalence is variable but is likely similar to that in the United States. Most studies report fixed drug eruptions to be the second or third most common skin manifestation of adverse drug events.^[16]

Mortality/Morbidity

Widespread lesions may initially mimic toxic epidermal necrolysis, but they have a benign clinical course.^[17] Localized hyperpigmentation is a common complication, but pain, infection, and, rarely, hypopigmentation, also may occur.^[1]

Race

Fixed drug eruptions have no known racial predilection. A genetic susceptibility to developing a fixed drug eruption with an increased incidence of HLA-B22 is possible.^{[18, 19]}

Sex

One large study of 450 patients revealed a male-to-female ratio of 1:1.1 for fixed drug eruptions.^[1]

Age

Fixed drug eruptions have been reported in patients as young as 1.5 years and as old as 87 years. The mean age at presentation is 30.4 years in males and 31.3 years in females.^[1]

Dyshidrotic Eczema Complications

Dyshidrotic Eczema 

• Author: Sadegh Amini, MD; Chief Editor: Dirk M Elsto

Background

Dyshidrotic eczema is a type of eczema (dermatitis) of unknown cause that is characterized by a pruritic vesicular eruption on the fingers, palms, and soles. The condition affects teenagers and adults and may be acute, recurrent, or chronic. A more appropriate term for this vesicular eruption is pompholyx, which means bubble. The clinical course of dyshidrotic eczema can range from self-limited to chronic, severe, or debilitating. The condition's unresponsiveness to treatment can be frustrating for the patient and physician (see the images below). (See Clinical.)

Tense vesicles and bullae on the palm. Courtesy of Norman Minars, MD, University of Miami, Department of Dermatology & Cutaneous Surgery.Multiple tense vesicles on the palm.

Some believe the terms pompholyx and dyshidrosis are obsolete and favor a new term, such as "acute and recurrent vesicular hand dermatitis." The etiology of dyshidrotic eczema is unresolved and is believed to be multifactorial. Dyshidrotic eczema is considered to be a reaction pattern caused by various endogenous conditions and exogenous factors. (See Etiology.)

Complications

Secondary bacterial infection of dyshidrotic eczema vesicles or bullae can result in cellulitis, lymphangitis, and septicemia (rare). Dystrophic nail changes may develop, with the occurrence of transverse ridging, thickening, discoloration, and pitting. Dyshidrotic eczema has no associated mortality, although some severe cases can become debilitating. (See Clinical.)

Prognosis

Dyshidrotic eczema follows a chronic, intermittent course, with fewer episodes occurring after middle age. Some mildly affected patients experience spontaneous resolution within 2-3 weeks. (See Epidemiology, Treatment, and Medications.)

Patient education

Instruct dyshidrotic eczema patients to avoid contact with certain allergens or irritants (eg, nickel), to follow a hand care routine that avoids irritants, and to use emollients regularly. In addition, inform individuals with this disorder about the difficulty of achieving successful treatment. For patient education information, see the Skin Conditions and Beauty Center, as well as Eczema (Atopic Dermatitis). (See Treatment and Medications.)

Severity index

The Dyshidrotic Eczema Area and Severity Index was developed based on severity grades for the number of vesicles per square centimeter, erythema, desquamation, itch, and the extent of affected areas.^[1] The index was found to be a simple standardized method for assessing the condition and was used to assess disease severity and treatment effectiveness in 2 clinical studies. Further evaluation with larger patient groups is needed.

Etiology

The hypothesis of sweat gland dysfunction has been disputed because vesicles have not been shown to be associated with sweat ducts. A 2009 case report provided clear histopathologic evidence that sweat glands do not play a role in dyshidrosis.^[2] However, hyperhidrosis is an aggravating factor in 40% of patients with dyshidrotic eczema. Improvement in pruritus, erythema, vesicles, and hand dermatitis with fewer or no signs of relapse has been obtained after botulinum toxin A injection.^[3]

Dyshidrotic eczema may be associated with atopy and familial atopy. Of patients with dyshidrosis, 50% have atopic dermatitis.

Exogenous factors (eg, contact dermatitis to nickel, balsam, cobalt; sensitivity to ingested metals; dermatophyte infection; bacterial infection) may trigger episodes. These antigens may act as haptens with a specific affinity for palmoplantar proteins of the stratum lucidum of the epidermis. The binding of these haptens to tissue receptor sites may initiate pompholyx.

