Background/Objectives: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most consumed drugs worldwide and the main cause of drug hypersensitivity reactions (HSRs). The most common NSAID-HSR class is cross-hypersensitivity (CR), with patients reacting to NSAIDs from different chemical groups without specific immunological recognition, with NSAID-induced acute urticaria/angioedema (NIUA) being the most frequent clinical phenotype. Although CR-HSRs are triggered by arachidonic acid (AA) alterations following cyclooxygenase (COX)-1 inhibition and cysteinyl-leukotrienes synthesis by 5-lypoxygenase (5-LO), current evidence supports the participation of additional mechanisms. As COX-1 and 5-LO head oxidative pathways, it is conceivable that enzymes participating in antioxidant control are involved in these mechanisms. In addition, as the CR-HSR susceptibility seems to be influenced by genetic factors, the possibility of genetic variants playing a role in such enzymes should not be excluded. Methods: In this observational case-control study, we analysed for the first time in NIUA the overall genetic variability in key antioxidant defence enzymes genes, including catalase (CAT), glutathione peroxidase (GPX)-1 and 3, and superoxide dismutase (SOD)-1. We selected a set of tagging single nucleotide polymorphisms (tSNPs) in these genes using data from Europeans in the 1000 Genomes Project. Two independent Spanish populations (discovery and replication) of NIUA patients and NSAID-tolerant individuals were included. Results: Twenty-six tSNPs were genotyped in the discovery population, with three that were significantly associated with NIUA: rs3448 (GPX-1), rs3792798 (GPX-3), and rs10432782 (SOD-1). They were then genotyped in the replication group, with rs3792798 being protective and rs10432782 being associated with an increased NIUA risk. Conclusions: Our results suggest that a role for antioxidant enzyme polymorphisms in NIUA is required. Nevertheless, further research is needed to replicate our findings in other populations and their meaning at the molecular level and to investigate the role of such variants in other CR-HSR-induced phenotypes.

Background and Objectives: Hereditary angioedema (HAE) represents a specific form of life-threatening inborn errors of immunity. Current guidelines recommend regular assessment of the disease burden, disease control and quality of life. This study describes the profile of HAE patients in Slovakia, disease control, quality of life, states of anxiety and depression, and socioeconomic situation. Materials and Methods: We used a set of standardized questionnaires-AE-QoL, AECT, HADS and Socioeconomic Status Questionnaire, and a non-standardized questionnaire-to describe the characteristics of the population. Results: We collected data on 56.44% (57 out of 101) of HAE adult patients registered in Slovakia. Moderate to severe HAE was present in 61.40% of patients; 73.68% were on long-term prophylactic treatment; and 19.30% received rescue treatment due to an acute HAE attack during the last 4 weeks. Most patients achieved lower AE-QoL scores, indicating a good quality of life. The AECT score indicated well-controlled disease in 91.23% of patients. Anxiety and/or depression scores were higher than normal in 17.54% of patients. Patients with HAE earned less than the average population, but most of them were economically active with relatively low rates of presenteeism and absenteeism. Only a minority of patients used social system benefits. Patients were exclusively cared for by relatives. Conclusions: The QoL scores achieved in all three standardized questionnaires indicate a good quality of life of HAE patients in Slovakia, which is associated with a high and specialized standard of care. Anxiety and/or depression were present in 17.54% of patients. Direct patients costs and social care costs are low, but there is an indirect socioeconomic burden on patients and their families.

Background/Objectives: Chronic urticaria (CU) is a heterogeneous inflammatory disorder generally attributed to mast cell activation. However, emerging evidence suggests that metabolic reprogramming and systemic immune dysregulation also contribute to the disease pathophysiology. This study aimed to investigate the interplay between epithelial barrier integrity, innate immune regulation, metabolic activity, and mast cell effector mechanisms in CU. Methods: Forty CU patients and 40 healthy controls were evaluated. Clinical parameters included disease severity, disease subtype, antihistamine response, IgE levels, anti-TPO status, gastrointestinal symptoms, and angioedema. Serum levels of histamine, intestinal fatty acid-binding protein (IFABP), soluble CD14 (sCD14), diamine oxidase (DAO), D-lactic acid, endotoxin, zonulin, calprotectin, and related ratios were measured. Disease activity and control were assessed using the UAS7 and UCT scores. Results: CU patients exhibited significantly higher DAO (p = 0.003) and lactic acid (p = 0.004) levels compared to controls, whereas other markers showed no significant differences. In anti-TPO-positive patients, sCD14 levels were reduced (p = 0.024), while histamine/sCD14 (p = 0.005), lactic acid/sCD14 (p = 0.014), IFABP/sCD14 (p = 0.008), and zonulin/sCD14 (p = 0.027) were significantly elevated, suggesting relative amplification of metabolic and barrier-related signals under impaired innate immune regulation. Severe anti-TPO-positive patients exhibited lower sCD14 (p = 0.022) and NLR (p = 0.013) but higher UAS7 (p = 0.032), histamine (p = 0.011), calprotectin (p = 0.041), and CD14-normalized ratios, including histamine (p = 0.003), IFABP (p = 0.028), lactic acid (p = 0.019), zonulin (p = 0.029), and calprotectin (p = 0.011) compared with severe anti-TPO-negative patients, indicating a mast cell-dominant and metabolically active inflammatory phenotype. The lactic acid/DAO ratio was significantly lower in controlled versus uncontrolled CU (p = 0.013) and showed discriminatory potential for disease control. Patients with angioedema had higher CRP (p = 0.038) and UAS7 scores (p < 0.001). Conclusions: CU exhibits marked immunometabolic heterogeneity. Elevated DAO and lactic acid indicate increased histamine turnover and metabolic activation, whereas altered sCD14-normalized biomarker profiles reveal immune dysregulation in anti-TPO-positive patients. Severe CU with features suggestive of thyroid autoimmunity manifests as a mast cell-dominant, metabolically active phenotype with relative suppression of innate immune modulators, contrasting with alternative pathways in other CU phenotypes. The lactic acid/DAO ratio may serve as a candidate biomarker of disease control. These results underscore the importance of phenotype-tailored therapeutic strategies in CU.

