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The recent recognition of a syndrome of tick-acquired mammalian meat allergy has transformed the previously held view that mammalian meat is an uncommon allergen. The syndrome, mediated by IgE antibodies against the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), can also involve reactions to visceral organs, dairy, gelatin and other products, including medications sourced from non-primate mammals. Thus, fittingly, this allergic disorder is now called the alpha-gal syndrome (AGS). The syndrome is strikingly regional, reflecting the important role of tick bites in sensitization, and is more common in demographic groups at risk of tick exposure. Reactions in AGS are delayed, often by 2-6 h after ingestion of mammalian meat. In addition to classic allergic symptomatology such as urticaria and anaphylaxis, AGS is increasingly recognized as a cause of isolated gastrointestinal morbidity and alpha-gal sensitization has also been linked with cardiovascular disease. The unusual link with tick bites may be explained by the fact that allergic cells and mediators are mobilized to the site of tick bites and play a role in resistance against ticks and tick-borne infections. IgE directed to alpha-gal is likely an incidental consequence of what is otherwise an adaptive immune strategy for host defense against endo- and ectoparasites, including ticks., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Coronavirus disease (COVID-19) pandemic presents several dermatological manifestations described in the present indexed literature, with around 700 cases reported until May 2020, some described as urticaria or urticarial rashes. Urticaria is constituted by evanescent erythematous-edematous lesions (wheals and flare), which does not persist in the same site for more than 24 to 48 hours and appears in other topographic localization, resolving without residual hyper pigmentation. During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, some cytokines are synthesized, including Interferon (IFN) type I, TNF-α, and chemokines which may induce mast cells (MCs) and basophils degranulation by mechanisms similar to the autoinflammatory monogenic or polygenic diseases. In this article, we discuss the spectrum of the urticaria and urticarial-like lesions in the COVID-19's era, besides other aspects related to innate and adaptative immune response to viral infections, interactions between dermal dendritic cells and MCs, and degranulation of MCs by different stimuli. Plasmacytoid dendritic cells share, in allergic patients, expression of the high-affinity IgE receptors on cell membranes and demonstrated a low pattern of type I IFN secretion in viral infections. We discuss the previous descriptions of the effects of omalizumab, a monoclonal antibody directed to IgE and high-affinity IgE receptors, to improve the IFN responses and enhance their antiviral effects., (© 2020 Wiley Periodicals LLC.)

Many women experience some skin reaction or trouble in their monthly menstrual cycle, including the exacerbation of pre-existing diseases and skin eruptions directly associated with sex hormones. We herein report a Japanese woman who experienced repeated systemic urticaria in her premenstrual period, and was diagnosed as having estrogen dermatitis based on a positive result of intradermal estrogen skin test. Of note, the expression of estrogen receptor-β was increased in small dermal vessels of this case as well as in those of patients with other inflammatory skin diseases. These results suggest that inflammation may induce estrogen receptor-β expression in small dermal vessels, which potentially modifies the pathological skin inflammation during the menstrual period, leading to the development of estrogen dermatitis., (© 2019 Japanese Dermatological Association.)

Antihistamines are the first-line treatment option for chronic urticaria. In recent years, omalizumab, an anti-immunoglobulin-E humanized monoclonal antibody, has been used in patients with recalcitrant disease. The present study aimed to retrospectively evaluate the efficacy and safety of omalizumab and determine whether there was a difference between complete and partial responses to omalizumab with respect to age, gender, disease duration and coexistence of angioedema. From May 2014 to December 2016, a total of 40 refractory chronic urticaria patients were treated with omalizumab. Complete response was observed in 19 (47.5%) patients, and partial response was observed in 18 (45%) patients. There were no statistically significant differences between the rates of complete and partial responses in patients with respect to gender, age, and disease duration. However, complete response was more frequent (60%) in patients without angioedema. Remission was observed in 40.5% (n = 15) of patients, and the follow-up time was 5.5 ± 2.4 months. There was a statistically significant association between remission and coexistence of angioedema (p < .05). Eighty-seven percent (13/15) of the remission patients did not have angioedema. Thus, omalizumab can be used effectively and safely in refractory chronic urticaria patients. However, the coexistence of angioedema may be an unfavorable factor for complete response and remission., (© 2018 Wiley Periodicals, Inc.)

Chronic urticaria (CU) may be closely pathogenically related to systemic lupus erythematosus (SLE). This study aims to investigate the association between CU and SLE patients in Taiwan. A nationwide population-based cohort study from 1997 to 2013 was conducted. Investigated subjects were selected from the Taiwan National Health Insurance Research Database using the International Classification of Disease, Ninth Revision code. Participants consisted of 13 845 subjects newly diagnosed with CU from 2003 to 2013. We estimated the incidence risk of SLE among patients with CU by time-to-event analysis. Patients with CU were more likely to be female, and had a significant difference in urbanization and length of hospital stays (P < 0.0001). The incidence rates of SLE for the CU and control groups were 3.55 and 1.68, respectively. The crude hazard ratio of SLE among subjects with CU was 2.113 compared with the non-urticarial control group. After adjusting the demographic, length of hospital stay and comorbidity, the adjusted hazard ratio (aHR) of SLE was still significantly higher in the CU group (aHR = 2.113) compared with the control group. The use of non-steroidal anti-inflammatory drugs or corticosteroids may decrease the risk of SLE in patients with CU (P = 0.0216 and 0.0120, respectively). In conclusion, CU is associated with a higher risk of incidental SLE in this population-based, nationwide, cohort study. Inflammation and immune dysregulation are considered two potential mechanisms. Clinically, patients with urticaria should be carefully evaluated for risk of future SLE., (© 2018 Japanese Dermatological Association.)