Evidence shows that the ingestion of metal ions such as cobalt can induce type I and type IV hypersensitivity reactions. In addition, they can also act as atypical haptens, activating T lymphocytes through human leukocyte antigen–independent pathways, causing systemic allergic dermatitis in the form of dyshidrotic eczema.^{[4, 5]}

Emotional stress^[6] and environmental factors (eg, seasonal changes, hot or cold temperatures, humidity) reportedly exacerbate dyshidrosis. In addition, dyshidrosislike eczematous eruptions with the use of intravenous immunoglobulin infusions have been reported.

Dyshidrosislike eczematous eruptions with the use of intravenous immunoglobulin (IVIG) infusions have been reported. A recent search of the literature identified pompholyx as one of the most important cutaneous adverse effects of IVIG, being present in 62.5% of the patients reported, with 75% of those patients developing the lesions after just one IVIG treatment.^[7] The eruption tends to be mild and to wane over time. It usually responds very well to topical steroids, but may become recurrent and more aggressive after repeated doses of IVIG.

In some patients, a distant fungal infection can cause palmar pompholyx as an id reaction. In one study, one third of pompholyx occurrences on the palms resolved after treatment for tinea pedis. The factors believed to be associated with dyshidrotic eczema are discussed in more detail below.

Genetic factors

Monozygotic twins have been affected simultaneously by dyshidrotic eczema. The pompholyx gene has been mapped to band 18q22.1-18q22.3 in the autosomal dominant form of familial pompholyx.^[8]

Mutations on the filaggrin gene leading to loss of filaggrin, a structural protein of the stratum corneum involved in the barrier function of the skin, causes dyskeratinization, increased transepidermal water loss, and an increase in the transepidermal antigen transfer. Combined, these features have been associated with the development of icthyosis and atopic dermatitis, and they may be involved in the development of irritant and allergic contact dermatitis, which are well-known conditions associated with dyshidrotic eczema. Chronic hand dermatitis, including dyshidrotis eczema, has also been associated with defects in the skin barrier, and, in a few cases, it has been also associated with mutations in the filaggrin gene; however, these have not reached statistical significance.^[9]

Atopy

As many as 50% of patients with dyshidrotic eczema have reportedly had personal or familial atopic diathesis (eczema, asthma, hay fever, allergic sinusitis). The serum immunoglobulin E (IgE) level frequently is increased, even in patients who do not report a personal or familial history of atopy. Occasionally, dyshidrotic eczema is the first manifestation of an atopic diathesis.

Nickel sensitivity

This may be a significant factor in dyshidrotic eczema. Nickel sensitivity was reportedly low in some studies of dyshidrosis patients, but significantly elevated in other studies. Increased nickel excretion in the urine has been reported during exacerbations of pompholyx. Ingested metals have been found to provoke exacerbations of pompholyx in some patients.

Low-nickel diets have reportedly decreased the frequency and severity of pompholyx flares. A high palmoplantar perspiration rate has been suggested to result in a local concentration of metal salts that may provoke the vesicular reaction. Contact allergy has been documented in 30% of patients with dyshidrotic eczema.

Cobalt sensitivity

The oral ingestion of cobalt manifests systemic allergic dermatitis as dyshidrotic eczema less frequently than does the oral ingestion of nickel. Much more common is the simultaneous occurrence of nickel and cobalt allergy seen in 25% of nickel-sensitive patients developing pompholyx. In these cases, the eczema is usually more severe. When suspected as the cause of the dyshidrotic eczema, high oral ingestion of cobalt should be taken in consideration, regardless of the patch test results.^[4]

A point-based, low-cobalt diet has been proposed to help patients limit cobalt ingestion and to keep the serum level below the threshold for developing flares, which is approximately less than 12 mcg/d. This diet has demonstrated higher compliance than an avoidance diet list. In addition, this diet reduces the amount of nickel consumed.^[4]

Exposure to sensitizing chemicals or metals

Dyshidrotic eczema outbreaks are sometimes associated with exposure to sensitizing chemicals or metals (eg, chromium, cobalt, carba mix, fragrance mix, diaminodiphenylmethane, dichromates, benzoisothiazolones, paraphenylenediamine, perfumes, fragrances, balsam of Peru, Primula plant).

Id reaction

Controversy surrounds the possible existence of an id reaction, which is considered to be a distant dermatophyte infection (tinea pedis, kerion of scalp) triggering a palmar pompholyx reaction (also termed pompholyx dermatophytid).

