Unrelated Nonsteroidal Anti-inflammatory Drugs Research Articles

Nimesulide-Induced Fixed Drug Eruption Followed by Etoricoxib-Induced Fixed Drug Eruption: An Unusual Case Report and Review of the Literature.

Fixed drug eruption (FDE) is a well-recognized, non-immediate, drug hypersensitivity reaction, often attributed to the use of various medications, most commonly non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics. Cross-reactivity between related NSAIDs in FDE has been reported, but among chemically unrelated NSAIDs, is rare. Herein, we present a rare well-documented case where a patient initially displayed tolerance to etoricoxib after experiencing a nimesulide-induced FDE. Subsequently, the patient developed an etoricoxib-induced FDE, accompanied by the development of bullous lesions. This case report and the literature review on comparable FDE occurrences shed light on the intricate nature of FDEs, suggesting the possibility of cross-reactivity between chemically related and unrelated NSAIDs or the emergence of new drug-specific T cells without cross-reactivity after multiple exposures to a drug in a susceptible patient. Our case underscores the importance of increased awareness and vigilance among both physicians and patients in the realm of personalized medicine. Further research is needed to unravel the intricate mechanisms behind these drug eruptions, improve diagnostic approaches, and enhance patient care.

Evaluation and Updated Classification of Acute Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAID-Exacerbated or -Induced Food Allergy (NEFA/NIFA).

There are hypersensitivity reactions (HRs) to foods in which nonsteroidal anti-inflammatory drugs (NSAIDs) act as aggravating factors (NSAID-exacerbated food allergy, NEFA) or cofactors (NSAID-induced food allergy, NIFA), often misdiagnosed as HRs to NSAIDs. Urticarial/angioedematous and/or anaphylactic reactions to ≥ 2 chemically unrelated NSAIDs do not meet the current classification criteria. However, they may be considered as part of a cross-reactive type of acute HR, which is NSAID-induced urticaria/angioedema with/without respiratory and/or systemic symptoms of anaphylaxis (NIUAA). To evaluate patients reporting acute HRs to NSAIDs and classify them according to updated criteria. 414 patients with suspected HRs to NSAIDs were studied prospectively. NEFA/NIFA was diagnosed in those who met all the following criteria: 1) mild reactions to (NEFA) or tolerance of (NIFA) the suspected foods without taking NSAIDs; 2) cutaneous and/or anaphylactic reactions to the combination foods + NSAIDs; 3) positive allergy tests to the suspected foods; 4) negative drug challenges (DCs) with the NSAIDs involved. 252 patients (60.9%) were diagnosed with NSAID hypersensitivity, 108 of whom had NIUAA. NSAID hypersensitivity was excluded in 162 patients (39.1%) who tolerated DCs with the suspected NSAIDs, 9 of whom were diagnosed with NEFA and 66 with NIFA. Pru p 3 was implicated in 67 of these 75 cases. NEFA/NIFA accounts for about 18% of patients reporting HRs to NSAIDs, with Pru p 3 as the main responsible food allergen. Therefore, patients with cutaneous and/or anaphylactic reactions to NSAIDs should be carefully questioned about all foods ingested within 4 hours before or after NSAID exposure, and targeted food allergy tests should be considered in the diagnostic workup of these patients. If testing is positive, DCs with the suspected NSAIDs should also be considered.

Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs.

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.

Characteristics and Contributing Factors Related to Nonsteroidal Anti-Inflammatory Drugs Hypersensitivity

