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What we know about nonsteroidal anti-inflammatory drug hypersensitivity.

ABSTRACT: Nonsteroidal anti-inf lammatory drugs (NSAIDs) are widely prescribed for the treatment of inflammatory diseases, but their use is frequently related to hypersensitivity reactions. This review outlines our current knowledge of NSAID hypersensitivity (NHS) with regard to its pathogenic, molecular, and genetic mechanisms, as well as diagnosis and treatment. The presentation of NHS varies from a local (skin and/or airways) reaction to systemic reactions, including anaphylaxis. At the molecular level, NHS reactions can be classified as cross-reactive (mediated by cyclooxygenase inhibition) or selective (specific activation of immunoglobulin E antibodies or T cells). Genetic polymorphisms and epigenetic factors have been shown to be closely associated with NHS, and may be useful as predictive markers. To diagnose NHS, inhalation or oral challenge tests are applied, with the exclusion of any cross-reactive NSAIDs. For patients diagnosed with NHS, absolute avoidance of NSAIDs/aspirin is essential, and pharmacological treatment, including biologics, is often used to control their respiratory and cutaneous symptoms. Finally, desensitization is recommended only for selected patients with NHS. However, further research is required to develop new diagnostic methods and more effective treatments against NHS.

SUBMITTER: Pham DL

PROVIDER: S-EPMC4855107 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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What we know about nonsteroidal anti-inflammatory drug hypersensitivity.

Pham Duy Le DL Kim Ji-Hye JH Trinh Tu Hoang Kim TH Park Hae-Sim HS

The Korean journal of internal medicine 20160331 3

Nonsteroidal anti-inf lammatory drugs (NSAIDs) are widely prescribed for the treatment of inflammatory diseases, but their use is frequently related to hypersensitivity reactions. This review outlines our current knowledge of NSAID hypersensitivity (NHS) with regard to its pathogenic, molecular, and genetic mechanisms, as well as diagnosis and treatment. The presentation of NHS varies from a local (skin and/or airways) reaction to systemic reactions, including anaphylaxis. At the molecular level ...[more]

PMID: 27030979

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Project description:BackgroundLipid transfer protein (LTP), an abundant protein in fruits, vegetables, and nuts, is a common food allergen in Mediterranean areas causing diverse allergic reactions. Approximately 40% of food-related anaphylaxis induced by LTPs requires nonsteroidal anti-inflammatory drugs (NSAIDs) as a triggering cofactor.ObjectiveWe sought to better understand the determinants of NSAID-dependent and NSAID-independent LTP-induced anaphylaxis (LTP-A).MethodsSelection of patients was based on a proved clinical history of NSAID-dependent or NSAID-independent anaphylaxis to LTPs, positive skin prick test response to LTPs, and serum LTP IgE. Whole-transcriptome (RNA sequencing) analysis of blood cells from 14 patients with NSAID-related LTP-A (NSAID-LTP-A), 7 patients with LTP-A, and 13 healthy control subjects was performed to identify distinct gene expression signatures.ResultsExpression of genes regulating gastrointestinal epithelial renewal was altered in both patient sets, particularly in those with LTP-A, who also presented with gene expression profiles characteristic of an inflammatory syndrome. These included altered B-cell pathways, increased neutrophil activation markers, and increased reactive oxygen species levels. Increased expression of the IgG receptor (CD64) in patients with LTP-A was mirrored by the presence of LTP-specific IgG1 and IgG3. Conversely, patients with NSAID-LTP-A were characterized by reduced expression of IFN-γ-regulated genes and IFN-γ levels, as well as upregulated expression of adenosine receptor 3 (ADORA3) and genes related to adenosine metabolism.ConclusionsGene ontology analysis suggests disturbances in gut epithelial homeostasis in both groups with LTP-A, with potential integrity breaches in patients with LTP-A that might explain their distinct inflammatory signatures. Differential regulation in patients with LTP-A and those with NSAID-LTP-A of the IFN-γ pathway, IgG receptors, and ADORA3 might provide the pathogenic basis of their distinct responses.

Project description:Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most highly consumed drugs worldwide and the main triggers of drug hypersensitivity reactions. The most frequent reaction, named cross-reactive NSAID-hypersensitivity, is due to the pharmacological activity of these drugs by blocking the cyclooxygenase-1 enzyme. Such inhibition leads to cysteinyl-leukotriene synthesis, mainly LTE4, which are responsible for the reaction. Although the complete molecular picture of the underlying mechanisms remains elusive, the participation of platelet-adherent leukocytes (CD61+) and integrins have been described for NSAID-exacerbated respiratory disease (NERD). However, there is a lack of information concerning NSAID-induced urticaria/angioedema (NIUA), by far the most frequent clinical phenotype. Here we have evaluated the potential role of CD61+ leukocytes and integrins (CD18, CD11a, CD11b, and CD11c) in patients with NIUA, and included the other two phenotypes with cutaneous involvement, NSAID-exacerbated cutaneous disease (NECD) and blended reactions (simultaneous skin and airways involvement). A group NSAID-tolerant individuals was also included. During the acute phase of the reaction, the three clinical phenotypes showed increased frequencies of CD61+ neutrophils, eosinophils, and monocytes compared to controls, which correlated with urinary LTE4 levels. However, no correlation was found between these variables at basal state. Furthermore, increased expressions of CD18 and CD11a were found in the three CD61+ leukocytes subsets in NIUA, NECD and blended reactions during the acute phase when compared with CD61-leukocyte subpopulations. During the acute phase, CD61+ neutrophils, eosinophils and monocytes showed increased CD18 and CD11a expression when compared with CD61+ leukocytes at basal state. No differences were found when comparing controls and CD61+ leukocytes at basal state. Our results support the participation of platelet-adherent leukocytes and integrins in cutaneous cross-hypersensitivity to NSAIDs and provide a link between these cells and arachidonic acid metabolism. Our findings also suggest that these reactions do not involve a systemic imbalance in the frequency of CD61+ cells/integrin expression or levels of LTE4, which represents a substantial difference to NERD. Although further studies are needed, our results shed light on the molecular basis of cutaneous cross-reactive NSAID-hypersensitivity, providing potential targets for therapy through the inhibition of platelet-leukocyte interactions.

Dataset Information

What we know about nonsteroidal anti-inflammatory drug hypersensitivity.

Publications

What we know about nonsteroidal anti-inflammatory drug hypersensitivity.

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