Fungal infection

Pompholyx occasionally resolves when a tinea pedis infection is treated, then relapses when the fungal infection recurs, supporting the existence of this reaction pattern. Of patients who have a vesicular reaction to intradermal trichophytin testing, less than one third have experienced a resolution of pompholyx after treatment with antifungal agents.

Emotional stress

This is a possible factor in dyshidrotic eczema. Many patients report recurrences of pompholyx during stressful periods. Improvement of dyshidrotic eczema using biofeedback techniques for stress reduction supports this hypothesis.

Other factors

Isolated reports describe other possible causative factors, such as aspirin ingestion, oral contraceptives, cigarette smoking, and implanted metals, among others. A 3-year prospective study of the causes of dyshidrotic eczema (pompholyx) in 120 patients found causes of pompholyx related to contact exposure (67.5%), including to cosmetic products (31.7%) and metals (16.7%); interdigital-plantar intertrigo (10%); and internal factors (6.7%), with an additional 15% of patients having undiagnosed (idiopathic) causes probably related to atopic factors.^[10]

Contact allergy was found in 89 (74.2%) of the 120 patients. The most frequent allergens were nickel, shower gel, chromium, fragrance, shampoo, and balsam of Peru. Less frequent allergens were lanolin, cobalt, thiuram, lauryl sulfate, fresh tobacco, p -phenylenediamine (PPD), formaldehyde, parabens, and octyl gallate. In 97 of 193 positive patch test results, correlation existed between the application of the agent and pompholyx recurrence. The relevance of the analysis was confirmed in 81 (67.5%) of the 120 patients. In summary, the most frequent causes of pompholyx related to contact with substances were hygiene product intolerance (46.7%), metal allergy (25%), and others (28.3%).

Intertrigo occurred in 19 (15.8%) of the 120 patients. Of those individuals, 80% presented with dermatophytosis and 20% presented with candidiasis. After 3 weeks of antifungal therapy, 6 of 19 patients remained symptomatic for pompholyx.

With regard to internal causes, 30 patients presented with a positive patch test result for metals, but only 2 presented with exacerbations of the lesions after a challenge test.

Of 58 patients with a history of smoking tobacco, 5 presented with a positive reaction, and 2 of those reactions were considered relevant. Drug allergy was determined to be the causative agent in 3 patients (amoxicillin in 2 and intravenous immunoglobulin in 1). Food-related pompholyx was detected in 4 patients, and, after a challenge test, reactivation occurred in 3 of these patients (2 for paprika and 1 for orange juice).

Ultraviolet A light

In a case series, 5 patients with prior diagnosis of pompholyx developed lesions morphologically and histologically consistent with a vesicular dermatitis after provocation with long-wavelength ultraviolet A (UVA) light. Further workup ruled outcontact dermatitis, polymorphic light eruption, and heat as the culprit, confirming that the reaction was due to true photosensitivity rather than to photoaggravation.^[11]

Pompholyx caused by UVA exposure may possibly be considered a variation of seasonal (summer) pompholyx. In the United States, dyshidrotic eczema is more commonly seen in warmer climates and during the spring and summer months. A study in Turkey also revealed a higher prevalence of dyshidrotic eczema in the summer months.^[12]

(Of interest, UVB phototherapy and photochemotherapy are well-known, efficient treatments for pompholyx.)

Epidemiology

Occurrence in the United States

Dyshidrotic eczema occurs in 5-20% of patients with hand eczema and more commonly develops in warmer climates and during spring and summer months (seasonal or summer pompholyx).

International occurrence

Dyshidrotic eczema accounted for 1% of initial consultations in a 1-year Swedish study. In a study of 107,206 Swedish individuals, 51 (0.05%) were diagnosed with dyshidrosis. Of all hand dermatitis cases in that population, 3% had dyshidrosis.^[13]

In a retrospective study reviewing records of 714 Portuguese patients during a 6-year period, Magina et al found dyshidrotic eczema to be the third most common type of hand dermatitis (20.3%).^[14]

Sex- and age-related demographics

The male-to-female ratio for dyshidrotic eczema has variably been reported as 1:1 and 1:2. Dyshidrotic eczema affects individuals aged 4-76 years; the mean age is 38 years. The peak incidence of the condition occurs in patients aged 20-40 years. After middle age, the frequency of dyshidrotic eczema episodes tends to decrease.