Introduction: Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) is reported to be the most common drug hypersensitivity. The aim of this study was to evaluate the characteristics of self-reported NSAID hypersensitivity and identify patients at high risk of NSAID hypersensitivity. Methods: Patients who presented at a single tertiary care hospital between January–December 2017 with reported NSAID hypersensitivity were evaluated. Clinical information obtained from a review of medical records was further supplemented with data gained from a telephone-administered questionnaire. Results: From a total of 535 patients with reported NSAID hypersensitivity, 301 were included in the study. The mean age of onset of NSAID hypersensitivity reaction was 30.3 ± 14.9 years old. A total of 84 patients (27.9%) were hypersensitive to 2 or more chemically unrelated NSAIDs. The leading NSAID hypersensitivity was to propionic acid derivatives (73%) followed by acetic acid derivatives (28.9%). Immediate reaction (≤1 h) was identified in 171 patients (57.8%), and angioedema was the most frequently reported symptom (179 patients, 59.5%), followed by urticaria and anaphylaxis in 85 (28.2%) and 62 (20.6%) patients, respectively. A drug provocation test was performed on 53 patients, and NSAID hypersensitivity was confirmed in 38 patients (71.6%). The independent factors identified, which could predict NSAID hypersensitivity, were personal history of allergic rhinitis/chronic rhinosinusitis (AR/CRS), onset of NSAID hypersensitivity over 15 years old, and immediate reaction. Conclusion: Angioedema was the most typical symptom, and propionic acid derivatives were the most frequently reported culprit drugs. The significant risk factors predicting NSAID hypersensitivity were personal history of AR/CRS, onset of NSAID hypersensitivity reaction over 15 years old, and immediate reaction.

Polymorphism of IL10, IL4, CTLA4, and DAO Genes in Cross‐Reactive Nonsteroidal Anti‐inflammatory Drug Hypersensitivity

Our aim was to evaluate genetic polymorphism of molecules involved in immunoregulatory/allergic processes in patients who presented with cutaneous hypersensitivity caused by chemically unrelated nonsteroidal anti-inflammatory drugs. Polymorphisms at IL10 (-1082 G>A), IL4 (-589 C>T), CTLA4 (+49A>G), and DAO (+8956 C>G) genes were studied in 55 cases and 97 controls by the polymerase chain reaction-restriction fragment length polymorphism technique. With regard to the polymorphism at IL10 -1082, higher frequencies of the AG genotype (57% vs 39%) and G allele carriers (70% vs 48%) were found among the patients, indicating a risk effect (odds ratio [OR] = 2.56 and P = .01 for AG genotype and OR = 2.52; P = .01 for AG/GG). For the CTLA4 +49 A/G single-nucleotide polymorphism (SNP), AG genotype (31.0%) (P = .02) and G carrier (54.0%) (P = .05) frequencies were found to be significantly lower in the patient group compared with the control group (51.0% and 69.0%, respectively). The SNP DAO +8956 C>G was associated with a strong protective effect, with OR values of 0.83 for CG and 0.11 for GG genotype (P = .04 for the codominant model), suggesting an allele dose effect. The combination of IL10 and DAO SNPs in a multivariate model did not alter the OR values, suggesting independent effects for both SNPs. The results are striking. In conclusion, these results suggest that polymorphisms in regulatory targets of the immune response and in DAO gene could modulate an individual's susceptibility to nonsteroidal anti-inflammatory drug hypersensitivity reactions. Further studies will be necessary to complement our results.

Immediate Reactions to More Than 1 NSAID Must Not Be Considered Cross-Hypersensitivity Unless Tolerance to ASA Is Verified.

Individuals who develop drug hypersensitivity reactions (DHRs) to chemically unrelated nonsteroidal anti-inflammatory drugs (NSAIDs) are considered cross-hypersensitive. The hallmark for this classification is that the patient presents a reaction after intake of or challenge with acetylsalicylic acid (ASA). Whether patients react to 2 or more NSAIDs while tolerating ASA remains to be studied (selective reactions, SRs). Objective: To identify patients with SRs to 2 or more NSAIDs including strong COX-1 inhibitors. Patients who attended the Allergy Service of Hospital Infanta Leonor, Madrid, Spain with DHRs to NSAIDs between January 2011 and December 2014 were evaluated. Those with 2 or more immediate reactions occurring in less than 1 hour after intake were included. After confirming tolerance to ASA, the selectivity of the response to 2 or more NSAIDs was demonstrated by in vivo and/or in vitro testing or by controlled administration. From a total of 203 patients with immediate DHRs to NSAIDs, 16 (7.9%) met the inclusion criteria. The patients presented a total of 68 anaphylactic or cutaneous reactions (mean [SD], 4.2 [2.1]). Most reactions were to ibuprofen and other arylpropionic acid derivatives and to metamizole. Two different NSAIDs were involved in 11 patients and 3 in 5 patients. Patients with NSAID-induced anaphylaxis or urticaria/angioedema should not be considered cross-hypersensitive unless tolerance to ASA is verified.