The clinical features of urticaria and anaphylaxis are similar, and they share common causal immune-mediated pathways. We aimed to investigate the risk of anaphylaxis among patients with urticaria. A 12-year population-based retrospective cohort study was conducted. Investigated subjects were identified from the Taiwan National Health Insurance Research Database by the International Classification of Disease, Ninth Revision, Clinical Modification. We included 126 031 subjects with newly diagnosed urticaria and 252 062 matched controls between 2000 and 2013. Risk of anaphylaxis among patients with urticaria was calculated by calculating adjusted hazards ratios (HR) after matching for confounding comorbidities. Urticaria was more common in women than it was in men (58% vs 42%), with a peak onset age of 20-40 years. The number of comorbidities including asthma, allergic rhinitis, herpes zoster, hepatitis B and C, rheumatoid arthritis and gout were higher in patients with urticaria than that in age- and sex-matched controls. The crude HR for anaphylaxis among urticaria subjects was 2.883 (95% confidence interval [CI], 2.787-2.982; P < 0.001). After adjustment for potential confounders which have been proposed to increase the risk of anaphylaxis, patients with urticaria were found to be at a significantly high risk of anaphylaxis with an adjusted HR of 2.529 (95% CI, 2.442-2.619; P < 0.001). We conclude that the incidence rate of anaphylaxis is significantly high in patients with urticaria in Taiwan., (© 2018 Japanese Dermatological Association.)

Background: Elevated levels of C-reactive protein (CRP), a sensitive marker of inflammation, have been consistently reported in chronic spontaneous urticaria (CSU). Here, we retrospectively analyzed data from 1253 CSU patients from 2 centers to answer the following questions: (i) What is the prevalence of elevated levels of CRP in CSU? (ii) Why do CSU patients show elevated levels of CRP? (iii) Are elevated CRP levels relevant?, Methods: Serum levels of CRP were measured by the nephelometric method. We collected information regarding various laboratory tests including ESR, CBC with differential, D-dimer, fibrinogen, C3, C4, IL-6, etc. For most patients, we also collected data on age, gender, duration of CSU, presence of angioedema, activity (UAS at the time of blood sampling and for 7 days), quality of life (CU-Q2oL and/or DLQI), comorbidities and possible causes of CSU, and autologous serum skin test (ASST) response. The efficacy of second-generation antihistamines was evaluated on the day of blood collecting., Results: One-third of CSU patients had elevated levels of CRP. Higher levels of CRP were associated with ASST positivity (P = .009) and arterial hypertension (P = .005), but not with other possible causes or comorbidities of CSU. C-reactive protein correlated with urticaria activity (P < .001), quality of life impairment (P = .026), and inflammatory and coagulation markers (P < .001). C-reactive protein levels were significantly higher in nonresponders to antihistamines as compared to responders (P < .001)., Conclusion: Elevated levels of CRP are common and relevant in CSU patients. The assessment of CRP levels may help to optimize the management of patients with CSU., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Omalizumab is an effective and well-tolerated treatment for chronic spontaneous urticaria (CSU). Markers and predictors of response are largely unknown, but needed to optimize omalizumab treatment. Omalizumab targets IgE, and IgE levels may be linked to the effects of treatment. We evaluated whether response rates to treatment with omalizumab in patients with CSU are linked to their baseline IgE levels, their IgE levels after omalizumab treatment, and the ratio of on treatment IgE and baseline IgE levels., Methods: Chronic spontaneous urticaria (CSU) patients (n = 113) were treated with omalizumab 300 mg/4 weeks for 12 weeks, when their treatment responses, that is, no, partial, or complete response, were assessed by use of the urticaria activity score, physician and patient visual analog scale, and treatment effectiveness score. Total IgE levels were measured before treatment (bIgE) with omalizumab and 4 weeks thereafter (w4IgE)., Results: Nonresponders to omalizumab had significantly lower bIgE levels (17.9, 17.0-55.0 IU/mL) than partial responders (82.0, 46.2-126.5 IU/mL, P = .008) and complete responders (73.7, 19.45-153.8 IU/mL, P = .032). Nonresponders also had lower w4IgE levels and lower ratios of w4IgE/bIgE levels than partial and complete responders (P < .001). Nonresponse to omalizumab was best predicted by patients' w4IgE/bIgE ratios, significantly better than by bIgE levels (P = .016)., Conclusions: In CSU, total IgE levels and their change predict the response to treatment with omalizumab. The assessment of pre- and post-treatment IgE levels and their ratio may help to improve the management of CSU in patients who require omalizumab treatment., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Clinical features and basophil activation levels correlate with serum autoreactivity and allergen sensitivity in patients with chronic spontaneous urticaria (CSU)., Objectives: To explore the relationship of the expression patterns of plasma T-helper cell (Th) 1-, Th2-, Th17- and Th22-related cytokines with the serum autoreactivity and the allergen sensitivity in CSU., Method: Twenty related cytokines were measured and analysed in 60 patients with CSU, 15 patients with acute urticaria, 10 patients with atopic dermatitis (AD) and 15 healthy persons, respectively. Autologous serum skin testing (ASST) and skin prick testing (SPT) were performed to detect autoreactivity and allergy sensitivity, respectively. The protein-protein interaction of cytokines and the molecular pathways were analysed by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and KyotoEncyclopedia of Genes and Genomes (KEGG database), respectively., Results: Th1-/Th2- and Th17-related cytokines were significantly elevated and correlated with disease activity in CSU than in healthy controls. Interleukin (IL)-6, IL-10 and IL-13 were significantly higher in acute urticaria than in patients with CSU. Granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-10 and IL-17 were significantly higher in ASST+ than in ASST- CSU patients. IFN-γ, IL-2, IL-12p70 and IL-21 were significantly higher in SPT+ than in SPT- CSU patients. The plasma levels of interferon-γ, IL-2 and IL-21 varied among ASST+/SPT+, ASST+/SPT-, ASST-/SPT+ and ASST-/SPT- CSU subgroups, which appeared to involve the positive regulation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway., Conclusion: This study indicates acute urticaria elicits a more prominent Th2 immune response than CSU. There was association between different expression patterns of plasma Th1-, Th2-, Th17- and Th22-related cytokines and serum autoreactivity or allergen sensitivity in CSU. Further studies on the JAK-STAT pathway in the pathogenesis of CSU are warranted., (© 2017 European Academy of Dermatology and Venereology.)