Drug-Induced Pigmentation 

• Author: David F Butler, MD; Chief Editor: Dirk M Elston

Background

Adverse cutaneous reactions to medications are a common reason for consultations with dermatologists. Drug-induced skin disorders may manifest in a variety of ways. Drugs may cause exanthems, urticaria, hypersensitivity syndromes, pustular eruptions, erythema multiforme, toxic epidermal necrolysis, cutaneous necrosis, and abnormal pigmentation of the skin and mucosa. Although pigmentary changes caused by drugs usually result in a limited degree of morbidity, these changes may be very disturbing to the patient.

The image below depicts a patient with amiodarone pigmentation.

Amiodarone pigmentation.

Drug-induced pigmentary abnormalities may be classified into 3 groups, which are (1) hyperpigmentation/melanosis, (2) hypopigmentation/leukoderma, and (3) dyspigmentation or occurrence of unusual skin color.

A related article is Fixed Drug Eruptions. Additionally, the Medscape Adverse Drug Event Reporting Resource Center may be of interest.

Pathophysiology

Multiple pathologic mechanisms are responsible for drug-induced pigmentation disorders. Compared with the immunological etiology underlying many drug allergies, most cases of pharmacologic pigmentation are not immunologically mediated.

The pathogenesis underlying drug-related dyspigmentation can also be categorized into 3 mechanisms, which are (1) drug or drug metabolite deposition in the dermis and epidermis, (2) enhanced melanin production with or without an increase in the number of active melanocytes, and (3) drug-induced postinflammatory changes to skin. Similarly, chemical hypopigmentation is also thought to occur through a variety of pathologic mechanisms, including a reduced number of skin melanocytes, enzymatic blockade of melanogenesis, and inhibition of melanosome transfer.

Epidemiology

Frequency

United States

The rate of drug-induced dyspigmentation varies depending on the drug and cumulative dose. Some drugs, such as amiodarone, have been reported to have a rate of blue-gray dyspigmentation as high as 24% when the cumulative dose is greater than 200 mg.

International

Drug-induced skin pigmentation is estimated to account for 10-20% of all cases of acquired dyspigmentation worldwide.

Mortality/Morbidity

Drug-induced pigmentation is not generally associated with increased mortality or morbidity, although it may result in considerable psychological and social impairment.

Race

Drug-induced pigmentary changes can occur in persons of any race, but hypomelanosis is seen more frequently and appears more dramatically in patients with darker-pigmented skin. Additionally, people with darker skin often exhibit more intense hyperpigmentation than individuals with fair skin.^[1]

Sex

No differences are reported in the prevalence of drug-related pigmentation among males versus females.

Age

Drug-related dyspigmentation is seen in persons of all ages.

Drug-Induced Photosensitivity 

• Author: Alexandra Y Zhang, MD; Chief Editor: Dirk M Elston

Background

Drug-induced photosensitivity refers to the development of cutaneous disease as a result of the combined effects of a chemical and light. Exposure to either the chemical or the light alone is not sufficient to induce the disease; however, when photoactivation of the chemical occurs, one or more cutaneous manifestations may arise. These include phototoxic and photoallergic reactions, a planus lichenoides reaction, pseudoporphyria, and subacute cutaneous lupus erythematosus. Photosensitivity reactions may result from systemic medications and topically applied compounds (see Table 1 below).

UV-A–associated phototoxicity is also common with vemurafenib,^{[1, 2, 3]} with reduced UV-A minimal erythema dose in 94% of those tested.^[1]

Wavelengths within the UV-A (320-400 nm) range and, for certain compounds, within the visible range, are more likely to cause drug-induced photosensitivity reactions, although occasionally UV-B (290-320 nm) can also be responsible for such effects. UV-B wavelengths are most efficient at causing sunburn and nonmelanoma skin cancer. In patients who present with photosensitivity, it is often difficult to differentiate phototoxic from photoallergic reactions. However, they have a number of distinguishing characteristics (see Table 2 below).

Table 1. Common Photosensitizing Medications (Open Table in a new window)