Nonsteroidal anti-inflammatory drug hypersensitivity among children.

Nonsteroidal anti-inflammatory drugs (NSAID) are the second-most frequent drugs that cause hypersensitivity reactions among children. Studies related to NSAIDs hypersensitivity in children are limited. In this study, we aimed to evaluate children admitted with suspicion of NSAIDs reaction. Between January 1, 2011, and November 30, 2014, we included patients with suspicion of NSAIDs hypersensitivity in our clinic. For evaluation, skin tests and oral provocation tests with the drug (suspected or alternative) were proposed. Reactions were classified and defined according to the latest European Academy of Allergy and Clinical Immunology position paper on NSAID hypersensitivity. During the study period, 123 patients (with 136 drug reactions) were admitted to our clinic with suspected NSAID hypersensitivity. The mean (standard deviation) age of the patients, 67 female (55%), was 83.10 ± 56.05 months. Thirteen patients described reactions to more than one chemically unrelated NSAID, and 110 patients described reactions with chemically similar drugs. Eight patients were not included because they did not have provocation tests. Thus, 115 patients were evaluated. A hundred and thirty provocations were performed. Twenty patients (17.4%) were diagnosed with NSAID hypersensitivity (13 patients diagnosed by provocation tests and 7 patients diagnosed according to their history). The most frequently encountered agent was ibuprofen (50% [10/20]). Eighty percent (16 patients) of the reactions were considered "non-cross-reactive type." Fifteen patients (75%) were classified as having single-NSAID-induced urticaria and/or angioedema, three patients were classified as having NSAID-induced urticaria and/or angioedema, one patient was classified as having NSAID-exacerbated respiratory disease, and the other patients were classified as having single-NSAID-induced delayed hypersensitivity reactions. Detailed history and drug provocation tests are important to verify NSAID hypersensitivity. The most common type is the non-cross-reactive type, and, in our study, the most common responsible drug was ibuprofen.

Tolerance To COX-2 Inhibitors In Children With Multiple Hypersensitivity To Non- Steroidal Anti-Inflammatory Drugs

