Abstract
Cross-hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is a relatively common, non-allergic, adverse drug event triggered by two or more chemically unrelated NSAIDs. Current evidence point to COX-1 inhibition as one of the main factors in its etiopathogenesis. Evidence also suggests that the risk is dose-dependent. Therefore it could be speculated that individuals with impaired NSAID biodisposition might be at increased risk of developing cross-hypersensitivity to NSAIDs. We analyzed common functional gene variants for CYP2C8, CYP2C9, and CYP2C19 in a large cohort composed of 499 patients with cross-hypersensitivity to NSAIDs and 624 healthy individuals who tolerated NSAIDs. Patients were analyzed as a whole group and subdivided in three groups according to the main enzymes involved in the metabolism of the culprit drugs as follows: CYP2C9, aceclofenac, indomethacin, naproxen, piroxicam, meloxicam, lornoxicam, and celecoxib; CYP2C8 plus CYP2C9, ibuprofen and diclofenac; CYP2C19 plus CYP2C9, metamizole. Genotype calls ranged from 94 to 99%. No statistically significant differences between patients and controls were identified in this study, either for allele frequencies, diplotypes, or inferred phenotypes. After patient stratification according to the enzymes involved in the metabolism of the culprit drugs, or according to the clinical presentation of the hypersensitivity reaction, we identified weak significant associations of a lower frequency (as compared to that of control subjects) of CYP2C8*3/*3 genotypes in patients receiving NSAIDs that are predominantly CYP2C9 substrates, and in patients with NSAIDs-exacerbated cutaneous disease. However, these associations lost significance after False Discovery Rate correction for multiple comparisons. Taking together these findings and the statistical power of this cohort, we conclude that there is no evidence of a major implication of the major functional CYP2C polymorphisms analyzed in this study and the risk of developing cross-hypersensitivity to NSAIDs. This argues against the hypothesis of a dose-dependent COX-1 inhibition as the main underlying mechanism for this adverse drug event and suggests that pre-emptive genotyping aiming at drug selection should have a low practical utility for cross-hypersensitivity to NSAIDs.
Highlights
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used to relieve pain and to decrease inflammation and fever
The role of COX-1 inhibition in the etiopathogenesis of crosshypersensitivity to NSAIDs has been the object of controversy for years (Kowalski et al, 2007; Doña et al, 2018; Mastalerz et al, 2019)
Supporting this hypothesis, it has been shown that COX-2 inhibitors are well tolerated among patients with crosshypersensitivity to NSAIDs (Morales et al, 2014; Bakhriansyah et al, 2019) and that patients with PTGS1 gene variants related to a decreased activity (Agúndez et al, 2014; Agúndez et al, 2015b; Lucena et al, 2019) are at increased risk of developing crosshypersensitivity to NSAIDs (García-Martín et al, 2021)
Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used to relieve pain and to decrease inflammation and fever. Prescription NSAIDs are effective to relieve chronic musculoskeletal pain and inflammation, and OTC NSAIDs, normally at lower doses, are effective to relieve acute or minor aches and pains. These drugs are quite safe, but despite being available OTC in many countries, they could bring about adverse drug reactions (ADRs). One specific type of ADRs, hypersensitivity drug reactions (HDRs) can be divided into two main groups: on one side those which are initiated by specific immunological mechanisms ( described as drug allergy), the response is induced by a single drug, and patients are classified as selective drug responders. HDRs whose mechanisms are nonimmunological ( described as nonallergic hypersensitivity), the reaction is induced by two or more chemically unrelated drugs, and patients are classified as cross-intolerant or cross-hypersensitivity subjects (Johansson et al, 2004; Szczeklik et al, 2009; Doña et al, 2011)
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