Class	Medication	Photo-toxic Reaction	Photo-allergic Reaction	Lichenoid Reaction	Pseudo-porphyria	Subacute Cutaneous Lupus Erythematosus
Antibiotics	Tetracyclines (doxycycline, tetracycline)	Yes	No	Yes	Yes	No
	Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin)[4]	Yes	No	No	No	No
	Sulfonamides	Yes	No	No	No	No
Nonsteroidal anti-inflammatory drugs[5]	Ibuprofen	Yes	No	Yes	No	No
	Ketoprofen	Yes	Yes	No	No	No
	Naproxen[6]	Yes	No	Yes	Yes	No
	Celecoxib[7]	No	Yes	No	Yes	No
Diuretics	Furosemide	Yes	No	No	Yes	No
	Bumetanide	No	No	No	Yes	No
	Hydro-chlorothiazide	Yes	No	No	No	Yes
Retinoid	Isotretinoin	Yes	No	No	No	No
	Acitretin	Yes	No	No	No	No
Hypoglycemics	Sulfonylureas (glipizide, glyburide)[4]	No	Yes	Yes	Yes	No
HMG-CoA* reductase inhibitors	Statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin)[8]	Yes	Yes	Yes	Yes	No
Epidermal growth factor receptor inhibitors	Cetuximab, panitumumab, erlotinib, gefitinib, lapatinib, vandetanib[9]	Yes	Yes	Yes	Yes	No
Photodynamic therapy prophoto-sensitizers	5-Aminolevulinic acid[10]	Yes	No	No	No	No
	Methyl-5-aminolevulinic acid	Yes	No	No	No	No
	Verteporfin[11]	Yes	No	No	No	No
	Photofrin[12]	Yes	No	No	No	No
Neuroleptic drugs[13]	Phenothiazines (chlorpromazine, fluphenazine, perazine, perphenazine, thioridazine)[14]	Yes	Yes	Yes	No	No
	Thioxanthenes (chlorprothixene, thiothixene)	Yes	No	No	No	No
Antifungals	Terbinafine	No	No	No	No	Yes
	Itraconazole	Yes	Yes	No	No	No
	Voriconazole[15, 16, 17, 18]	Yes	No	No	Yes	No
	Griseofulvin	Yes	Yes	No	No	Yes
Other drugs	Para-aminobenzoic acid	Yes	Yes	No	No	No
	5-Fluorouracil	Yes	Yes	Yes	Yes	No
	Paclitaxel[5, 19]	Yes	No	No	No	Yes
	Amiodarone	Yes	No	No	Yes	No
	Diltiazem	Yes	No	No	No	Yes
	Quinidine	Yes	Yes	Yes	No	No
	Hydroxychloroquine	No	No	Yes	No	No
	Coal tar	Yes	No	No	No	No
	Enalapril	No	No	No	No	Yes
	Dapsone	No	Yes	Yes	Yes	No
	Oral contraceptives[20, 21]	No	Yes	No	Yes	No
Sunscreens[22]	Para-aminobenzoic acid	No	Yes	No	No	No
	Cinnamates	No	Yes	No	No	No
	Benzophenones	No	Yes	No	No	No
	Salicylates	No	Yes	No	No	No
Fragrances	Musk ambrette	No	Yes	No	No	No
	6-Methylcoumarin	No	Yes	No	No	No
*3-Hydroxy-3-methylglutaryl coenzyme A.

Phototoxic reactions occur because of the damaging effects of light-activated compounds on cell membranes and, in some instances, DNA. By contrast, photoallergic reactions are cell-mediated immune responses to a light-activated compound. Phototoxic reactions develop in most individuals if they are exposed to sufficient amounts of light and drug. Typically, they appear as an exaggerated sunburn response, as shown in the image below.

Phototoxic reaction.

Photoallergic reactions resemble allergic contact dermatitis, with a distribution limited to sun-exposed areas of the body. However, when the reactions are severe or prolonged, they may extend into covered areas of skin.

Table 2. Distinguishing Characteristics of Phototoxic and Photoallergic Reactions(Open Table in a new window)

Feature	Phototoxic Reaction	Photoallergic Reaction
Incidence	High	Low
Amount of agent required for photosensitivity	Large	Small
Onset of reaction after exposure to agent and light	Minutes to hours	24-72 hours
More than one exposure to agent required	No	Yes
Distribution	Sun-exposed skin only	Sun-exposed skin, may spread to unexposed areas
Clinical characteristics	Exaggerated sunburn	Dermatitis
Immunologically mediated	No	Yes; Type IV

Photoallergic reactions develop in only a minority of individuals exposed to the compound and light; they are less prevalent than phototoxic skin reactions. The amount of drug required to elicit photoallergic reactions is considerably smaller than that required for phototoxic reactions. Moreover, photoallergic reactions, as shown in the image below, are a form of cell-mediated immunity; their onset often is delayed by as long as 24-72 hours after exposure to the drug and light. By contrast, phototoxic responses often occur within minutes or hours of light exposure.

Photoallergic reaction.