U E S D A Y 913 Non-Steroidal Antiinflammatory Drugs (NSAIDs)-Induced Acute Urticaria: A Genome-Wide Association Study In The Spanish Population Dr. Jose A. Cornejo-Garcia, PhD, Dr. Mike Lee, Dr. Natalia BlancaL opez, MD, PhD, Dr. Lieh-Bang Liou, Dr. Chien-Hsiun Chen, Dr. Inmaculada Do~na, MD, PhD, Veronique Godineau, Dr. Jose Julio Laguna, Dr. F. Javier Fernandez, MD, PhD, Dr. Pedro Ayuso Parejo, PhD, Mrs. Maria del Carmen Plaza-Ser on, Bsc, Dr. Gabriela Canto, MD, PhD, Dr. Miguel Blanca, MD, PhD; Research Laboratory, Carlos Haya Hospital, Malaga, Spain, Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, Yokohama Kanagawa, Japan, Allergy Service, Infanta Leonor Hospital, Madrid, Spain, Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital at Lin-kou, Kwei-san, Tao-yuan, Taiwan, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Allergy Service, Carlos Haya Hospital, M alaga, Spain, Hospital De La Cruz Roja, Madrid, Spain, UMH Alicante G.University Hospital Allergy Sect., Alicante, Spain. RATIONALE: The most important group of medicaments responsible for hypersensitivity drug reactions (HDRs) is NSAIDs, with acute urticaria/ angioedema (AUA) induced by cross-intolerance themost frequent clinical entity. Most of the genetic studies carried out have focused in the study of single nucleotide polymorphisms in genes related with prostaglandins and leukotrienes synthesis. In order to identify new genetic variants potentially involved in NSAIDs-induced AUA we conducted a GWAS in a Spanish population. METHODS: Patients and controls were recruited in clinical centers integrated in the Spanish Network for Allergic Diseases. All patients experienced more than 2 episodes with at least 2 different unrelated NSAIDs, and those with airways or chronic urticaria were excluded. Whole-genome scan was conducted using Axiom Genome-Wide CEU Array chip on 308 NSAIDs-induced AUA patients and 144 NSAIDs tolerant age, sex-matched controls. RESULTS: Although no SNPs reached genomewide p-value after Bonferroni correction, our results revealed 32 SNPs with suggestive significant associations (10<p<10) with NSAIDs-induced AUA. The lowest p values corresponded to polymorphisms located on chromosome 17; rs7225428 in GOSR2 (p51.11x10), rs197111 (p57.68x10), and rs1071682 in EFTUD2 (p51.77x10). CONCLUSIONS: The identification of new variants potentially associated with NSAIDs-induced AUA opens up new clues for understanding the mechanisms underlying this disease, the most important clinical entity induced by HRs.

A Genome-Wide Association Study of Non-Steroidal Antiinflammatory Drugs (NSAIDs)-Induced Acute Urticaria in the Spanish Population

NSAIDs are the most frequently involved in hypersensitivity drug reactions (HDRs), being acute urticaria/angioedema (AUA) induced by cross-intolerance the most important group. Most of the genetic studies carried out consist of the analysis of polymorphisms related with the arachidonic acid pathway. In order to identify genetic variants involved in NSAID NSAIDs-induced AUA we carried out a GWAS in a Spanish population. Samples were obtained from centers integrated in the Spanish Network for Allergic Diseases. All patients experienced more than 2 episodes with at least 2 different unrelated NSAIDs. Airways and chronic urticaria patients were excluded. Whole-genome scan was conducted using Affymetrix® Genome-wide Human SNP Array 6.0 on 121 NSAIDs-induced AUA patients and 128 NSAID tolerant age, sex-matched controls. Three major clusters with more than one SNPs located within 500kb of each other were identified. The first included rs2249625 (P=5.30x10-6) and rs2496515 (P=1.48x10-5), and is located in the intron of regulating synaptic membrane exocytosis 1 gene (RIMS1) on chromosome 6; the second contains three SNPs, rs282674 (P=1.17x10-5), rs282673 (P=1.82x10-5) and rs3125447 (P=4.77x10-5), is located approximately 40kb downstream of protein bicaudal C homolog 1 (BICC1) on chromosome 10; the last loci consists of two SNPs, rs8008961 (P=5.85x10-6) and rs3784099 (P=7.10x10-5), and are clustered in the introns of RAD51-like 1 (RAD51L1) on chromosome 14. The identification of these variants opens up new potential pathways for understanding the mechanisms of NSAID induced AUA.

Basophil activation test for the in vitro diagnosis of nonsteroidal anti-inflammatory drug hypersensitivity