Background: Chronic urticaria (CU) is a frequent skin disease characterized by relapsing appearance of pruritic hives. While clinical symptoms are due to the release of histamine by cutaneous mast cells, the underlying pathophysiology is still unknown. However, previous studies indicate that basophils might be of relevance. Besides, the occurrence of autoantibodies against IgE or its receptor, FcεRI, and the therapeutic efficacy of anti-IgE antibodies imply that IgE-mediated mechanisms also play an important role in CU., Methods: Reactivity of CU patients' peripheral blood basophils (n=60) to specific anti-FcεRI and IgE-independent fMLP stimulation was determined by basophil activation test in comparison with patients suffering from IgE-mediated allergic rhinitis (n=10) and healthy controls (n=10). In addition, immunoglobulin receptor (FcεRI, FcγRII) expression and surface bound antibodies (IgE, IgG) were quantified on basophils. Furthermore, the autoreactive capacity of CU sera was evaluated and urticaria-related symptoms were assessed by both UCT and CU-Q 2 oL., Results: Stimulating CU patients' basophils via FcεRI, we identified three distinct immunologic phenotypes. One subgroup of patients' basophils reacted to FcεRI stimulation, whereas the others had anti-FcεRI nonreactive basophils. Among the latter, a subgroup with pronounced basopenia was identified. Of note, this group was characterized by augmented serum-induced basophil activation, increased levels of autoantibodies against thyroid peroxidase, and also exhibited the strongest disease impact on their quality of life., Conclusions: Patients with CU can be categorized into three immunologic subgroups based on their basophil reactivity and frequency. These phenotypes are associated with different clinical characteristics, pointing to basophils as important players in CU pathophysiology., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: The knowledge about chronic spontaneous urticaria (CSU) phenotypes is based on its clinical characteristics, associated comorbidities, course of the disease, and its response to the available effective drugs. Genotype expression and its further correlation with CSU phenotypes are still unknown. We describe the cutaneous transcriptome of patients suffering a severely active CSU refractory to antihistamine treatment., Methods: Through the bioinformatic analysis of the whole Human Genome with Oligo Microarrays and quantitative real-time polymerase chain reaction (qPCR), relevant genes expressed in nonlesional (NLS-CSU) and lesional skin (LS-CSU) and peripheral blood were identified in 20 patients suffering from severely active CSU and 10 healthy controls (HCs)., Results: From 39 genes differentially expressed in NLS-CSU when compared with HCs, 31 (79.48%) were confirmed by qPCR corresponding to genes involved in epidermal homeostasis and dermal repair. From the analysis comparing LS-CSU with NLS-CSU, a selection of 142 genes was studied with qPCR, and 103 (72.53%) were confirmed. Differentially expressed genes in the phenomenon of wheal development are involved in a variety of biological functions as, epidermal differentiation, intracellular signal function, transcriptional factors cell cycle differentiation, inflammation, or coagulation. Differentially expressed genes that uniformly increase or decrease along the skin worsening until the wheal appearance is shown., Conclusion: The skin of CSU patients with a severely active disease shows an overall immunological skin involvement showing a peculiar gene profile., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Patients with chronic spontaneous urticaria (CSU) are widely held to often have other autoimmune disorders, including autoimmune thyroid disease. Here, we systematically evaluated the literature on the prevalence of thyroid autoimmunity in CSU and vice versa. There is a strong link between CSU and elevated levels of IgG antithyroid autoantibodies (AAbs), with most of a large number of studies reporting rates of ≥10%. Levels of IgG against thyroid peroxidase (TPO) are more often elevated in CSU than those of other IgG antithyroid AAbs (strong evidence). Levels of IgG antithyroid AAbs are more often elevated in adult patients with CSU than in children (strong evidence). Patients with CSU exhibit significantly higher levels of IgG antithyroid AAbs (strong evidence) and IgE-anti-TPO (weak evidence) than controls. Elevated IgG antithyroid AAbs in CSU are linked to the use of glucocorticoids (weak evidence) but not to disease duration or severity/activity, gender, age, or ASST response (inconsistent evidence). Thyroid dysfunction rates are increased in patients with CSU (strong evidence). Hypothyroidism and Hashimoto's thyroiditis are more common than hyperthyroidism and Graves' disease (strong evidence). Thyroid dysfunction is more common in adult patients with CSU than in children (strong evidence) and in female than in male patients with CSU (weak evidence). Urticaria including CSU is more prevalent in patients with thyroid autoimmunity than in controls (weak evidence). CSU can improve in response to treatment with levothyroxine or other thyroid drugs (strong evidence). Pathogenic mechanisms in CSU patients with thyroid autoimmunity may include IgE against autoantigens, immune complexes, and complement., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequent triggers of drug hypersensitivity with NSAIDs-induced urticaria/angioedema (NIUA) the most common phenotype. Loss of hypersensitivity has been reported for IgE-mediated reactions; however, it has not been assessed in nonimmunological reactions such as NIUA. We evaluated NSAID-hypersensitivity over time in NIUA patients., Methods: Patients confirmed as NIUA by positive drug provocation test (DPT) with acetylsalicylic acid (ASA) during 2005-2012 (V1) were included (n=38). Subjects were prospectively re-evaluated by DPT with ASA/other NSAIDs at two time points between 2013 and 2015 (V2 and V3). Atopy was assessed by skin prick test (SPT) using inhalant and food allergens., Results: Patients were evaluated at V1 and re-evaluated after 60 months (V2; IR:48-81) and a further 18 months (V3; IR:14-24). At V2, the majority (24; 63.15%) tolerated ASA and other NSAIDs (Group A) while 14 (36.84%) still reacted (Group B). At V3, all Group A patients remained tolerant; all Group B patients remained hypersensitive. The number of previous episodes reported at V1 and the percentage of reactions induced by ASA/ibuprofen were significantly lower in Group A (P=.005 and P=.006, respectively). Group A patients developed tolerance 72 months (IR:45-87) after their last evaluated reaction (V1); this interval was shorter in nonatopics (P=.003), patients who experienced reactions over 1 hour after NSAIDs administration (P=.001), and those who experienced isolated urticaria after NSAID intake (P=.024)., Conclusions: NIUA patients may develop tolerance to NSAIDs over time, a process that seems to be influenced by atopy and type of clinical reaction., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Omalizumab is recombinant humanized monoclonal antibody to immunoglobulin E. Guidelines for the treatment of chronic idiopathic urticaria (also known as chronic spontaneous urticaria) recommend the use of omalizumab as third-line therapy in addition to high doses of histamine receptor type 1 (H 1 ) antihistamines when they are unsuccessful as first- and second-line therapy. We performed a systematic review of the literature to identify studies that evaluated the efficacy of omalizumab for the treatment of chronic idiopathic urticaria, in both controlled and real-world settings, to assess its potential role as a preferred therapy. The PubMed, ScienceDirect, LILACS (Latin American and Caribbean Health Sciences Literature), and Google Scholar databases were searched between January 1, 2000, and November 21, 2016. The search was limited to articles published in peer-reviewed journals in the English language, and 29 studies were included in this review. Omalizumab 300 mg administered every 4 weeks appears to be the most effective and safe dosage, with a rapid response time, for the treatment of chronic idiopathic urticaria, with few minor adverse effects, and appears to be safe in the offspring of pregnant patients who received the drug. However, as published studies of omalizumab are sparse, future studies are warranted. When findings are confirmed in larger studies, due to its efficacy, safety, and increased benefit/cost ratio, omalizumab could become the preferred method of treatment for chronic idiopathic urticaria in patients unresponsive to H 1 antihistamines., (© 2017 Pharmacotherapy Publications, Inc.)