Pathophysiology

Phototoxicity

Phototoxic reactions result from direct damage to tissue caused by a photoactivated compound. Many compounds have the potential to cause phototoxicity. Most have at least one resonating double bond or an aromatic ring that can absorb radiant energy. Most compounds are activated by wavelengths within the UV-A (320-400 nm) range, although some compounds have a peak absorption within the UV-B or visible range.

In most instances, photoactivation of a compound results in the excitation of electrons from the stable singlet state to an excited triplet state. As excited-state electrons return to a more stable configuration, they transfer their energy to oxygen, leading to the formation of reactive oxygen intermediates. Reactive oxygen intermediates such as an oxygen singlet, superoxide anion, and hydrogen peroxide damage cell membranes and DNA. Signal transduction pathways that lead to the production of proinflammatory cytokines and arachidonic acid metabolites are also activated. The result is an inflammatory response that has the clinical appearance of an exaggerated sunburn reaction.

The exception to this mechanism of drug-induced phototoxicity is psoralen-induced phototoxicity. Psoralens intercalate within DNA, forming monofunctional adducts. Exposure to UV-A radiation produces bifunctional adducts within DNA. Exactly how bifunctional adducts cause photosensitivity is unknown.

Photoallergic reactions

Photoallergic reactions are cell-mediated immune responses in which the antigen is a light-activated drug. Photoactivation results in the development of a metabolite that can bind to protein carriers in the skin to form a complete antigen. The reaction then proceeds exactly as other cell-mediated immune responses do. Specifically, Langerhans cells and other antigen-presenting cells take up the antigen and then migrate to regional lymph nodes. In those locations, the Langerhans cells present the photoallergen to T lymphocytes that express antigen-specific receptors. The T cells become activated and proliferate, and they return to the site of photoallergen deposition. In the skin, the T cells orchestrate an inflammatory response that usually has an eczematous morphology if the photoallergen is applied topically or the characteristics of a drug eruption if the photoallergen is administered systemically.

Epidemiology

Frequency

United States

Although the incidence of drug-induced photosensitivity in the United States is uncertain. Phototoxic reactions are considerably more common than photoallergic reactions.

International

The incidence of drug-induced photosensitivity is unknown.

Mortality/Morbidity

Drug-induced photosensitivity is associated with death only in rare individuals who are exposed to large amounts of sunlight after taking large doses of psoralens. Although mortality is rare, drug-induced photosensitivity can cause significant morbidity in some individuals, who must severely limit their exposure to natural or artificial light.

Voriconazole photosensitivity is associated with a risk of skin cancer.^{[23, 24]} The changes that occur with long-term exposure resemble accelerated photo-aging. Acute photosensitivity occurs in 1–2% or more of patients taking voriconazole for more than 12 weeks. It appears to be UV-A induced, but it is not strictly dose-dependent. Cheilitis and facial erythema are typical initial manifestations.

Race

The racial incidence of drug-induced photosensitivity reactions is unknown. Photosensitivity reactions can occur in races with heavily pigmented skin.

Sex

Men are more likely to have photoallergic reactions than women.

Age

Drug-induced photosensitivity reactions can occur in persons of any age.

Drug Eruptions 

• Author: Jonathan E Blume, MD; Chief Editor: Dirk M Elston

Practice Essentials

Drug eruptions can mimic a wide range of dermatoses. The morphologies are myriad and include morbilliform, urticarial, papulosquamous, pustular, and bullous. Medications can also cause pruritus and dysesthesia without an obvious eruption. A drug-induced reaction should be considered in any patient who is taking medications and who suddenly develops a symmetric cutaneous eruption.

Signs and symptoms

The first steps in the history are as follows:

• Review the patient’s complete medication list, including prescription and over-the-counter drugs
• Document any history of previous adverse reactions to drugs or foods
• Consider alternative etiologies (eg, viral exanthems and bacterial infections)
• Note any concurrent infections, metabolic disorders, or immunocompromise

In addition, the following should be noted and detailed:

• Interval between introduction of a drug and onset of the eruption
• Route, dose, duration, and frequency of drug administration
• Use of parenterally administered drugs (more likely to cause anaphylaxis)
• Use of topically applied drugs (more likely to induce delayed-type hypersensitivity)
• Use of multiple courses of therapy and prolonged administration (risk of allergic sensitization)
• Any improvement after drug withdrawal and any reaction with readministration

Physical examination should address clinical features that may indicate a severe, potentially life-threatening drug reaction, including the following:

• Mucous membrane erosions
• Blisters
• Nikolsky sign
• Confluent erythema
• Angioedema and tongue swelling
• Palpable purpura
• Skin necrosis
• Lymphadenopathy
• High fever, dyspnea, or hypotension