There is need for an in vitro diagnostic test for hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs). The purpose of this study was to assess the reliability of one such diagnostic, the basophil activation test. Forty-three drug hypersensitive patients referring several immediate reactions (anaphylaxis, urticaria, angioedema, asthma, and rhinoconjunctivitis) to one or more NSAIDs and 29 controls participated. Using the Basotest commercial kit, 63 determinations were performed with the drugs implicated in the adverse reactions (ASA, ibuprofen, metamizol, diclofenac, paracetamol, and ketorolac). In 16 patients additional determinations were made with other chemically unrelated NSAIDs. Forty-two determinations were made for controls. The analysis was performed by flow colorimetric cytometry and double staining with the monoclonal antibodies anti-IgE and anti-CD63. A Basophil Activation Index (percentage of activated basophils after allergen stimulation/percentage of basally activated basophils) of two or more was considered a positive result. Specificity of 100% and sensitivity of 42.85% were achieved. The positive predictive value was 100%, and the negative predictive value was 53.84%. In 35.29% of intolerant patients there was a positive reaction to at least two drugs implicated in adverse reactions, and in 27.27% of these patients there was a positive reaction to other chemically unrelated NSAIDs. The basophil activation test is useful for the in vitro diagnosis of NSAID hypersensitivity, providing good specificity and positive predictive value and diagnostic reliability in the assessment of NSAID intolerance.

Etoricoxib challenge in patients with chronic urticaria with NSAID intolerance

Patients with chronic urticaria frequently experience flares of hives following the ingestion of chemically unrelated nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenic mechanism of these reactions is based on cyclooxygenase-1 (COX-1) enzyme inhibition. In most cases, nonselective NSAIDs, which inhibit both COX-1 and COX-2, are responsible for such adverse reactions; in contrast, analgesic and anti-inflammatory drugs exerting limited inhibition on COX-1 are generally better tolerated by these patients. This study aimed to detect tolerability of etoricoxib, a selective COX-2-inhibiting drug, in patients with chronic urticaria with a history of NSAID intolerance. Single-blind, placebo-controlled oral challenges with increasing doses of etoricoxib were carried out in 17 adult patients with chronic urticaria exacerbated by NSAID. All patients tolerated the drug at therapeutic doses. The study suggests that etoricoxib, with its favourable COX-1/COX-2 ratio, is well tolerated by patients with chronic urticaria exacerbated by NSAID intolerance.

Nonsteroidal anti-inflammatory drugs inhibit the growth of C6 and U138-MG glioma cell lines

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used drugs for the treatment of inflammatory disease and have a chemopreventive effect in a variety of tumors. Several studies have demonstrated unequivocally that certain NSAIDs cause antiproliferative effects independent of cyclooxygenase (COX) activity. In this study, we investigated the effect of chemically unrelated NSAIDs in the proliferation of glioma cell lines and the possible mechanisms involved in indomethacin-mediated inhibition of proliferation in glioma cells lines. The glioma cell lines were treated with NSAIDs and proliferation was measured by cell counting. Indomethacin, acetaminophen, sulindac sulfide and NS-398 ( N-[2-cyclohexyloxy)-4-nitrophenyl]methane-sulfonamide) induced a time- and concentration-dependent inhibition of C6 rat glioma cell proliferation. The inhibition of COX by chemically unrelated NSAIDs leads to inhibition of rat and human glioma cell proliferation. The tetrazolium reduction assay (MTT) indicated a reduction in cell viability induced by indomethacin. None of the NSAIDs tested induced caspase-3/7 activation, assayed with a fluorigenic substrate. The indomethacin-induced inhibition of C6 cells proliferation was abrogated by the use of the c-Src inhibitor, PP2 and the MEK inhibitor, PD 098059, suggesting COX-independent mechanisms. Indomethacin decreased the percentage of cells in the S phase, with relative increases in the G 0/G 1 and/or the G 2/M phase. NSAIDs may be clinically important for pharmacological intervention in gliomas.

Neuronal zinc stores are modulated by non-steroidal anti-inflammatory drugs: An optical analysis in cultured hippocampal neurons

Zinc chelation and non-steroidal anti-inflammatory drugs (NSAIDs) have been explored as potential neuroprotective agents. However, it remains unknown whether NSAIDs and zinc chelation may converge on a similar cellular process. Using two-photon microscopy to observe hippocampal neurons labeled with a zinc-sensitive dye, we provide evidence that three chemically unrelated NSAIDs, niflumic acid, ibuprofen, and naproxen, acutely increase intracellular zinc stores from extracellular metal pools. Phospholipase A2 inhibitors triggered similar responses, suggesting that NSAIDs likely control zinc stores by their activity as cyclooxygenase inhibitors. These results provide evidence for a new link between cyclooxygenase metabolites and the mechanisms controlling neuronal zinc pools.

