Reviews and feature article
Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug–related urticaria and angioedema

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Nonsteroidal anti-inflammatory drug (NSAID)–induced urticarial and angioedema reactions are among the most commonly encountered drug hypersensitivity reactions in clinical practice. Three major clinical phenotypes of NSAID-induced acute skin reactions manifesting with angioedema, urticaria, or both have been distinguished: NSAID-exacerbated cutaneous disease, nonsteroidal anti-inflammatory drug–induced urticaria/angioedema (NIUA), and single NSAID–induced urticaria and angioedema. In some patients clinical history alone might be sufficient to establish the diagnosis of a specific type of NSAID hypersensitivity, whereas in other cases oral provocation challenges are necessary to confirm the diagnosis. Moreover, classification of the type of cutaneous reaction is critical for proper management. For example, in patients with single NSAID–induced reactions, chemically nonrelated COX-1 inhibitors can be safely used. However, there is cross-reactivity between the NSAIDs in patients with NSAID–exacerbated cutaneous disease and NIUA, and thus only use of selective COX-2 inhibitors can replace the culprit drug if the chronic treatment is necessary, although aspirin desensitization will allow for chronic treatment with NSAIDs in some patients with NIUA. In this review we present a practical clinical approach to the patient with NSAID-induced urticaria and angioedema.

Section snippets

Classification of NSAID reactions

The current classification of NSAID hypersensitivity reactions is based on timing, the clinical pattern of symptoms, and the presence or absence of cross-reactivity to other NSAIDs.7, 8, 9 An additional criterion is the presence of underlying chronic disease of the skin or respiratory tract, which is typical for some (10 cross-reactive types) but not all (single drug–induced type) reactions (Table I).10

Using this classification system, a physician can assess the putative pathomechanism of a

NSAID-exacerbated cutaneous disease

Patients with chronic urticaria who experience hypersensitivity reactions to NSAIDs are now identified as having aspirin-exacerbated cutaneous disease or, more precisely, nonsteroidal anti-inflammatory drug–exacerbated cutaneous disease (NECD).8

NSAID-induced urticaria/angioedema

Aspirin and other NSAIDs can also induce urticaria, angioedema, or both in an otherwise healthy subject without a history of pre-existing chronic skin disease (eg, spontaneous urticaria).

Single NSAID–induced urticaria/angioedema, anaphylaxis, or both

Wheals, angioedema, and/or anaphylaxis induced by a single NSAID or by 2 or more NSAIDs with similar chemical structures (ie, belonging to the same chemical group; Table II) are typical for this type of NSAID hypersensitivity.48

Mixed reactions

Although the vast majority of NSAID-induced acute (within 24 hours) skin reactions can fall into one of the 3 phenotypes presented by the current classification, some patients can manifest atypical or blended reactions. Approximately 10% of patients with NECD will have respiratory symptoms (bronchoconstriction) resembling the reactions observed in patients with NSAID-exacerbated respiratory disease.59 In a study by Doña et al,33 who reviewed 384 patients with NSAID-induced skin reactions,

Diagnostic algorithm

Diagnosis of a specific type of hypersensitivity is a prerequisite for proper management of a patient with a history of NSAID hypersensitivity. Based on the current classification, a practical diagnostic algorithm to determine the type of NSAID hypersensitivity has been proposed8, 61 and can be easily adapted when hypersensitivity is manifested with cutaneous symptoms (urticaria/angioedema, Fig 2). Although a detailed analysis of the patient's history might be sufficient to establish the

Management

Once the diagnosis of NSAID hypersensitivity has been established, the mainstay of treatment is avoidance of NSAIDs.7, 65 However, recommendations for management and alternative NSAIDs have to be tailored to a specific type of NSAID hypersensitivity (Table III).66

Conclusions and suggestions for future work

In susceptible subjects urticaria, angioedema, or both develop after NSAID intake, usually within hours (rarely within minutes). Physicians can follow a simple algorithm based on current classification, leading to diagnosis of the type of NSAID hypersensitivity. Identification of the specific type of hypersensitivity allows for identification of the proper management options. However, because the history of NSAID hypersensitivity is not very specific, in many instances an oral challenge test

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    Disclosure of potential conflict of interest: K. Woessner has consultant arrangements with and has received payments for lectures from Merck, TEVA, Shire, Meda, and AstraZeneca. The rest of the authors declare that they have no relevant conflicts of interest.

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