It is important to appreciate the morphology and physical features of drug eruptions, as follows:

• Acneiform
• Acral erythema (erythrodysesthesia)
• AGEP
• Dermatomyositislike
• DRESS
• Erythema multiforme (EM), including EM minor, SJS, TEN, and SJS/TEN overlap
• Erythema nodosum
• Erythroderma
• Fixed drug eruptions
• Hypersensitivity syndrome
• Leukocytoclastic vasculitis
• Lichenoid
• Lupus
• Morbilliform or exanthematous
• Pseudoporphyria^[1]
• Serum sickness and serum sickness–like
• Sweet syndrome (acute febrile neutrophilic dermatosis)
• Urticaria
• Vesiculobullous

See Clinical Presentation for more detail.

Diagnosis

With mild asymptomatic eruptions, the history and physical examination are often sufficient for diagnosis; with severe or persistent eruptions, further diagnostic testing may be required, as follows:

• Biopsy
• Complete blood count (CBC) with differential
• Serum chemistry studies (especially for electrolyte balance and indices of renal or hepatic function in patients with severe reactions)
• Antibody or immunoserology tests
• Direct cultures to investigate a primary infectious etiology or secondary infection
• Urinalysis, stool guaiac tests, and chest radiography for vasculitis
• Skin prick or patch testing to confirm the causative agent

See Workup for more detail.

Management

Principles of medical care are as follows:

• The ultimate goal is to identify and discontinue the offending medication if possible
• Patients can sometimes continue to be treated through morbilliform eruptions; nevertheless, all patients with severe morbilliform eruptions should be monitored for mucous membrane lesions, blistering, and skin sloughing
• Treatment of a drug eruption depends on the specific type of reaction
• Therapy for exanthematous drug eruptions is supportive, involving the administration of oral antihistamines, topical steroids, and moisturizing lotions
• Severe reactions (eg, SJS, TEN, and hypersensitivity reactions) warrant hospital admission
• TEN is best managed in a burn unit, and intravenous immunoglobulin (IVIG) may improve outcomes^{[2, 3, 4]}
• Hypersensitivity syndrome may have to be treated with liver transplantation if the offending drug is not stopped in time; treatment with systemic corticosteroids has been advocated in the acute phase; in the chronic phase, patients may require treatment for hypothyroidism or diabetes mellitus

For most drug eruptions, full recovery without any complications is expected; however, the following should be noted:

• Patients with exanthematous eruptions should expect mild desquamation as the rash resolves
• Patients with hypersensitivity syndrome are at risk of becoming hypothyroid, usually within the first 4-12 weeks after the reaction; there is also a risk of diabetes
• The prognosis for patients with TEN is guarded; scarring, blindness, and death are possible

Image library

Stevens-Johnson syndrome.

Background

Drug eruptions can mimic a wide range of dermatoses. The morphologies are myriad and include morbilliform (most common, see image below), urticarial, papulosquamous, pustular, and bullous. Medications can also cause pruritus and dysesthesia without an obvious eruption. Both calcium channel blockers and interferon are strongly associated with eczematous eruptions.

Morbilliform drug eruption.

A drug-induced reaction should be considered in any patient who is taking medications and who suddenly develops a symmetric cutaneous eruption. Medications that are known for causing cutaneous reactions include antimicrobial agents,^[5] nonsteroidal anti-inflammatory drugs (NSAIDs), cytokines, chemotherapeutic agents, anticonvulsants, and psychotropic agents.

Prompt identification and withdrawal of the offending agent may help limit the toxic effects associated with the drug. The decision to discontinue a potentially vital drug often presents a dilemma.

Pathophysiology

Drug eruptions may be divided into immunologically and nonimmunologically mediated reactions.

Immunologically mediated reactions

Coombs and Gell proposed 4 types of immunologically mediated reactions, as follows:

• Type I is immunoglobulin E (IgE)–dependent reactions, which result in urticaria, angioedema, and anaphylaxis (see the image below).Urticaria.
• Type II is cytotoxic reactions, which result in hemolysis and purpura (see the image below).Oral ulcerations in a patient receiving cytotoxic therapy.
• Type III is immune complex reactions, which result in vasculitis, serum sickness, and urticaria.
• Type IV is delayed-type reactions with cell-mediated hypersensitivity, which result in contact dermatitis, exanthematous reactions, and photoallergic reactions.