Multiple NSAID intolerance in chronic idiopathic urticaria is correlated with delayed, pronounced and prolonged autoreactivity.

Autologous serum skin test (ASST) reactivity is positive in up to 60% of patients with chronic idiopathic urticaria (CIU). About 21 to 30% of patients with CIU have intolerance to acetyl salicylic acid (ASA) and/or other chemically unrelated non-steroidal anti-inflammatory drugs (NSAIDs). To investigate the relationship between ASA/NSAID intolerance and ASST reactivity, a case-control study was performed in 110 patients with CIU and 60 healthy controls. A positive ASST was defined as an erythematous wheal with a diameter of > 5 mm more than the saline-induced response. Patients were assessed at 10-minute intervals for a minimum of three hours. ASA/NSAID intolerance was ascertained by a placebo controlled-provocation test with offending drug (s). Forty-two patients with CIU (38.2%) had autoreactivity whereas only two of the controls (3.3%) displayed early and weak skin responses (P<.0001). ASA/NSAID intolerance was demonstrated in 30 (27.3%) patients with CIU. The prevalences of autoreactivity were 93.3% (28/30) and 17.5% (14/80) in patients with and without ASA/NSAID intolerance, respectively (P<.001). Thirteen of the 25 ASST-positive patients (52%) who had single (n: 7) or multiple (n: 6) NSAID intolerance showed early (before or at 30 min) and mild autoreactivity of short duration, whereas 15 of the remaining 17 ASST-positive patients (88.2%) who all had multiple NSAID intolerance showed delayed (later than 30 min) and prolonged autoreactivity (P<.05). These findings suggest that a common mechanism may be responsible for the pathogeneses of both delayed autoreactivity and multiple NSAID intolerance in CIU. It might be further speculated that delayed, prolonged, and pronounced autoreactivity may be a possible predictor for multiple NSAID sensitivity in CIU.

Intolerance to nonsteroidal anti-inflammatory drugs might precede by years the onset of chronic urticaria

Background: Recent studies have found that most otherwise normal subjects with a history of acute urticaria induced by several nonsteroidal anti-inflammatory drugs (NSAIDs) show a wheal-and-flare reaction on intradermal injection of autologous serum. This phenomenon has been previously observed in patients with chronic urticaria (CU) and suggests a possible common background in CU and NSAID-induced urticaria. A relationship between these 2 conditions is further suggested by the fact that up to 30% of patients with CU have a worsening of their skin disorders after the ingestion of chemically unrelated NSAIDs. Objective: I sought to assess whether otherwise normal subjects with multiple or single NSAID intolerance show a propensity to have CU. Methods: Two hundred eighty otherwise normal patients with an unequivocal history of acute urticaria induced by NSAIDs seen during the last 10 years were studied. On the basis of both clinical history and oral challenge tests with at least 2 alternative NSAIDs, the patients were classified as having single or multiple NSAID intolerance. All the patients were re-evaluated within the end of 2002, 1 to 10 years after the first visit, to assess the onset of CU. One hundred allergic adults without a history of CU and of drug allergy followed up for 1 to 10 years were used as control subjects. Results: One hundred fifty-nine and 121 patients were finally considered as having single or multiple NSAID intolerance, respectively. At the follow-up visit, 93 (33%) of 280 patients had CU. The prevalence of CU was very similar in subjects with single or multiple NSAID intolerance (48/159 [30%] vs 45/121 [37%], respectively; P = not significant). Only 1 (1%) of 100 atopic control subjects had CU during the follow-up period (P < .001). Among single NSAID reactors, patients who had CU had a significantly higher prevalence of intolerance to aspirin than those who did not have CU (36/48 [75%] vs 41/111 [37%], P < .001), whereas the latter had a markedly higher prevalence of intolerance to pyrazolone drugs (52/111 [47%] vs 10/48 [21%], P < .01). Altogether, only 12 (15%) of 82 patients intolerant to drugs other than aspirin versus 36 (47%) of 77 aspirin reactors had CU (P < .001). Conclusion: NSAID intolerance might precede the onset of CU by years. Both multiple and single NSAID reactors with a history of aspirin-induced urticaria seem at higher risk for CU than patients with a history of single intolerance to NSAIDs other than aspirin. (J Allergy Clin Immunol 2003;111:1095-8.)