Background: The underlying causes and factors contributing to the disease severity of chronic spontaneous urticaria (CSU) are unknown., Objective: Given the important role of basophils in the pathogenesis of urticaria and that CD63 serves as a useful marker for basophil activation and detecting, CD63 expression of basophils is a reliable tool for diagnosing allergy and hypersensitivity reactions to different allergens; the objective of this study was to investigate whether the level of basophil CD63 expression is correlated with allergen sensitization, serum autoreactivity and basophil reactivity in patients with CSU., Methods: Basophil-enriched leucocytes were separated from the blood of 64 patients with chronic urticaria (54 CSU patients and 10 symptomatic dermographism patients), 18 healthy control subjects and seven atopic donors without urticaria. Flow cytometry was then used to detect CD63 expression on the cell membrane of basophils from all samples. Analysis was also preformed on basophils incubated with sera from CSU patients with positive or negative autologous serum skin test (ASST)., Results: CD63 expression was significantly higher in the basophils from patients with CSU than in those from patients with symptomatic dermographism and the healthy control group. The levels of CD63 expression in CSU patients with ASST + and/or allergen sensitization were higher than those with ASST - and/or no allergen sensitization patients. Incubation with ASST + serum resulted in an increased expression of CD63 in the basophils of ASST + CSU patients, whereas no such response was observed in healthy controls or ASST - CSU patients., Conclusion: The increased CD63 expression in basophils from CSU patients may correlate with allergen sensitization, autoreactivity of serum and basophil reactivity. Our results suggest that CD63 may contribute new insight into the pathogenesis of CSU., (© 2016 European Academy of Dermatology and Venereology.)

Background: Cholinergic urticaria (CholU) is a frequent chronic urticaria disorder with itchy weal and flare-type skin reactions in response to physical exercise or passive warming. A higher frequency of atopy among CholU patients has been reported, but the significance of this observation is unclear., Objective: To assess the prevalence and relevance of atopy in CholU patients., Materials and Methods: Thirty CholU patients were assessed for atopic skin diathesis (atopic predisposition) by use of the Erlangen Atopy Score and divided into atopic and non-atopic predisposed CholU individuals. Both groups were assessed for disease severity (CholUSI) and activity (CholUAS7), quality of life impairment [Dermatology Life Quality Index (DLQI) and CU-Q 2 OL], seasonal exacerbation, total and specific serum IgE and comorbidities., Results: CholU patients were found to exhibit high rates of atopic predisposition (57%), with higher prevalence and scores in female than in male patients. High Erlangen Atopy Scores were linked to high CholU severity, activity and impact on QoL. Atopic predisposed CholU patients show different seasonal exacerbation patterns, IgE specificity and comorbidity profiles as compared to non-atopic CholU patients., Conclusion: Atopic predisposition and cholinergic urticaria appear to be linked more closely than previously thought, which suggests shared pathogenetic mechanisms. Atopic patients with cholinergic urticaria have more severe disease and poorer quality of life than those who do not. Thus, all cholinergic urticaria patients should be assessed for atopic predisposition., (© 2016 European Academy of Dermatology and Venereology.)

Background: In March 2014, omalizumab, a monoclonal anti-IgE antibody, was approved for the treatment of chronic spontaneous urticaria (CSU). The primary mode of action of omalizumab is considered to be the reduction in free IgE serum levels and the subsequent down-regulation of FcεRI, the high affinity receptor for IgE, on mast cells and basophils. Recently, it has been suggested that most CSU patients have an autoimmune aetiology which may lead to chronic activation of mast cells and basophils., Objective: To understand more of the mechanisms by which omalizumab may exert its effects in CSU, its efficacy was tested on human mast cells and basophils., Methods: Omalizumab, which was or was not preincubated with serum from healthy donors or CSU patients, was coincubated with isolated healthy donor skin mast cells or peripheral blood-derived monocytes containing 1-2% basophils. Degranulation was induced using anti-human IgE, C5a, or substance P and histamine release determined., Results: Anti-human IgE-induced histamine release from mast cells or basophils was not altered in the presence or absence of omalizumab. In contrast, preincubation of mast cells with DARPin Fc fusion protein, a positive control for negative signalling via FcεRI-FcγRIIb cross activation, significantly diminished histamine release. Moreover, omalizumab, that was preincubated with healthy donor serum, CSU patient serum or auto-reactive CSU serum to allow for the formation of potential immune complexes, did not alter induced histamine release in a coincubation setup with mast cells or basophils as compared to the absence of omalizumab. In vivo, blood basophil numbers and basophil histamine content increase under omalizumab therapy., Conclusion: Our results suggest that the rapid response to omalizumab therapy is more likely to result from the elimination of an activating signal rather than the generation of a negative, inhibitory signal., (© 2014 European Academy of Dermatology and Venereology.)

