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.