Anaphylactic and anaphylactoid reactions to aspirin and other NSAIDs.

Aspirin and non-steroidal antiinflammatory drugs (NSAIDs) may cause anaphylactic or anaphylactoid reactions. Constitutively-expressed cyclooxygenase (COX-1) inhibition is likely to be responsible for the cross-reactions and side effects associated with these drugs, as well as the anaphylactoid reactions sometimes seen in aspirin-sensitive respiratory disease. Though anaphylactic and anaphylactoid reactions may be clinically indistinguishable, they involve different mechanisms. Anaphylactic reactions are due to immediate hypersensitivity involving cross-linking of drug-specific IgE. Regardless of COX selectivity pattern, NSAIDs may function as haptens capable of inducing allergic sensitization. Unlike anaphylaxis, anaphylactoid reactions are most likely related to inhibition of COX-l by NSAIDS. Thus, an anaphylactoid reaction caused by a particular COX-1 inhibiting NSAID will occur with a chemically unrelated NSAID which also inhibits COX-1 enzymes. Selective COX-2 inhibitors appear to be safe in patients with a history of NSAID-related anaphylactoid reactions but can function as haptens, with resulting sensitization and anaphylaxis upon next exposure. This article will discuss the mechanisms, prevalence and population-based studies of anaphylactic and anaphylactoid reactions caused by aspirin and NSAIDs. The evaluation and management of patients suspected of having experienced an anaphylactic or anaphylactoid reaction to aspirin or other NSAIDs will also be reviewed.

Autoreactivity is highly prevalent in patients with multiple intolerances to NSAIDs

A subset of drug-allergic patients show a marked propensity to react against several, chemically unrelated nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenesis of such multiple drug reactions is unclear. Approximately 30% of patients with chronic idiopathic urticaria, a condition frequently characterized by autoreactivity on autologous serum skin test (ASST), experience flares of hives after taking chemically unrelated NSAIDs. To detect whether a clinically unapparent autoreactivity may represent the nonspecific mechanism facilitating drug-induced histamine release in patients with a history of urticaria/angioedema induced by several, chemically unrelated NSAIDs. Thirty-six adults with a history of acute NSAID-induced urticaria (22 with multiple NSAID sensitivity [MNS]; 14 with single NSAID sensitivity [SNS]; and 20 atopic controls without a history of drug allergy) underwent ASST. Sera from 14 MNS and 4 SNS subjects (all ASST-positive) underwent histamine release assay with basophils from normal donors. Sera from five MNS patients were tested on autologous basophils as well. Twenty of 22 (91%) MNS subjects versus 5 of 14 (36%) SNS subjects were positive on ASST (P < 0.01). No atopic control was ASST-positive. Sera from 4 of 14 (29%) MNS patients versus 0/4 SNS subjects (P = NS) induced significant histamine release from basophils of normal donors. The use of autologous basophils did not significantly change these results. Most patients with multiple NSAID intolerance and approximately one-third of those with single NSAID hypersensitivity are characterized by the presence of circulating histamine-releasing factors. Their nature is still unclear, but the fact that only a minority of sera from ASST+ subjects were able to induce histamine release from normal basophils in vitro suggests that these factors might not differ from those involved in most patients with chronic urticaria. These factors might play a relevant pathogenic role in NSAID-induced urticaria reactions.