Chronic spontaneous urticaria (CSU) significantly impacts the quality of life of those affected through symptoms of pruritus and recurrent skin lesions. In active CSU disease, reduced IgE-mediated basophil histamine release (HR) and basopenia are observed. We sought to examine the relationship between interval changes in basophil measures and shifts in patient-reported disease impairment. Simultaneous symptom and basophil evaluations were completed at two sequential study visits, and interval changes in measures were compared between visits for each subject (n = 38). These measures included Skindex-29, current itch and hives scores, total leukocyte histamine content (an indirect measure of blood basophil presence), and basophil HR in response to anti-IgE and formyl-methionine-leucine-phenylalanine. Overall, interval improvements in disease measures in CSU subjects were associated with increased basophil numbers (total leukocyte histamine content) and IgE-mediated HR. This suggests these measures are potential biomarkers for CSU disease improvement and further implicates a role for basophils in CSU., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequent medicaments involved in drug hypersensitivity reactions, with NSAID-induced urticaria/angioedema (NIUA) being the most frequent clinical entity. The natural evolution of NIUA has been suggested to lead to chronic urticaria (CU) in an important proportion of patients, such that NIUA may therefore precede CU. Our aim was to verify whether these entities are related by following up a large cohort of patients with NIUA as well as a control group over a long period of time., Methods: The study comprised three groups: (i) patients with a confirmed history of NIUA (more than two episodes with at least two different NSAIDs or positive drug provocation tests), (ii) patients with more than two episodes of urticaria/angioedema to a single NSAID with good tolerance to a strong COX-1 inhibitor and/or evidence by in vivo tests supporting specific IgE antibodies to the drug (single NSAID-induced urticaria/angioedema, SNIUA), and (iii) controls who tolerated NSAIDs. All cases in the three groups were followed up over a period of 12 years., Results: There were 190 patients with NIUA (64.6% female; mean age 43.71 ± 15.82 years, 110 with SNIUA, and 152 controls. At the 12-year evaluation, 12 patients with NIUA (6.15%) had developed CU over a 1- to 8-year period. Similar proportions were seen in SNIUA and controls., Conclusions: Nonsteroidal anti-inflammatory drugs-induced urticaria/angioedema does not seem to precede the onset of CU over the medium term. Further research including a longer follow-up is necessary to verify this observation., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Hypocomplementemic urticarial vasculitis syndrome (HUVS) is characterized by recurrent urticaria along with dermal vasculitis, arthritis, and glomerulonephritis. Systemic lupus erythematosus (SLE) develops in >50% of patients with HUVS, although the pathogenesis is unknown. The aim of this study was to identify the causative DNA mutations in 2 families with autosomal-recessive HUVS, in order to reveal the pathogenesis and facilitate the laboratory diagnosis., Methods: Autozygosity mapping was combined with whole-exome sequencing., Results: In a family with 3 affected children, we identified a homozygous frameshift mutation, c.289&#95;290delAC, in DNASE1L3. We subsequently identified another homozygous DNASE1L3 mutation leading to exon skipping, c.320+4delAGTA, in an unrelated family. The detected mutations led to loss of function, via either nonsense-mediated messenger RNA decay or abolished endonuclease activity, as demonstrated by a plasmid nicking assay., Conclusion: These results show that HUVS is caused by mutations in DNASE1L3, encoding an endonuclease that previously has been associated with SLE., (Copyright © 2013 by the American College of Rheumatology.)

Background: Multiple NSAID-induced urticaria/angioedema (MNSAID-UA) is an entity well differentiated from aspirin-exacerbated respiratory disease (AERD), although no detailed phenotype analysis has yet been performed. The objective was to evaluate the functional characteristics of MNSAID-UA subjects by analyzing the response to nasal lysine-aspirin challenge and measurement of nasal inflammatory mediator release compared with AERD subjects and controls., Methods: The study included 85 subjects with confirmed hypersensitivity to NSAIDs (≥3 episodes with >2 different NSAIDs or positive drug provocation) with either cutaneous (MNSAID-UA, n = 25) or respiratory manifestations (AERD, n = 60) and 30 tolerant controls (15 aspirin-tolerant asthmatic patients and 15 healthy controls). Nasal lavages at 0, 15, 60, and 120 min after lysine-aspirin challenge were analyzed for ECP, tryptase, PGE2 , PGD2 , LTD4 , and LTE4 ., Results: Lysine nasal challenge was positive in 80% of the AERD cases but positive only in 12% of the MNSAID-UA group. MNSAID-UA subjects showed no changes in nasal ECP, whereas subjects with AERD had increased levels of ECP, with the highest peak at 15 min after challenge (P < 0.05). Tryptase levels were higher in AERD compared with MNSAID-UA and controls with the highest release of tryptase at 60 min (P < 0.05). Significant increases in PGD2 , LTD4 , and LTE4 were observed in AERD (at 60 min for PGD2 , LTD4 , and LTE4 ) but not in MNSAID-UA or control subjects (P < 0.05)., Conclusions: Data support the observation that MNSAID-UA, although sharing a common response with AERD to COX inhibitors, seems to have a distinctive phenotype, based on the response to nasal challenge and the release of inflammatory mediators., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Platelet-activating factor (PAF) causes wheal and flare responses which are abrogated by H1-antihistamines giving rise to the hypothesis that PAF-induced wheal development is secondary to histamine release from dermal mast cells. But is this hypothesis correct?, Methods: Wheal and flare responses were induced by intradermal injection of PAF, codeine and histamine in 14 healthy volunteers. Dermal histamine and PGD2 contractions were measured using microdialysis., Results: PAF, unlike histamine and codeine, did not cause a statistically significant rise in mean histamine levels with ten persons showing negligible histamine release. Codeine caused a significant but variable histamine release, ranging from 29 to 282 ng/ml. Codeine, but not PAF or histamine, caused a small but statistically significant release of PGD2., Conclusion: Wheal and flare reactions in human skin induced by PAF are not associated with histamine release and, therefore, appear to be independent of mast cell degranulation., (© 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Background: Participation of Helicobacter pylori (HP) in the pathogenesis of chronic spontaneous urticaria (CU) is subject to dispute, although its eradication proved to be effective for some patients., Aims: To investigate the cases of CU following eradication of HP., Methods: The cases of patients in whom CU was diagnosed following triple therapy for HP eradication were retrospectively reviewed. The identified patients underwent follow-up examination to exclude drug hypersensitivity and repeated autologous serum skin test (ASST) was done., Results: From 831 patients with CU, 9 (1.08%) cases of CU related to triple therapy for HP eradication have been detected. In 8 (88.9%) patients CU was associated with positive ASST., Conclusions: CU can be triggered by eradication of HP. The pathophysiological mechanisms of CU development following HP eradication are far from being clear, but it could be speculated that the systemic effects of HP eradication may involve some kind of immunomodulation, activating autoimmune mechanisms of CU., (© 2012 Blackwell Publishing Ltd.)