Background: The interaction between coagulation pathways, inflammatory markers, and hematological parameters has not been sufficiently clarified in patients with chronic angioedema (AE) and urticaria. This study aimed to validate previously observed associations and to further explore their relationship with clinical disease control. Methods: In this cross-sectional validation study, 102 participants were enrolled and stratified into three groups: isolated AE (n = 33), AE associated with urticaria (AE/Urt; n = 34), and healthy controls (n = 35). Serum levels of coagulation factors (D-dimer, fibrinogen, factor VII), inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]), and complete blood count parameters were analyzed. Disease control was assessed using the Angioedema Control Test (AECT). Appropriate non-parametric statistical tests were applied. Results: Only D-dimer values differed significantly between groups and were higher in patients with AE/Urt than in controls. At the same time, D-dimers were significantly more often elevated in both AE groups than in healthy individuals. Additionally, CRP values in both AE groups were significantly more often elevated than in controls, with significantly higher values in both AE groups (in both groups 85%) than in controls (57%). Coagulation markers and CRP demonstrated a positive correlation with age (r = 0.268-0.392; p ≤ 0.007), with fibrinogen of all coagulation markers showing the strongest age dependency (r = 0.334; p = 0.001). Gender-related differences in coagulation parameters were not statistically significant, although elevated fibrinogen levels were more common in male participants (p = 0.030). Disease control did not correlate linearly with any inflammatory markers, coagulation factor, age or gender. Conclusions: The findings support a contributory role of coagulation pathway activation and systemic inflammation in the pathophysiology of chronic angioedema and urticaria. These mechanisms may influence clinical disease expression and could represent potential targets for improved diagnostic stratification and therapeutic approaches. However, the interpretation of the present results should be approached with caution in light of several important study limitations, including demographic heterogeneity between the study groups and the relatively limited sample size.

Background: Urticaria, particularly chronic urticaria (CU), is a highly prevalent inflammatory skin disorder characterized by recurrent wheals and/or angioedema with a fluctuating and unpredictable course that significantly impairs quality of life and requires long-term monitoring. Despite established therapeutic guidelines, disease control remains suboptimal in a considerable proportion of patients. Telemedicine has emerged as a promising adjunctive strategy for chronic disease management. This review aims to critically evaluate the role, applications, benefits, and limitations of telemedicine and digital health interventions in urticaria management. Methods: A scoping review of the literature was conducted focusing on studies addressing telemedicine, digital patient-reported outcomes, mobile health applications, and remote monitoring strategies in urticaria. Evidence from pandemic and post-pandemic telemedicine models was also analyzed to identify transferable approaches. Results: Telemedicine demonstrates significant potential in urticaria management by enabling structured symptom monitoring, facilitating remote follow-up during therapeutic escalation (including biologic therapies), improving patient empowerment and adherence, and reducing healthcare utilization and indirect costs. Digital tools such as electronic diaries and validated PRO-based applications support continuous disease assessment. However, telemedicine cannot replace direct clinical examination, and limitations include diagnostic uncertainty, digital inequalities, data privacy concerns, and lack of large disease specific trials. Conclusions: Telemedicine represents a valuable complementary and integrative model for urticaria care, particularly suited for chronic disease monitoring. Hybrid care pathways combining remote and in-person management appear to be the most effective and sustainable strategy. Further high-quality urticaria-specific studies and standardized digital frameworks are required to optimize its clinical implementation.

