NSAID-exacerbated Cutaneous Disease Research Articles

Review of NSAID Hypersensitivity Reactions Based on Clinical Phenotyping

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic, antipyretic, and anti-inflammatory properties. However, they are also associated with a broad spectrum of hypersensitivity reactions, ranging from mild cutaneous manifestations to severe systemic responses. The complex nature of these reactions and their underlying mechanisms pose challenges in diagnosis and management. We review the clinical evidence to six distinct clinical phenotypes of NSAID hypersensitivity, including: NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA), NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous disease (NECD), NSAID-induced urticaria/angioedema (NIUA), food-dependent NSAID-induced hypersensitivity reactions (FDNIH), and selective NSAID-induced delayed reactions (SNIDR). This review aims to provide a comprehensive review of NSAID hypersensitivity reactions based on clinical phenotyping, which can aid in understanding and managing these adverse events.

Recent Updates in Understanding NSAID Hypersensitivity.

To provide a review of available literature regarding nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity with an emphasis on more recent findings. Oral provocation tests with aspirin are important for diagnosis and management in adult and pediatric populations with reported NSAID hypersensitivity. Risk of cross-reactivity to COX-2 inhibitors varies by NSAID hypersensitivity phenotype. COX-2 inhibitors are tolerated in aspirin-exacerbated respiratory disease. Reported NSAID allergy is associated with a higher risk of a substance use disorder. Effective treatment of underlying chronic spontaneous urticaria can allow tolerance of NSAIDs in NSAID-exacerbated cutaneous disease. The pathophysiology, cross-reactivity, and appropriate diagnostic evaluation differ between the 5 distinct NSAID hypersensitivity phenotypes. Further research into the pathophysiology of NSAID hypersensitivity in patients with and without underlying disease is needed.

Acetylsalicylic acid challenge or desensitization in sensitive patients with cardiovascular disease.

The use of acetylsalicylic acid (ASA) is problematic in subjects with histories of hypersensitivity reactions (HRs) to it or with cross-reactive types of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. We sought to evaluate the efficacy of low-dose ASA challenge (LDAC) and desensitization to allow ASA therapy at an antiplatelet dose in patients with atherosclerotic cardiovascular disease (ASCVD) or multiple related risk factors and histories of HRs to ASA or ≥ 2 chemically unrelated NSAIDs. We studied prospectively all patients with such histories and ≥ 3 risk factors for ASCVD (group I), chronic coronary syndrome (CCS, group II), and acute coronary syndrome (ACS) with indication for ASA desensitization (group III). Patients from groups I and II underwent LDACs (cumulative dose of 110mg), while those from group III were desensitized (cumulative dose of 100.1mg). We evaluated 103 patients: 62 from group I, 24 from group II, and 17 from group III. Eighty-two of the 86 patients from the first two groups underwent LDACs and 2 reacted. Subsequently, 22 (27.5%) of the 80 patients with negative LDACs were administered dual antiplatelet therapy with ASA after successful percutaneous coronary interventions, thus sparing desensitizations. The remaining 4 patients with CCS and all 17 patients from group III were successfully desensitized. In this pragmatic study,LDAC proved to be a safe and reliable diagnostic tool for identifying patients with histories of HRs to ASA or ≥ 2 different NSAIDs who can tolerate ASA at antiplatelet doses. Routine LDAC is advisable in all patients at high risk for ASCVD or with CCS who report HRs to ASA or ≥ 2 NSAIDs. ASA desensitization remains a safe and effective option in patients with ACS. Study flow-chart. ASCVD atherosclerotic cardiovascular disease; CCS chronic coronary syndrome; ACS acute coronary syndrome; ASA acetylsalicylic acid; DAPT dual antiplatelet therapy; PCI percutaneous coronary intervention; NSAIDs nonsteroidal anti-inflammatory drugs; NERD NSAID-exacerbated respiratory disease; NECD NSAID-exacerbated cutaneous disease; NIUAA NSAID-induced urticaria-angioedema or anaphylaxis; SNIUAA single NSAID-induced urticaria-angioedema or anaphylaxis; SNIDHR single NSAID-induced delayed hypersensitivity reaction.