An autoimmune subset of chronic spontaneous urticaria is increasingly being recognized internationally, based on laboratory and clinical evidence that has accrued over the last 20 years. This evidence has been reviewed by a taskforce of the Dermatology section of the European Academy of Allergy and Clinical Immunology. Functional autoantibodies in chronic urticaria (CU) patient sera have been demonstrated against IgE and FcεRIα by basophil and mast cell histamine release assays and by basophil activation assays. Antibody specificity has been confirmed by immunoassay, but there is a poor correlation between functionality and immunoreactivity. Approximately 25% of CU patients have a positive basophil histamine release assay and show autoreactivity (a positive autologous serum skin test), whereas 50% are negative regarding both. Functionality of CU sera appears to be complement dependent on mast cells but not exclusively on basophils. Basophil activation by CU sera is predominantly restricted to IgG1 and IgG3 subclasses. Circumstantial evidence for CU being an autoimmune disease comes from an observed association with other autoimmune diseases, a strong association between serum functionality and HLA-DR4 haplotype and the good response of CU patients to immunotherapies. It was proposed that a study should be undertaken to prospectively validate potentially relevant clinical criteria (from the history, examination and routinely available clinical investigations) against a new 'gold standard' for the diagnosis of ACU (positive autoreactivity, functional bioassay and immunoassay) to define preliminary criteria sets for the diagnosis of ACU based on clinical and laboratory features with highest individual sensitivity and specificity., (© 2012 John Wiley & Sons A/S.)

Background: Allergen-specific immunotherapy (SIT) has long been a controversial treatment for chronic urticaria (CU), although SIT has been used in patients with allergic diseases for more than 90 years., Objectives: To evaluate the efficacy and safety of SIT vs. conventional treatment (CT) in the treatment of CU., Methods: Systematic searches were conducted without language restrictions in MEDLINE, EMBASE, the Cochrane Library, ISI Web of Knowledge, China National Knowledge Infrastructure, and Chinese Scientific Journals Full Text Database. The primary outcomes were efficacy and quality of life (QOL) and the secondary outcomes were relapse rate and adverse events (AEs)., Results: Fourteen studies (1838 patients) were included. None of them was double-blind placebo controlled. Our study demonstrated that SIT seemed to show more clinical efficacy rate (OR 2.39; 95% CI, 1.73-3.30; I(2) = 55%, P = 0.008), more complete recovery rate (OR 2.13; 95% CI, 1.55-2.91; I(2) = 61%, P=0.008) and less relapse rate 2 weeks after treatment (OR 0.38; 95% CI, 0.24-0.61; I(2) = 6%, P=0.20) than CT. Only one study reported improved QOL and no study reported serious AEs after SIT., Conclusions: Current evidence indicates that IgE-mediated allergy may be causative in a small number of CU patients and specific immunotherapy with these allergens may be beneficial in those patients. However, the number of included studies was small and those qualities were low. So, available evidence is not adequate to draw an affirmative conclusion and larger studies of high quality are needed to provide increasingly convincing data and cases., (© 2011 The Authors. Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology.)

A 24-year-old man with a long history of severe atopic eczema presented with a marked exacerbation requiring hospital admission. It emerged that his occupation as an animal house technician required him to work closely with laboratory animals, particularly mice and rats. Radioallergosorbent tests to mice allergens were markedly elevated. Avoidance of animal work, in conjunction with medical treatment, resulted in a marked improvement of his eczema., (© 2011 The Authors. Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists.)

Treatment of chronic urticaria consists of antihistamines as the first-line treatment. For more severe symptoms, combinations can be necessary as well as dose augmentations. The recent guidelines suggest the possibility of using omalizumab in resistant cases, but this therapy is still investigational. We treated two patients with idiopathic recurrent angioedema and 12 patients with chronic spontaneous urticaria (CSU) with omalizumab, who had not benefited from the recommended first-line, second-line and third-line treatments. To evaluate the efficacy of the omalizumab treatment, urticaria activity scores (UAS) and chronic urticaria quality of life (CU-Q2oL) scores were measured at baseline, and at the end of the first and sixth month of the therapy. The dosage and intervals of omalizumab therapy were determined according to the rules suggested for severe asthma treatment. CU-Q2oL scores and UAS displayed significant improvements in all 14 patients. None of the patients reported any adverse effect during the treatment until the submission of this data. Our results show that omalizumab apparently improves CU-Q2oL as well as UAS in treatment-resistant CSU in a real life setting., (© 2012 Japanese Dermatological Association.)

