Immunologic and Pharmacogenomic Studies of Non-Steroidal Anti-Inflammatory Drug (NSAID) Hypersensitivity

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are a class of drugs that provides analgesic, antipyretic and anti-inflammatory effects that are commonly used for many clinical indications, such as osteoarthritis, rheumatoid arthritis, low back pain, headache, acute gout and fever. Although NSAIDs are commonly used in clinical practice, they are responsible for 21–25% of reported adverse drug events and NSAIDs hypersensitivity may affect 0.6%~5.7% of the general populations. In Taiwan, diclofenac, ketorolac, aspirin (drugs belonging to NSAIDs) were ranked on the top 1 to 4 commonly reported drugs in the ADR reporting system of Taiwan (2013). Most NSAIDs-induced hypersensitivity reactions are immediate type that are in a spectrum of severity, varying from urticaria, angioedema to respiratory symptoms, such as dyspnea, wheezing, bronchospasm, to life-threatening anaphylaxis. Currently, there is no preventive method for NSAIDs hypersensitivity and identification of causative agents for patients with multiple NSAIDs hypersensitivity or predict alternative tolerable NSAIDs for patients with ambiguous history of NSAIDs hypersensitivity are challenging in clinical practice. The unpredictability of NSAIDs hypersensitivity does not only hinder the treatment on patients, but is also life-threatening. The pathogenesis of NSAIDs hypersensitivity is not well known. There are two types of mechanisms: (1) immediate type (type 1): through IgE or non-IgE mediated activation of basophils/mast cells, and leukotrienes release pathway (2) delayed type (type 4): through T-cell-mediated reactions. For NSAIDs-induced type 1 reactions, there are 2 proposed hypotheses (A) pharmacological mechanism (pseudoallergy) which activation of lipooxygenase pathway due to Cox-1 inhibition is involved (B) IgE mediated activation of basophils/mast cells. In this 3-year proposal, I propose to investigate immunologic mechanism and genetic susceptibility to NSAIDs hypersensitivity that can improve clinical diagnosis and prevention of NSAIDs-induced hypersensitivity reactions. The specific aims are: (1). To establish a database of clinical information and a biomaterial repository for patients with NSAIDs induced hypersensitivity reactions and tolerant controls. The clinical phenotypes of hypersensitivity reactions include immediate type/type1 (urticaria, angioedema to bronchospasm and anaphylaxis) and delayed type/type4 (fixed drug eruption and Steven-Johnson syndrome or toxic epidermal necrolysis). (2).To investigate whether specific immune responses of basophils are involved in NSAIDs-induced type 1 hypersensitivity reactions and identify specific immune molecules as useful markers for in vitro test for patients with type 1 NSAIDs hypersensitivity . (3). To investigate the specific B cell and IgE involved in the pathogenesis of NSAIDs-induced type 1 hypersensitivity reactions and identify which type of BCR repertoire is involved (4) To investigate genetic susceptibility to NSAIDs-induced hypersensitivity reactions (type 1 and type 4). We anticipate that this project will improve our understanding of NSAIDs hypersensitivity, translate the immunologic and genetic determinants to clinical tests. In a broader view, this project will reduce the incidence and prevent NSIADs hypersensitivity, and drive the optimum drug selection for NSAIDs therapy.

Project ID:PC10408-2637
External Project ID:MOST104-2314-B182-040-MY3