Continuing Education Activity

Cutaneous adverse drug reactions (CADR), also known as toxidermia, are skin manifestations resulting from systemic drug administration. These reactions range from mild erythematous skin lesions to much more severe reactions such as Lyell's syndrome. They represent a heterogeneous field, including various clinical patterns without specific features suggesting drug causality. This activity describes the evaluation and management of cutaneous adverse drug reactions and explains the role of the interprofessional team in managing patients with this condition.

Objectives:

• Describe the range of skin manifestations of cutaneous adverse drug reactions.
• Explain the pathophysiology of cutaneous adverse drug reactions.
• Outline the most common causes of a cutaneous adverse drug reaction.
• Review the importance of the interprofessional team working together to find the underlying explanation for a cutaneous adverse drug reaction to improve outcomes.

Introduction

Cutaneous adverse drug reactions (CADR), also known as toxidermia, are skin manifestations resulting from systemic drug administration. These reactions range from mild erythematous skin lesions to much more severe reactions such as Lyell's syndrome. They represent a heterogeneous field, including various clinical patterns without specific features suggesting drug causality. It is essential to search for the causative agent.[1][2]

Issues of Concern

Most systemic drugs are potential causes of cutaneous adverse reactions. Contrast media and certain drug classes are known to be common offenders, such as antibiotics, anticonvulsants, antineoplastic drugs, nonsteroidal anti-inflammatory drugs, and allopurinol. Antibiotics and anti-epileptics develop toxidermia complications in 1% to 5% of treatments.[3][4]

There are multiple mechanisms that account for the variability in drug reactions. They can be classified into two general categories: immunologic and nonimmunologic.[5] Most (75%-80%) adverse drug reactions are secondary to predictable, non-immunologic effects, while the residual (20%-25%) adverse reactions are caused by unpredictable effects, some of which may be immune-mediated.[6] Only 5%-10% of all adverse drug reactions are immune-mediated.[7] Immune-mediated reactions most commonly consist of either immediate or delayed immunologic mechanisms, mediated by cellular or humoral immune responses.

It is often necessary to test for potential allergens to further classify drug reaction etiology. The most common testing methods include epicutaneous patch testing, prick testing, and intradermal testing. In vivo or in vitro tests are unable to confirm the drug causality. To determine the cause of a drug eruption clinically, a logical approach based on clinical characteristics, chronologic factors, and generation of a focused differential diagnosis is required. It is essential to report serious suspected CADR to a pharmacovigilance network if the involved drug is a newly marketed medication or unusually related to cutaneous reactions.[8]

Cutaneous adverse drug reactions are a common public health problem. They affect about 10% of hospitalized patients and occur in 1% to 3% of multi-medicated patients.

Severe reactions (fatal outcomes, severe sequelae), including bullous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis-also known as Lyell syndrome), acute generalized exanthematous pustulosis (AGEP), and drug reactions with eosinophilia and systemic symptoms (DRESS), represent 2% of CADR.[9][10] These reactions must be quickly identified in order to guide management and decrease mortality.

Clinical Significance

There are several types of toxidermia that are distinguished secondary to their unique clinical presentations.[11][12][13]

Exanthematous eruptions, also described as morbilliform or ery­thematous maculopapular eruptions, are the most common type of drug reaction, accounting for approximately 40% of all reactions. The rash develops one day to three weeks after the offending drug is first given, although the timing can differ if previously sensitized. The eruptions appear clinically as polymorphic maculopapular lesions with no mucosal involvement, resembling a viral exanthem. Lesions usually appear first on the trunk or in areas of pressure or trauma. They spread to involve the extremities, usually in a symmetrical distribution. The most frequent drug offenders include antibiotics (beta-lactams, sulfonamides), nonsteroidal anti-inflammatory drugs (NSAIDs), antiepileptics (carbamazepine, hydantoins), and allopurinol.

Urticarial toxidermia, also known as "urticaria and Quincke's edema", typically presents in two distinct ways. Immediate urticaria occurs very rapidly after the start of treatment within 1 or 2 hours. Immediate reactions require discontinuation of the drug due to the potential for the development of anaphylaxis. Delayed urticaria usually occurs several days after the administration of the medication. Since the delayed urticaria is linked to the pharmacological properties of the medicinal product, the continuation of its use is not contraindicated.

Fixed pigmented erythema (FPE), also known as a fixed drug eruption, occurs 24 hours to a few days after administration of the offending medication. The classic form is characterized by a single or multiple round to oval-shaped, red to brown macules. These lesions have the potential to evolve into plaques with vesicles or blistering.