Th17 T cells are implicated in many drug eruptions, and sulfamethoxazole induces a T-cell switch mechanism based on the TCRVβ20-1 domain altering peptide-HLA recognition. In severe drug reactions, micro RNA-18a-5p down-regulates the expression of the antiapoptotic B-cell lymphoma/leukemia-2–like protein 10 (BCL2L10), promoting apoptosis.

Insulin and other proteins are associated with type I reactions. Penicillin, cephalosporins, sulfonamides, and rifampin are known to cause type II reactions. Quinine, salicylates, chlorpromazine, and sulfonamides can cause type III reactions. Type IV reactions, the most common mechanism of drug eruptions, are often encountered in cases of contact hypersensitivity to topical medications, such as neomycin. Sulfonamides are most frequently associated with toxic epidermal necrolysis (TEN).

Although most drug eruptions are type IV hypersensitivity reactions, only a minority are IgE-dependent. That is, antibodies can be demonstrated in less than 5% of cutaneous drug reactions. Type IV cell-mediated reactions are not dose dependent, they usually begin 7-20 days after the medication is started, they may involve blood or tissue eosinophilia, and they may recur if drugs chemically related to the causative agent are administered.

Nonimmunologically mediated reactions

Nonimmunologically mediated reactions may be classified according to the following features: accumulation, adverse effects, direct release of mast cell mediators, idiosyncratic reactions, intolerance, Jarisch-Herxheimer phenomenon, overdosage, or phototoxic dermatitis. (Symptoms of Jarisch-Herxheimer reactions disappear with continued therapy. Drug therapy should be continued until the infection is fully eradicated.)

An example of accumulation is argyria (blue-gray discoloration of skin and nails) observed with use of silver nitrate nasal sprays.

Adverse effects are normal but unwanted effects of a drug. For example, antimetabolite chemotherapeutic agents, such as cyclophosphamide, are associated with hair loss.

The direct release of mast cell mediators is a dose-dependent phenomenon that does not involve antibodies. For example, aspirin and other NSAIDs cause a shift in leukotriene production, which triggers the release of histamine and other mast-cell mediators. Radiographic contrast material, alcohol, cytokines, opiates, cimetidine, quinine, hydralazine, atropine, vancomycin, and tubocurarine also may cause release of mast-cell mediators.

Idiosyncratic reactions are unpredictable and not explained by the pharmacologic properties of the drug. An example is the individual with infectious mononucleosis who develops a rash when given ampicillin.

Imbalance of endogenous flora may occur when antimicrobial agents preferentially suppress the growth of one species of microbe, allowing other species to grow vigorously. For example, candidiasis frequently occurs with antibiotic therapy.

Intolerance may occur in patients with altered metabolism. For example, individuals who are slow acetylators of the enzyme N -acetyltransferase are more likely than others to develop drug-induced lupus in response to procainamide.

Jarisch-Herxheimer phenomenon is a reaction due to bacterial endotoxins and microbial antigens that are liberated by the destruction of microorganisms. The reaction is characterized by fever, tender lymphadenopathy, arthralgias, transient macular or urticarial eruptions, and exacerbation of preexisting cutaneous lesions. The reaction is not an indication to stop treatment because symptoms resolve with continued therapy. This reaction can be seen with penicillin therapy for syphilis, griseofulvin or ketoconazole therapy for dermatophyte infections, and diethylcarbamazine therapy for oncocerciasis.

Overdosage is an exaggerated response to an increased amount of a medication. For example, increased doses of anticoagulants may result in purpura.

Phototoxic dermatitis is an exaggerated sunburn response caused by the formation of toxic photoproducts, such as free radicals or reactive oxygen species (see the image below).

Phototoxic reaction after use of a tanning booth. Note sharp cutoff where clothing blocked exposure.

Frequency

United States

Drug eruptions occur in approximately 2-5% of inpatients and in greater than 1% of outpatients.

International

Drug eruptions occur in approximately 2-3% of inpatients.

Mortality/Morbidity

Most drug eruptions are mild, self-limited, and usually resolve after the offending agent has been discontinued. Severe and potentially life-threatening eruptions occur in approximately 1 in 1000 hospital patients. Mortality rates for erythema multiforme (EM) major are significantly higher. Stevens-Johnson syndrome (SJS) has a mortality rate of less than 5%, whereas the rate for TEN approaches 20-30%; most patients die from sepsis.

Sex

Adverse cutaneous reactions to drugs are more prevalent in women than in men.

Age

Elderly patients have an increased prevalence of adverse drug reactions