Vitamin D plays key roles in innate and adaptive immunity through the stimulation of Toll-like receptors, increasing pro-inflammatory cytokine production, and possibly enhancing T helper type 2 responses. These mechanisms may explain the growing body of evidence connecting vitamin D to allergic diseases, including asthma, food allergies, and allergic rhinitis. The data relating vitamin D to allergic skin diseases are equivocal with studies linking both high and low vitamin D levels to an increased risk of developing atopic dermatitis. In this paper, we describe the role of vitamin D in the immunopathogenesis of atopic dermatitis and other allergic skin diseases., (© 2011 John Wiley & Sons A/S.)

Background: Chronic urticaria (CU) is one of the most common skin disorders whose pathogenic mechanisms are not fully clarified. Autoimmune aetiology can be ascribed to 45% of patients with CU, and basophil histamine release is positive in 40% of cases. Our aim was to use a novel approach to evaluate the serum permeabilizing effect to identify the mediators of endothelial cell (EC) leakage and to define the role of mast cells (MCs) in the process., Methods: Permeabilizing activity of sera from 19 patients with CU and 11 healthy blood donors was evaluated by measuring serum-induced degranulation of two MC lines, expressing (LAD2) or lacking (HMC-1) the IgE receptor. Mast cell supernatant (SN) was then incubated with an EC monolayer, and endothelial permeability was evaluated by Fluorescein isothiocyanate-bovine serum albumin leakage in a transwell system., Results: All 19 patient sera failed to induce direct EC leakage, but 15/19 and 17/19 promoted degranulation of HMC-1 and LAD2, respectively. Interestingly, 85% of autologous serum skin test-negative sera were able to cause MC degranulation. Also, 17/19 SNs from HMC-1 and all SNs from LAD2 incubated with CU sera increased endothelial permeability. Endothelial cell leakage remained unchanged after Ig depletion and was prevented by antihistamine, platelet-activating factor or leukotriene antagonist., Conclusions: Our study shows that CU sera are able to degranulate MCs through an IgE- and IgG-independent mechanism. The nature of histamine-releasing factors involved is still unclear, but our finding opens new ways to the understanding of the pathogenesis of CU, particularly in patients not showing circulating autoantibodies to FcεRI or IgE., (© 2011 John Wiley & Sons A/S.)

Background/objectives: Compelling evidence indicates a significant role for a population of CD4(+) T regulatory cells in suppressing immune responses and in maintaining immunological homeostasis. This study aims to investigate the potential role of CD4(+) CD25(HIGH) FOXP3(+) T regulatory cells in patients with chronic autoimmune urticaria and to define the characteristics of CD4(+) CD25(HIGH) FOXP3(+) cells in chronic urticaria., Methods: We used flow cytometry to assess the expression of CD4(+) CD25(HIGH) FOXP3(+) cells in the peripheral blood mononuclear cells of patients with chronic autoimmune urticaria., Results: In this study, we found that patients with chronic autoimmune urticaria have a significantly reduced frequency of CD4(+) CD25(HIGH) FOXP3(+) cells (1.39 ± 0.27% vs 2.09 ± 0.34%; P = 0.001) in their peripheral blood, accompanied by a decreased intensity of FOXP3 expression (50.13 ± 9.79 vs 68.19 ± 6.40; P < 0.001). Notably, although patients with chronic idiopathic urticaria had a reduced frequency of CD4(+) CD25(HIGH) FOXP3(+) cells (1.85 ± 0.46% vs 3.64 ± 0.48%; P < 0.001), their FOXP3 expression levels did not differ from those in healthy controls., Conclusions: Patients with chronic autoimmune urticaria displayed a reduced percentage of CD4(+) CD25(+) FOXP3(+) regulatory T cells. The results imply CD4(+) CD25(+) FOXP3(+) regulatory T cells may contribute to the autoimmune pathological process of chronic autoimmune urticaria., (© 2010 The Authors. Australasian Journal of Dermatology © 2010 The Australasian College of Dermatologists.)

Background: The evaluation of disease severity and activity of chronic urticaria (CU) is essential for the adequate treatment of patients. However, there is no reliable biomarker for such evaluations. Recently, markers of blood coagulation and fibrinolysis have been revealed to be elevated in severe cases of CU. In this article, we studied the coagulation/fibrinolysis and inflammation markers and their relationship to disease activity in patients with CU., Methods: Plasma fibrin degradation products (FDP), d-dimer and serum C-reactive protein (CRP) were measured with the assessment of disease severity and skin reaction to autologous serum in 82 patients with CU and 37 patients with acute urticaria, idiopathic angioedema (AE) or inducible types of urticaria (IU)., Results: The levels of FDP in patients with CU were significantly higher than those in patients with IU, but no other differences in FDP, d-dimer and CRP were observed among patients with different types of urticaria. These markers of patients with CU were well correlated with each other and significantly associated with disease severity of CU, but not with skin reactions to autologous serum. In 37 patients with CU, levels of all these parameters reduced as their disease condition improved, while they increased when the disease became aggravated. Regarding FDP, this relationship was observed even if FDP concentrations were within normal range throughout the study., Conclusions: The measurement of plasma FDP, d-dimer and serum CRP may be useful for the assessment of disease activity of CU.

The immunological characterization in the pathogenesis of urticaria, mainly regarding cytokine profile, needs more investigation. In this study, subgroups of the T, B and natural killer (NK) lymphocyte from peripheral blood and serum levels of interleukin (IL)-15, IL-21 and immunoglobulin (Ig)E were examined in patients with acute urticaria (AU) and chronic urticaria (CU). Moreover, symptom scores and course of the patients were assessed. The percentage of NK cells and the ratio of CD4(+)/CD8(+) increased, however, CD8(+) decreased in CU compared to controls (P < 0.01). But no significant changes of T, B and NK lymphocyte were found in AU. IL-15 and IL-21 significantly decreased in AU and CU, but IgE increased. CU with a positive autologous serum skin test were more likely to be associated with longer course and higher CD3(+), B cells and IL-21, and lower IgE (P < 0.01). Weak negative correlations were demonstrated between CD3(+), CD8(+) and scores in CU (r = -0.23, -0.25, P < 0.05). Significant correlations were found between B cells and scores and course in CU (r = 0.49, 0.65, P < 0.01). Moreover, a significant correlation was found between IL-21 and IgE (r = 0.42, P < 0.01) in CU. But no significant correlations were found in AU. Our findings supported the concept that both humoral immunity and cellular immunity dysregulation in the pathogenesis of urticaria - mainly related to the decrease of the serum levels of IL-15 and IL-21 - may induce the increasing expression of IgE produced by B cells.