Selective inhibition of interleukin-4 gene expression in human T cells by aspirin

Previous studies indicated that aspirin (acetylsalicylic acid [ASA]) can have profound immunomodulatory effects by regulating cytokine gene expression in several types of cells. This study is the first in which concentrations of ASA in the therapeutic range were found to significantly reduce interleukin (IL)-4 secretion and RNA expression in freshly isolated and mitogen-primed human CD4+ T cells. In contrast, ASA did not affect IL-13, interferon-gamma, and IL-2 expression. ASA inhibited IL-4, but not IL-2, promoter-driven chloramphenicol acetyltransferase expression in transiently transfected Jurkat T cells. The structurally unrelated nonsteroidal anti-inflammatory drugs indomethacin and flurbiprofen did not affect cytokine gene expression in T cells, whereas the weak cyclo-oxygenase inhibitor salicylic acid was at least as effective as ASA in inhibiting IL-4 expression and promoter activity. The inhibitory effect of ASA on IL-4 transcription was not mediated by decreased nuclear expression of the known salicylate target nuclear factor (NF)-kappaB and was accompanied by reduced binding of an inducible factor to an IL-4 promoter region upstream of, but not overlapping, the NF of activated T cells- and NF-kappaB-binding P1 element. It is concluded that anti-inflammatory salicylates, by means of a previously unrecognized mechanism of action, can influence the nature of adaptive immune responses by selectively inhibiting the expression of IL-4, a critical effector of these responses, in CD4+ T cells.

NSAID intolerance in chronic idiopathic urticaria: A study of its relationship with histamine-releasing activity of patients’ sera

about one fourth of patients with chronic idiopathic urticaria (CIU) experience flares of hives after taking chemically unrelated nonsteroidal anti-inflammatory drugs (NSAID). The reasons for such intolerance are still elusive. this study aimed to investigate NSAID intolerance in patients with CIU in view of the in vivo and in vitro histamine releasing activity of their sera. 117 adults (M/F 41/76) with CIU underwent intradermal test with autologous serum, and the ability of their sera to induce histamine release from normal blood donors was evaluated. NSAID intolerance was ascertained by careful interview. overall, 32/117 (27 %) patients reported NSAID intolerance. The prevalence on NSAID intolerance did not differ in the three subgroups: negative on both in vivo and in vitro tests (9/36; 25 %), positive or intradermal test but negative on basophil histamine release assay (16/58; 28 %), or positive on both in vivo and in vitro tests (7/23; 30 %). in patients with CIU intolerance to NSAID does not depend on the mechanism of histamine release.

Clinical experience with specific COX-2 inhibitors in arthritis.

The common mechanism of action of aspirin and the chemically unrelated non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of prostaglandin (PG) production due to interference with the enzymatic activity of cyclooxygenase (COX). These agents have long been used as effective treatments for arthritis. The recognition that the inducible isoform COX-2 was associated with inflammation and arthritis led to the hypothesis that PGs produced by a COX-2-dependent pathway were responsible for the inflammation, pain, and tissue destruction. Since the constitutive COX-1 enzyme was identified as responsible for gastroprotection and inhibition of platelet function, the potential for compounds that were both effective and safer than NSAIDs led to rapid development of agents that specifically inhibit COX-2. These agents have now been tested and approved for use by the US Food and Drug Administration for patients with osteoarthritis and rheumatoid arthritis. They have been shown equally effective to comparitor NSAIDs. More importantly, there is a 3.5-fold reduction in the incidence of endoscopic gastroduodenal ulcerations and early data suggesting a similar reduction in clinically significant perforations, symptomatic ulcers, and bleeds. In patients with arthritis at risk for gastrointestinal complications of NSAIDs, specific inhibitors of COX-2 provide an effective and apparently safer form of anti-inflammatory agent.