Hypersensitivity to Ibuprofen: Real-Life Experience in Children with History of Suspected Immediate Reactions

Introduction: Ibuprofen is the most common culprit drug causing nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity in children. We aimed to evaluate the frequency, clinical characteristics, and risk factors of confirmed ibuprofen allergy in children presenting with a history of suspected immediate type ibuprofen-induced hypersensitivity reactions. Methods: We evaluated 50 (35 M, 15 F) children with a median age of 7 years, who were referred to our clinic with suspected immediate ibuprofen hypersensitivity. Patients were subjected to a diagnostic work up including drug provocation tests (DPTs) with the culprit drug. Reactions were classified according to the European Academy of Allergy and Clinical Immunology Task Force recommendations for pediatric patients. Proven ibuprofen allergic patients underwent DPT to find a safe alternative drug. Results: Ibuprofen allergy was confirmed in 34% (n: 17) of children; 9 patients were diagnosed by DPTs and 8 patients diagnosed based on their histories. Angioedema was the most common clinical manifestation (n: 30, 60%). Among patients with proven ibuprofen allergy, 7 of them were classified as cross-intolerant. Cross-intolerance reactions were further classified as NSAID-exacerbated cutaneous disease (n = 1) and NSAID-induced urticaria/angioedema/anaphylaxis (n = 6). As an alternative drug, paracetamol was safely tolerated, whereas 1 patient developed angioedema and urticaria with nimesulide. Older age and male gender were identified as independent risk factors for immediate-type ibuprofen allergy. Conclusion: DPTs should be performed to confirm or exclude ibuprofen allergy in children and to find safe alternative drugs. Male gender and older age are risk factors for ibuprofen allergy. NSAID-induced hypersensitivity reactions in the pediatric population cannot be well defined using the adult classification system.

Nonsteroidal anti-inflammatory drugs hypersensitivity in chronic spontaneous urticaria in the light of its pathogenesis.

Up to 15% of patients with chronic spontaneous urticaria (CSU) experience severe exacerbations of their baseline cutaneous disease after taking nonsteroidal anti-inflammatory drugs that inhibit cycloxygenase-1 (COX-1) enzyme. These subjects are defined as having a NECD (NSAID-exacerbated cutaneous disease). The way NSAID hypersensitivity correlates with the different pathogenic mechanisms of CSU has not been investigated so far. 235 adults with severe CSU submitted to omalizumab treatment were studied. A rapid omalizumab response was considered as a marker of auto-allergic (Type I) CSU whereas patients showing a slow response or not responding at all were regarded as having a type IIb autoimmune disease. At the first visit medical history of tolerance to aspirin and/or other COX-1 inhibiting NSAID was ascertained. Duration of disease, atopic status, thyroid autoimmunity, CRP, D-dimer plasma levels, and total IgE were assessed appropriately. 23 (10%) were hypersensitive to NSAID. Patients with or without did not differ in any of the variable considered, and a similar proportion in the two groups showed type I or type IIb CSU. The study suggests that in CSU hypersensitivity to NSAID represents a phenomenon that is independent on the pathogenesis of the underlying skin disease.

Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.

PurposeData on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.MethodsThe clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.ResultsMore than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.ConclusionsNIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.Trial RegistrationClinicalTrials.gov Identifier: NCT03849625

Platelet-Adherent Leukocytes Associated With Cutaneous Cross-Reactive Hypersensitivity to Nonsteroidal Anti-Inflammatory Drugs.

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.