Background: Although chronic urticaria (CU) is often regarded as autoimmune in nature, only less than 50% of sera from CU patients contain histamine-releasing autoantibodies. This suggests that other factors may contribute to its pathogenesis. We evaluated the possible involvement of vascular endothelial growth factor (VEGF), one of the major mediators of vascular permeability, in CU., Methods: Eighty consecutive adult patients with CU and 53 healthy subjects were studied. VEGF and prothrombin fragment F(1+2) were measured by enzyme immunoassays. Autologous plasma skin test (APST) was performed in CU patients and, in six of them, skin biopsy specimens were taken from wheals to evaluate the immunohistochemical expression of VEGF and eosinophil cationic protein (ECP)., Results: Plasma VEGF concentrations were higher in CU patients (8.00 +/- 0.90 pmol/l) than in controls (0.54 +/- 0.08 pmol/l) (P = 0.0001) and tended to parallel both the severity of CU and to correlate with F(1+2) levels. APST was positive in 85.1% of patients. VEGF concentration was significantly higher in APST-positive than in APST-negative patients (P = 0.0003). Immunohistochemically, all specimens from patients with CU showed a strong expression of VEGF (P = 0.002) that colocalized with ECP, a classic eosinophil marker., Conclusions: VEGF plasma levels are elevated in CU and parallel the disease severity. This supports a possible role of this molecule in CU pathophysiology. Eosinophils are the main cellular source of VEGF in CU lesional skin.

Injection of autologous serum collected during disease activity from some patients with chronic spontaneous urticaria (CU) into clinically normal skin elicits an immediate weal and flare response. This observation provides a convincing demonstration of a circulating factor or factors that may be relevant to the understanding of the pathogenesis and management of the disease. This test has become known as the autologous serum skin test (ASST) and is now widely practised despite incomplete agreement about its value and meaning, the methodology and the definition of a positive response. It should be regarded as a test for autoreactivity rather than a specific test for autoimmune urticaria. It has only moderate specificity as a marker for functional autoantibodies against IgE or the high affinity IgE receptor (FcepsilonRI), detected by the basophil histamine release assay, but high negative predictive value for CU patients without them. It is usually negative in other patterns of CU, including those that are physically induced. Positive ASSTs have been reported in some subjects without CU, including those with multiple drug intolerance, patients with respiratory allergy and healthy controls, although the clinical implications of this are uncertain. It is essential that failsafe precautions are taken to ensure that the patient's own serum is used for skin testing and aseptic procedures are followed for sample preparation and handling. CU patients with a positive ASST (ASST(+)) are more likely to be associated with HLADR4, to have autoimmune thyroid disease, a more prolonged disease course and may be less responsive to H1-antihistamine treatment than those with a negative ASST (ASST(-)) although more evidence is needed to confirm these observations conclusively.

Background: Histamine plays an important role in allergic inflammation. Histamine levels are regulated by histamine N-methyltransferase (HNMT)., Objective: To investigate the functional variability of HNMT gene in relation to genetic polymorphisms in patients with aspirin intolerant chronic urticaria (AICU)., Methods: Two single-nucleotide polymorphisms of the HNMT gene (314C>T, 939A>G) were genotyped in chronic urticaria patients. The functional variability of 3'-untranslated region polymorphism (3'-UTR) was assessed using the pEGFP-HNMT 3'-UTR reporter construct to examine mRNA stability and fluorescence-tagged protein expression. The HNMT enzymatic activities related to the 939A>G polymorphism were examined both in the human mast cells (HMC-1) transfected with the pHNMT CDS-3'-UTR construct and in the patients' red blood cells (RBCs). Histamine release from the basophils of AICU patients was examined., Results: The 939A>G polymorphism was significantly associated with the AICU phenotype, while no association was found with the 314C>T polymorphism. An in vitro functional study using HMC-1 cells demonstrated that the 939A allele gave lower levels of HNMT mRNA stability, HNMT protein expression, and HNMT enzymatic activity and higher histamine release than the 939G allele. The in vivo functional study demonstrated that the AICU patients with the 939A allele had lower HNMT activity in RBC lysates and higher histamine release from their basophils., Conclusion: The HNMT 939A>G polymorphism lowers HNMT enzymatic activity by decreasing HNMT mRNA stability, which leads to an increase in the histamine level and contributes to the development of AICU.

Aim: To compare the patterns of Type 1 sensitization of common food and aeroallergens among infants and older patients with atopic dermatitis (AD)., Methods: All skin prick tests (SPTs) performed over a 6-month period were examined, and patients with urticaria were used for comparison., Results: Dust mite was the most common aeroallergen and dog dander the least common. Egg white was the most common food allergen and beef the least common. Dust mite and peanut sensitization was more prevalent in AD than in urticaria. Dust mite sensitization was more prevalent in older children than infants with AD. Cow's milk sensitization only occurred in one-tenth of these patients. Prevalence of sensitization to common aeroallergens, but not food allergens, was generally higher in children beyond 5 years of age., Conclusion: Milk sensitization is far less prevalent than egg white, and the prevalence does not change beyond infancy. There is no significant change in prevalence in many of the common food allergens beyond infancy. Many infants with AD develop eczema before they show atopy to the common food and aeroallergens. The SPT information is useful in reassuring parents of the unlikelihood of severe Type 1 immediate IgE reaction to some of the common food and aeroallergens, so that empirical and multiple food avoidance/restriction can be avoided.