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.