Eosinophil/Neutrophil/Platelet-to-Lymphocyte Ratios in Various Types of Immediate Hypersensitivity to NSAIDs: A Preliminary Study

Background: The eosinophil/neutrophil/platelet-to-lymphocyte ratios (ELR, NLR, and PLR) have been used as clinical markers of systemic inflammation. However, they have not yet been tested in various subtypes of immediate hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs). Objectives: To assess the ELR, NLR, and PLR in various types of hypersensitivity to NSAIDs. Materials and Methods: A retrospective analysis of complete blood cell count and the ELR, NLR, and PLR was performed. Appropriate types of hypersensitivity to NSAIDs were diagnosed based on the anamnesis and drug provocation tests. The analysis covered 97 patients. Twenty were diagnosed with NERD (NSAID-exacerbated respiratory disease), 20 with NECD (NSAID-exacerbated cutaneous disease), 38 with NIUA (NSAID-inducted urticaria/angioedema), and 19 with SNIUAA (single-NSAID-induced urticaria/angioedema or anaphylaxis). Two controls groups were included: the first covered 15 patients with bronchial asthma and the second 28 patients with chronic spontaneous urticaria without NSAID hypersensitivity. Results: The NLR did not differ significantly between the NSAID hypersensitivity types. The ELR was significantly higher in NERD patients, and the PLR was significantly lower in NECD patients than in patients with other types of NSAID hypersensitivity and in controls. Conclusions: The ELR and PLR may be useful in differentiating various types of immediate hypersensitivity to NSAIDs. Moreover, the ELR may be helpful in differentiating patients with bronchial asthma with and without NSAID hypersensitivity and PLR in differentiating patients with chronic spontaneous urticaria from NECD.

Clinical Control of CSU with Antihistamines Allows for Tolerance of NSAID-Exacerbated Cutaneous Disease

Many patients with chronic spontaneous urticaria (CSU) experience exacerbations after the administration of nonsteroidal anti-inflammatory drugs (NSAIDs), with clinical implications for the selection of therapeutic options for pain management. Case reports suggest that antihistamines could prevent these reactions. To determine whether antihistamines can prevent NSAID-exacerbated reactions in patients with CSU. Data on 121 patients with CSU and a history of NSAID exacerbations were evaluated. Two types of challenge with NSAIDs were performed using the NSAIDs reported in the medical record (a diagnostic challenge test without the use of antihistamines and a challenge test using antihistamines). The order in which the tests were performed in each patient was dependent on the treating physician. Patients with a positive first diagnostic challenge underwent a second challenge using H1-antihistamines (anti-H1), patients with a negative first challenge using anti-H1 underwent a second diagnostic challenge without the use of anti-H1, and patients with a negative first diagnostic challenge or a positive first challenge using anti-H1 did not undergo a second challenge. In some patients, additional challenges were performed with an alternative NSAID before performing the diagnostic challenge test or the challenge test using anti-H1. In the diagnostic challenge test, 96 patients tested positive. Seventy-two (75%) of these patients tolerated the NSAIDs involved in the reaction when they used antihistamines. NSAID restrictions create many inconveniences for patients with CSU. Clinical control of CSU with the use of antihistamines can prevent further exacerbations due to NSAID intake in many patients to help them avoid unnecessary restrictions.

Eicosanoid mediator profiles in different phenotypes of nonsteroidal anti-inflammatory drug-induced urticaria.

The role of arachidonic acid metabolites in NSAID-induced hypersensitivity has been studied in depth for NSAID-exacerbated respiratory disease (NERD) and NSAID-exacerbated cutaneous disease (NECD). However, no information is available for NSAID-induced urticarial/angioedema (NIUA), despite it being the most frequent clinical entity induced by NSAID hypersensitivity. We evaluated changes in leukotriene and prostaglandin metabolites for NIUA patients, using patients with NECD and single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) for comparison. Urine samples were taken from patients with confirmed NSAID-induced urticaria and healthy controls, at baseline and at various time intervals after ASA administration. Eicosanoid measurement was performed using high-performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. No differences were found between groups at baseline. Following ASA administration, LTE4 and 9α,11β-PGF2 levels were increased in both NIUA and NECD patients compared to baseline, rising initially, before decreasing toward initial levels. In addition, the levels of these metabolites were higher in NIUA and NECD when compared with the SNIUAA and control groups after ASA administration. No changes were found with respect to baseline values for SNIUAA and control groups. We present for the first time data regarding the role of COX-1 inhibition in NIUA. Patients with this entity show a similar pattern eicosanoid levels following ASA challenge to those with NECD. Further studies will help ascertain the cell populations involved and the underlying molecular mechanisms.