Toxic epidermal necrolysis (TEN), also known as Lyell syndrome, in addition to Stevens-Johnson syndrome (SJS), are the most serious toxidermia manifestations, accounting for a 25% mortality rate. There is a continuum between SJS and TEN, which are differentiated by the amount of skin involvement (<10% in SJS,> 30% in NET, 10% to 30% in SJS-TEN overlap syndrome). Symptoms appear 21 days after initiation of the causative medication. From the rash onset, the progression of skin lesions takes anywhere from a few hours to a few days. The skin lesions typically consist of a dark red or purpuric macular rash with pseudo-cockades conflated into a detachment dermis made of large shreds exposing the oozing dermis. The eruption often starts on the face and then gradually spreads symmetrically to the rest of the body. A specific indicator of SJS or TEN is the presence of a positive Nikolsky sign, which manifests clinically as detachment of the epidermis from the underlying dermis by a shearing force. Another indicator of SJS or TEN is the presence of painful erosions of mucous membranes affecting at least two anatomic locations (conjunctiva, nose, mouth, anal or genital area). The patient's general state of health is seriously altered by high fever, rapid dehydration, and the superinfection of skin lesions. Respiratory deterioration with tachypnea and hypoxia can be a sign of underlying necrosis of the bronchial tree, which correlates with a poor clinical prognosis.

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome, is characterized by a late-onset skin eruption 2 to 6 weeks after initiation of the medication. The eruption is nonspecific, typically manifesting as a pruritic maculopapular exanthem or a febrile erythroderma. 30% of cases are associated with an infiltrated facial edema. Rarely, small pustules, purpura, or erythema multiforme lesions can appear. DRESS is distinguished from other drug eruptions by its association with voluminous adenopathies in several lymph nodes and visceral involvement. Common organ involvement includes the liver (hepatitis), kidney (interstitial nephritis), lungs, heart, and pancreas. The clinical picture of DRESS is supplemented by eosinophilia (> 1500 PNN / mm3) and a mononucleosis-like syndrome. DRESS visceral sequela can persist for several weeks and can present after the onset of the skin eruption. In addition, eosinophilia may be lacking during the initial phase of the disease. The exact pathogenesis is unknown. Patients suffering from severe cutaneous manifestations from DRESS should be hospitalized and undergo extensive clinical follow-up after hospitalization.

Acute generalized exanthematous pustulosis (AGEP) is a scarlatiniform erythematous rash with semi-small pustules, predominantly in the large pleats (axillary folds, inguinal folds). The pustules can coalesce and subsequently lead to superficial cutaneous desquamation. Mucosal involvement is possible but limited. It is generally triggered by antibiotics, most commonly aminopenicillins and macrolides. This eruption typically begins with an abrupt onset, appearing within 24 hours to 4 days after initiation of medication. The most common symptoms are burning and pruritus. The eruption generally regresses in ten days. AGEP diagnosis is established based on history, clinical manifestations, and laboratory findings. Generalized pustular psoriasis is similar appearing dermatologic pathology that should be differentiated from AGEP. Patients with generalized pustular psoriasis often have a history of psoriasis, and these lesions clinically do not evolve as much. In addition, the two pathologies possess contrasting histological findings. The diagnosis of AGEP is important secondary to its potential severe prognosis and 5% mortality rate.

Other Issues

The first approach to a CADR is to initiate the withdrawal of medication. This approach can be used if the offending medication can be replaced with another drug, or if the skin reaction is severe enough to require the rapid cessation of suspect drugs (evaluation of the risk/benefit ratio).

The search for bibliographic information and the pharmacovigilance statement is essential.

Treatment of CADR is mainly symptomatic consisting of topical corticosteroids and oral antihistaminics. Oral corticosteroids (0.5 to 1 mg/kg/day of prednisone) are frequently used, but no evidence of their efficacy has been reported. Severe toxidermia may occur with a systemic corticosteroid. 

Hospitalization is indicated when there are certain signs of severity:

• Cutaneous: Skin surface > 60%, erythema confluence, facial edema, skin pain, palpable purpura, skin necrosis, bullae or epidermal detachment, positive Nikolski sign, mucosal erosions, urticaria, and/or tongue edema
• General: High fever, lymphadenopathy, arthralgia or arthritis, expiratory dyspnea, hypotension
• Biological: Eosinophilia greater than 1000 / mm3, lymphocytosis with atypical lymphocytes, liver function abnormalities

Enhancing Healthcare Team Outcomes

Each year thousands of people develop adverse drug reactions (ADR), with a minority resulting in fatalities. Skin reactions are the most common type of ADR and can be diagnostically challenging. Healthcare workers, including nurses and pharmacists, must be vigilant about ADR as they can present at any time in any patient and have a wide range of presentations. The skin reactions can confound even the most experienced specialist. Polypharmacy, or the use of multiple medications, can make the determination of the offending agent even more difficult. Furthermore, there are genetic variations linked to skin reactions, usually related to anti-epileptic medications. It is important for healthcare workers to understand that FDA approval does not ensure safety in each and every patient. During the FDA approval process, the drug is usually studied in a small number of people for a short time, and hence, many side effects can be missed. These trials do not always determine the rare side effects of drugs, and often the ADRs are picked up during post-marketing surveillance. Drugs can be FDA approved and enter the market after phase 3 of clinical trials, which is typically before long-term effects are well-documented. Thus, it is essential for the team of healthcare workers to be vigilant about ADR and monitor patients closely.[14][15]