DISCUSSION
NSAIDs, especially ibuprofen and other APs, are among the most widely used drugs in clinical practise for treating pain and different inflammatory conditions [1]. They are often available over the counter, and patients may obtain them without any medical supervision, which contributes to their high consumption. Thus, 57.8% of the Danish [25] and 43.6% of the French [26] general populations claimed at least one prescription for NSAIDs during the period 1997-2005 and 2009-2010, respectively; and 16.9% of children were exposed to at least one NSAID according to a population-based European study [27]. In addition, their consumption has been increasing over recent years. For example, in Spain the NSAID consumption has increased 26.5% from 2000 to 2012, mainly due to ibuprofen, whose use has multiplied by 4 over this period of time [17]. This high consumption may contribute to NSAIDs, especially ibuprofen and other APs, being the main triggers of DHRs [1, 2].
The most frequent type of DHR induced by APs is CR, as it has been described in general with NSAIDs [4, 5, 11]. Similarly, the most common clinical entity observed was NIUA, as other previous reports dealing with NSAIDs had described [4, 5, 11, 28, 29]. However, although all APs could potentially induce all types of reactions and clinical entities, analysing the APs involved in the reported reaction, we found that ibuprofen and dexketoprofen induced most frequently NIUA, whereas naproxen induced most commonly SNIUAA, and ketoprofen induced SNIDR. Nevertheless, the symptoms experienced by patients were most commonly isolated angioedema and urticaria in both NIUA and SNIUAA. It is not known the reason why different APs molecules induce similar clinical symptoms although the reactions are suspected to be mediated by different mechanisms: COX-1 inhibition related mechanism for NIUA and specific IgE mediated mechanism for SNIUAA [3, 11]. Atopy has been associated with CR induced by NSAIDs [4, 6, 11, 30], however, in our study no differences were found in the percentage of atopic patients in NIUA and SNIUAA induced by APs. A reason why naproxen induces more frequently SNIUAA could be the immunogenic potency of the naproxen molecule. In fact, analysing the cases in which the diagnosis was not confirmed (data not shown), naproxen induced the highest percentage of anaphylaxis compared with the others APs, thus the percentage of SNIUAA induced by naproxen may be higher than what we found. Moreover, ketoprofen has been implicated in SNIDR more frequently than other APs. It is known that ketoprofen is the main NSAID involved in contact dermatitis and this reaction seems to be reported more commonly with topical formulations, which may be due to the higher concentrations of the drug in the skin [31]. This reaction could be due to its chemical structure [31], however, like with others APs, the molecular basis of ketoprofen-induced DHR remains to be fully elucidated. Therefore, more studies are needed in other to achieve a better knowledge of the underlying mechanisms in DHRs induced by APs, which will also influence in a better diagnosis approach.
The most important issue in the diagnosis of DHRs to NSAIDs is the differentiation between CRs and SRs, as in the first group patients must avoid all NSAIDs while in the latter patients must avoid only the culprit. A diagnosis of CRs, whether confirmed or not, implies a great impact on the patient quality of life as therapeutic alternatives are highly reduced, especially in children [3]. Another relevant matter regarding diagnosis is that nowadays skin tests and in vitro tests are not available for all NSAIDs, including APs, being the gold standard DPT, a costly and risky procedure [9-11, 13, 14]. NPT-LASA is a faster and safer method than oral DPT that has demonstrated to be useful in the diagnosis of DHRs induced by NSAIDs when airways are involved [8, 12, 14]. In our study, we also found this technic useful in both NERD and blended cases induced by APs, allowing confirming the 77% and 68% of cases, respectively. This means that in a high percentage of cases we could avoid an oral DPT. However, when NPT-LASA are negative and when skin is the only organ involved, DPT is the only method available to achieve the diagnosis, and it is not always performed due the risks and costs. This implies that a considerable percentage of patients with an unconfirmed diagnosis, who could be SR or even non-allergic, are recommended to avoid NSAIDs, which reduces highly the therapeutic alternatives.
Summarising, APs are the most frequently NSAIDs involved in DHRs to NSAIDs, probably related to their high consumption. Skin is the most common organ involved in DHRs induced by APs, in both CR and SR, with ibuprofen and dexketoprofen inducing most frequently CR, and naproxen and ketoprofen inducing SR. More studies are needed to clarify the underlying mechanism in DHR induced by APs.
Table 1 . Demographic and clinical characteristics of the patients included in the study. CR: Cross-reactive type hypersensitivity. NA Not applicable. SR: Selective reaction.