Discrepancies in the diagnosis and classification of nonsteroidal anti-inflammatory drug hypersensitivity reactions in children

BackgroundHypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently encountered in daily clinical practice. The aim of this study was to determine the confirmation rates, risk factors of NSAID hypersensitivity in children and to try to classify them with a standardized diagnostic protocol. MethodsAll patients with a suspicion of NSAID-induced hypersensitivity were evaluated with European Network for drug Allergy (ENDA) recommendations. The children were classified as selective responders (SRs) or cross-intolerant (CI) depending on the drug provocation test (DPT) results. ResultsWe evaluated 106 children with a suspicion of NSAID hypersensitivity. NSAID hypersensitivity was confirmed with tests in 31 patients; 4 (12.9%) were diagnosed by skin tests and 27 (87.1%) by DPTs and two patients with a history of anaphylaxis by medical records. Eleven patients (33.3%) were classified as SRs, whereas twenty-two (66.6%) children as CIs. SRs and CIs were further classified as NSAID-induced urticaria/angioedema (n = 8), NSAID-exacerbated cutaneous disease (n = 6) and NSAID-exacerbated respiratory disease (n = 1) and single NSAID-induced urticaria/angioedema and/or anaphylaxis (n = 11). Eight (24.2%) patients could not be categorized according to ENDA/GA2LEN classification; one CI patient could not be classified based on pathomechanisms, seven CIs could not be categorized based on the underlying disease and clinical manifestations. A reaction within an hour of drug intake (aOR:3.0, 95% confidence interval: 1.18–7.67, p = 0.021), a history with multiple NSAIDs hypersensitivity (aOR:2.9, 95% confidence interval: 1.16–7.60, p = 0.022), and family history of atopy (aOR:4.0, 95% confidence interval: 1.50–10.82, p = 0.006) were found as the independent risk factors related to confirmed NSAID hypersensitivity. ConclusionsThis study suggests the presence of different phenotypes which do not fit into the current classifications in children with NSAID hypersensitivity.

Different Phenotypes of Non-Steroidal Anti-Inflammatory Drug Hypersensitivity during Childhood

Background: Although non-steroidal anti-inflammatory drug hypersensitivity (NSAID-H) has been widely studied in adults, there is still a lack of data regarding the features and phenotypes of NSAID-H in children. Our aim was to define risk factors and different phenotypes according to clinical patterns. Methods: Patients with a history of reaction to any NSAIDs referred between January 2012 and October 2014 were included. After completing a European Network for Drug Allergy (ENDA) questionnaire, initial skin and/or oral provocation tests (OPTs) were performed for the offending drug. Additional OPTs were done with aspirin in case of NSAID-H to determine cross-reactivity. NSAID-hypersensitive patients were defined as being either a selective responder (SR) or cross-intolerant (CI) and further categorized according to either the ENDA/GA²LEN classification or an alternative scheme by Caimmi et al. [Int Arch Allergy Immunol 2012;159:306-312]. Results: Among 121 patients [58.7% male, average age 7.8 years (4.7-10.8)] with 161 NSAID-related reactions, 110 patients with 148 reactions were assessed. NSAID-H was diagnosed in 30 (27%) patients with 37 (25%) reactions. Multivariate regression analysis revealed that an immediate-type reaction and respiratory symptoms during the reaction increased the risk of a reproducible NSAID-related reaction (OR 3.508, 95% CI 1.42-8.7, p = 0.007; OR 3.951, 95% CI 1.33-11.77, p = 0.014, respectively). Additional OPTs revealed 13 SRs and 14 CIs. A family history of allergic disease was more frequent in CIs compared to SRs (57.1 vs. 15.4%, p = 0.031). Reactions belonging to CIs were more frequently characterized by angioedema compared to those of SRs (81.3 vs. 46.2%, p = 0.019). SRs and CIs were further classified as single NSAID-induced urticaria/angioedema and/or anaphylaxis (n = 13), NSAID-induced urticaria/angioedema (n = 7), NSAID-exacerbated cutaneous disease (n = 2) and NSAID-exacerbated respiratory disease (n = 1). Four CIs could not be categorized according to either classification system. One SR could not be categorized according to ENDA/GA²LEN. Conclusion: During childhood, NSAID-H exhibits different phenotypes and the majority of them can be categorized with current classification systems; however, classifications based on adult data may not exactly fit NSAID-H in paediatric patients.

Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug–related urticaria and angioedema

Nonsteroidal anti-inflammatory drug (NSAID)-induced urticarial and angioedema reactions are among the most commonly encountered drug hypersensitivity reactions in clinical practice. Three major clinical phenotypes of NSAID-induced acute skin reactions manifesting with angioedema, urticaria, or both have been distinguished: NSAID-exacerbated cutaneous disease, nonsteroidal anti-inflammatory drug-induced urticaria/angioedema (NIUA), and single NSAID-induced urticaria and angioedema. In some patients clinical history alone might be sufficient to establish the diagnosis of a specific type of NSAID hypersensitivity, whereas in other cases oral provocation challenges are necessary to confirm the diagnosis. Moreover, classification of the type of cutaneous reaction is critical for proper management. For example, in patients with single NSAID-induced reactions, chemically nonrelated COX-1 inhibitors can be safely used. However, there is cross-reactivity between the NSAIDs in patients with NSAID-exacerbated cutaneous disease and NIUA, and thus only use of selective COX-2 inhibitors can replace the culprit drug if the chronic treatment is necessary, although aspirin desensitization will allow for chronic treatment with NSAIDs in some patients with NIUA. In this review we present a practical clinical approach to the patient with NSAID-induced urticaria and angioedema.

Management of patients with nonaspirin-exacerbated respiratory disease aspirin hypersensitivity reactions.

Because of widespread use, nonsteroidal anti-inflammatory drugs (NSAIDs) are the second most common cause of all adverse drug reactions, with hypersensitivity reported in ∼1% of the population. NSAID hypersensitivity can be categorized into five types by the underlying disease, symptoms of reaction, and timing of reaction. These include rhinitis and asthma induced by NSAIDs (also known as aspirin-exacerbated respiratory disease), NSAID-exacerbated cutaneous disease (NECD), urticaria or angioedema induced by multiple NSAIDs, single NSAID-induced reactions, and delayed NSAID reactions. NECD occurs in one-third of patients with chronic urticaria who develop an exacerbation of their urticaria, sometimes with angioedema, typically beginning 30-90 minutes after ingestion of NSAIDs that inhibit cyclooxygenase (COX)-1. In urticaria or angioedema induced by multiple NSAIDs, patients without underlying disease develop urticaria or angioedema 30-90 minutes after ingestion of COX-1-inhibiting NSAIDs including aspirin. Single NSAID-induced reactions are immediate and specific to a single NSAID and are thought to occur because of an IgE-mediated reaction against a specific epitope of the NSAID. Delayed NSAID reactions occur days to weeks after initiating an NSAID. These are T-cell mediated and not amenable to desensitization or rechallenge. Classifying the type of NSAID hypersensitivity is important because many patients with a prior history of urticaria or angioedema induced by multiple NSAIDs will often tolerate aspirin test dose. This would allow the use of an aspirin for primary or secondary prevention in patients with coronary artery disease despite a presumed history of NSAID hypersensitivity.