INTRODUCTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs in clinical practise worldwide [1]. This may contribute to them being the main triggers of drug hypersensitivity reactions (DHRs) [2].
The latest classification of NSAID-hypersensitivity proposed by the European Academy of Allergy and Clinical Immunology (EAACI) differentiates between cross-reactive type hypersensitivity (CRs) and selective reactions (SRs) [3]. The first one is the most frequent (up to 75%) in all age groups [4, 5], with patients reacting to NSAIDs from different chemical groups without specific immunological recognition, and which have been linked to COX-1 inhibition in susceptible individuals. In SRs, patients react to one or more NSAIDs from the same chemical group through a specific immune mechanism (IgE or T cell mediated) while tolerating other non-chemically related NSAIDs [3].
CRs to NSAIDs induce at least three clinical entities [3]: a) NSAIDs-exacerbated respiratory disease (NERD), in patients with underlying rhinitis and/or asthma with or without nasal polyposis; b) NSAIDs-exacerbated cutaneous disease (NECD), in patients with underlying chronic spontaneous urticaria (CSU); and c) NSAIDs-induced urticaria/angiodema (NIUA), in otherwise healthy individuals, being the most frequent clinical entity and also the most frequently induced by hypersensitivity to drugs [2]. SRs include: single-NSAID-induced urticaria/angioedema and anaphylaxis (SNIUAA), in which the reaction appears within seconds to the first hour after taking the NSAID; and single-NSAID-induced delayed reactions (SNIDRs), in which patients develop a reaction from 24 hours to days or weeks after the intake of a NSAID [3].
However, this classification does not take into consideration some entities that are frequently observed in clinical practice. One of them is blended reactions, with simultaneous cutaneous and respiratory manifestations [4, 6-8], which account for more than 25% of the total DHRs to NSAIDs [8]. They are probably not identified as such and classified as NERD or NIUA, or they may be even confused with anaphylactic (IgE-mediated) reactions. These facts have important consequences for the patient, as all NSAIDs may be avoided and other therapeutic alternatives used unnecessarily.
The diagnosis approach of DHRs to NSAIDs is complex as there are no useful in vitro methods and skin tests are only applicable for pyrazolones. Therefore, diagnosis usually relies on a compatible clinical history and, in many cases, also on drug provocation test (DPT) with the culprit NSAID, a test that represents a risk for the patient and a considerable consumption of resources [3, 4, 9]. Recently, some progress has been made regarding the management of DHRs to NSAIDs, highlighting the role of the nasal provocation test (NPT) with lysine acetylsalicylate (LASA) when airways are involved [4, 8, 10-14].
NSAIDs include a wide number of drugs with different chemical structures. Aryl-propionic derivatives (APs) are characterised by the presence of an asymmetrical carbon atom adjacent to a carboxylic acid and include a wide number of molecules: ibuprofen, loxoprofen, naproxen, ketoprofen, dexketoprofen, fenoprofen, flurbiprofen, indoprofen, tiaprofenic acid, and oxaprozin [15]. In Spain, only ibuprofen, flurbiprofen, naproxen, dexketoprofen, and ketoprofen are commercialised. Ibuprofen and other APs are among the most consumed NSAIDs worldwide [16]. In fact, in Spain they account for 65.1% of NSAID consumption [17]. However, despite their common consumption, the specific role of APs in DHRs to NSAIDs and the different clinical phenotypes they induce have not been defined. Therefore, our aim was to perform a detailed clinical characterisation of DHRs induced by ibuprofen and others APs through the analysis of the clinical history, the reported reactions, as well as the diagnostic approach used.