Yellow urticaria is a rare clinical variant of urticaria characterized by yellowish wheals, typically associated with hyperbilirubinemia. Its occurrence as a transfusion-related reaction is uncommon and may mimic more serious transfusion complications. We report the case of a 15-year-old Saudi female patient who presented with prolonged vaginal bleeding and severe iron deficiency anemia requiring packed red blood cell transfusion. Approximately 15 minutes after transfusion initiation, she developed pruritic yellowish urticarial wheals over the trunk and extremities, without angioedema or hemodynamic instability. Laboratory evaluation revealed mild hyperbilirubinemia, while direct and indirect Coombs tests were negative, and no clinical or laboratory evidence suggestive of hemolysis was identified. The transfusion was temporarily interrupted, and the patient was treated with antihistamines, corticosteroids, and epinephrine, leading to complete resolution of the lesions within 24 hours. Transfusion was later resumed without recurrence. This case highlights transfusion-related yellow urticaria as a benign but rare reaction. Early recognition is essential to avoid misdiagnosis and unnecessary interruption of life-saving transfusion therapy.

Background and Clinical Significance: Angiotensin-converting enzyme inhibitors (ACE-Is) are commonly used for treatment of hypertension and are well known among primary care specialists. ACE-I-induced angioedema is a rare, yet possible side effect. It should not be taken lightly, as it can be life-threatening. It is characterized by erythematous or skin-coloured, self-limiting, localized, non-pitting swelling of the submucosal and/or subcutaneous layers of tissue. Usually, it develops in the first year of using the medication, although it can also start several years after using it. Herein, we describe a late-onset ACE-I-induced angioedema, which developed 7 years after using the ACE-I. This case report depicts the challenges of diagnosing ACE-I-induced angioedema, especially if it is late-onset. It highlights the importance of actively asking patients questions about possible side effects of medication even several years after using it and the patients themselves not having any complaints. Case Presentation: We present a 61-year-old Caucasian male with recurring swelling of the lips, tongue and an uncomfortable feeling in the throat, which started 7 years after using an ACE-I: perindopril. There was no airway obstruction or urticaria in any of the episodes. Hereditary angioedema was ruled out by blood analysis. Based on the clinical presentation, images and blood analysis, it was diagnosed as late-onset ACE-I-induced angioedema. After discontinuing the ACE-I, there were two more episodes of angioedema reported, which were a lot milder in symptoms and lasted a shorter time period. Since then, there have been no other episodes of angioedema. Conclusions: It is important to keep in mind angioedema as a possible side effect for patients on ACE-Is. Patients should be regularly and actively questioned about side effects, even if the medication has been started several years ago and no complaints are brought up by the patient.

Urticaria is a condition characterized by the presence of pruritic wheals and/or angioedema, and is classified according to its duration as acute (less than or equal to 6 weeks) and chronic (CU) (greater than 6 weeks). Chronic urticaria is subdivided into chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), depending on the presence or absence of a defined stimulus. The predominant form is CSU, affecting more than 75% of patients. Despite this, in some cases, both types of CU may coexist. The lifetime prevalence of CU is approximately 1%, with a 2:1 ratio of women predominating. The maximum incidence is observed between 20 and 40 years of age, being most of the time self-limited, with a duration between 1 to 5 years, although in up to 20% of patients it can last longer, generating great affectation in the quality of life, academic and/or work performance. The diagnosis of CU is clinical, based on the patient's history and physical examination. Laboratory tests are requested based on the patient's clinical history, and extensive laboratory tests are most often unnecessary. To date, there are no curative treatments for this pathology, and treatment is based on the use of 2nd generation antihistamines, the dose of which can be quadrupled according to response. In patients who are refractory to antihistamines, systemic treatments such as omalizumab, a monoclonal antibody that must be indicated by a specialist, is suggested. The national consensus on the diagnosis and treatment of chronic urticaria is presented below, comprising Parts I and II. The objective of this consensus is to review the diagnostic and therapeutic recommendations for CU based on the experience of expert dermatologist and immunologists belonging to the respective Chilean scientific societies, in relation to the available guidelines and evidence.

Hemophilia and hereditary angioedema (HAE) are rare monogenic disorders characterized by the dysregulation of serine protease-based biological pathways, that is, blood coagulation and the kallikrein-kinin system. Although clinical manifestations differ profoundly (bleeding vs angioedema), both diseases have recently undergone parallel therapeutic revolutions, shaped by advances in molecular biology and biotechnology. Early management in the 1970s relied for both diseases on the episodic administration of plasma-derived products, subsequently replaced by recombinant products that improved safety and feasibility of prophylaxis regimens. In the last 20 years, the development of nonreplacement products, such as emicizumab and rebalancing agents in hemophilia and kallikrein/bradykinin pathway inhibitors in HAE, shifted clinical practice from the episodic management of clinical events to their prevention. More recently, gene and RNA-based therapies are further transforming both diseases toward curative attempts: in hemophilia, adeno-associated virus vector-mediated gene therapy and lentiviral stem-cell approaches; in HAE, antisense oligonucleotide-mediated kallikrein suppression. Emerging genome-editing approaches and biomarker- and genotype-driven strategies are poised to further improve and personalize treatment. The therapeutic trajectories of rare diseases such as hemophilia and HAE illustrate how mechanistic insights enable the transition from the episodic management of acute events to long-term disease control, offering prospects for curative interventions.