ABSTRACT
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequent agents involved in hypersensitivity drug reactions, with NSAID-induced urticaria and/or angioedema (NIUA) being the most common entity. Mast cells are key players in NIUA and are activated by thymic stromal lymphopoietin (TSLP). This cytokine functions through recognition by its receptor, composed of IL7Rα (interleukin-7 receptor alpha) and TSLPR (TSLP receptor). These genes have been previously associated with other inflammatory diseases. METHODS: We assessed the genetic association between single nucleotide polymorphisms (SNPs) in TSLP, IL7R and TSLPR and NIUA in Spanish individuals, using genotyped and imputed data. A total of 369 unrelated NIUA patients and 580 NSAID-tolerant control subjects were included, and 6 SNPs in TSLP, 6 in IL7R and 3 in TSLPR were genotyped. Further variants were imputed using Mach and the 1,000 Genomes Project (Phase 3) data. Association testing and statistical analyses were performed with Mach2dat and R. RESULTS: A total of 139 SNPs were tested for association following quality control. Two SNPs in TSLP (rs1816678 and rs764917) showed a nominal association (p = 0.033 and 0.024, respectively) with NIUA, although these results were not statistically significant after correcting for multiple comparisons. CONCLUSIONS: Although TSLP, IL7R and TSLPR are important genes involved in the development of the inflammatory response, we found no significant genetic association with NIUA in our population for common SNPs in these genes.
Subject(s)
Angioedema/diagnosis , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Cytokines/genetics , Drug Hypersensitivity/diagnosis , Drug Hypersensitivity/etiology , Genetic Variation , Urticaria/diagnosis , Adult , Alleles , Case-Control Studies , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Odds Ratio , Polymorphism, Single Nucleotide , Young Adult , Thymic Stromal LymphopoietinABSTRACT
PURPOSE OF REVIEW: Selective immediate reactions to NSAIDs imply that patients develop a urticarial/anaphylactic response to a single drug with good tolerance to other compounds. No systematic review of these reactions has yet been made. RECENT FINDINGS: With the increase in consumption of NSAIDs, these have become one of the most common drugs inducing hypersensitivity reactions. Although cross-intolerance reactions are the most common, a significant proportion is selective responses. As specific IgE antibodies are not always found, there is only indirect evidence supporting an IgE-mediated mechanism in selective NSAID reactors. SUMMARY: Selective immediate reactions to NSAIDs must be considered when a patient develops urticaria or anaphylaxis after intake of one drug with good tolerance to drugs from other groups or even a drug from the same group with a slightly different chemical structure. Further research is required to identify the antigenic determinant structures recognized.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Drug Hypersensitivity/immunology , Hypersensitivity, Immediate/immunology , Models, Chemical , Anaphylaxis , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Drug Hypersensitivity/diagnosis , Drug Hypersensitivity/epidemiology , Drug Hypersensitivity/physiopathology , Humans , Hypersensitivity, Immediate/diagnosis , Hypersensitivity, Immediate/epidemiology , Hypersensitivity, Immediate/physiopathology , Sensitivity and Specificity , Skin Tests , Structure-Activity Relationship , UrticariaABSTRACT
NSAIDs are the most important group of drugs involved in hypersensitivity drug reactions, and include heterogeneous compounds with very different chemical structures. These reactions can be IgE dependent (immediate reactions), T cell-mediated (non-immediate), or induced by a non-specific immunological mechanism related with the blocking of the COX-1 enzyme and the shunting to the lipooxygenase pathway (cross-intolerant reactions). Cutaneous symptoms are the most frequent, with ibuprofen, naproxen and diclofenac being common culprit drugs worldwide, although others can be involved because patterns of consumption and exposure rates vary between countries. A very important proportion of immunological reactions are immediate, with urticaria and anaphylaxis being the typical clinical manifestations. Non-immediate reactions comprise a number of heterogeneous entities ranging from mild exanthema to severe TEN or DRESS syndrome, as well as organ-specific reactions such as hepatitis or pneumonitis. Cross-intolerant reactions appear to non-chemically related drugs, and involve respiratory airways, skin or both. In vivo diagnostic tests are based on the capacity of the skin to respond to the culprit drug, but their sensitivity is in many instances rather low. The approach for in vitro testing consists of either detecting specific IgE antibodies or studying the proliferation of T lymphocytes toward the eliciting drug. No appropriate tests are yet available for the in vitro validation of cross-intolerance reactions, although techniques based on the stimulation of basophils have been proposed. Based on these findings, the diagnostic approach is often based on the controlled administration of the drug to assess tolerance. In this work we review current knowledge on hypersensitivity reactions to NSAIDs, including diagnostic approach and genetic studies.
