Second-generation H1-antihistamines Research Articles

Clinical Characteristics, Investigations and Treatment in Children with Chronic Urticaria: An Observational Study.

Background and Objectives: The guidelines for chronic urticaria in children contain recommendations that are often based on adult studies. The diagnostic pathway has not been standardized and the effectiveness of anti-H1, omalizumab, montelukast, and systemic glucocorticoids is rarely reported in the pediatric population. There is a wide variation in the rate of remission of chronic urticaria between studies. The aim of this study is to enhance our understanding of pediatric chronic urticaria. Materials and Methods: This study enrolled 37 children with chronic urticaria aged from 0 to 18 years. Demographic parameters, medical history, clinical features, laboratory data and treatment information were collected. Children were treated with the recommended dosage of second-generation H1-antihistamines, which was increased by up to twofold. Omalizumab was added for refractory anti-H1 patients. A three-day course with systemic glucocorticoids was administered for severe exacerbations. Montelukast was administered to some children. Results: Wheals without angioedema were common. Chronic urticaria was spontaneous in 32 children (86.48%), inducible in 2 (5.41%), induced by a parasite in 1 and vasculitic in 2. Treatment of the potential causes of chronic urticaria was of no benefit, except for eradication of Dientamoeba fragilis. Chronic urticaria was resolved within three years in 45.9% of cases. Allergic diseases were present in nine children (24.32%) and autoimmune diseases were present in three (8.11%). All children were treated with anti-H1 at the licensed dose or at a higher dose. A partial or complete response to anti-H1 was observed in 29 (78.38%) patients. Montelukast showed no benefit. All children treated with omalizumab responded. Systemic glucocorticoids were successfully used to treat exacerbations. Conclusions: Our findings indicate that laboratory tests should not be routinely performed in children with chronic urticaria without clinical suspicion. However, comorbidities such as thyroid autoimmune disease and coeliac disease are suggested to be monitored over the chronic urticaria course. These clinical conditions could be diagnosed from the diagnostic framework of chronic urticaria. Increasing the dosage of anti-H1 and omalizumab was effective in children resistant to standard treatment but we still need further studies to generate a standard patient-centered treatment.

Leukotriene receptor antagonists as adjuvant therapy of antihistamines in chronic urticaria: a systematic review and meta-analysis.

Certain guidelines recommend a second-generation H1-antihistamine (AH) as first-line treatment for patients with chronic urticaria (CU). However, some patients show insufficient response to a standard dose of this therapy and might benefit from adding leukotriene receptor antagonists (LTA). Therefore, we aimed to perform a systematic review and meta-analysis comparing LTA plus antihistamines with antihistamines alone. We performed a systematic review and meta-analysis, searching PubMed, EMBASE, and Cochrane Central for randomized clinical trial (RCT) data comparing LTA plus AH treatment to AH alone in patients with CU. Statistical analysis was performed using R Studio 4.3.2. Heterogeneity was assessed with I2 statistics. Three studies comprising 234 patients with urticaria were included. The mean age was 37.23 years in the leukotriene antagonist + antihistamines (LTA + AH) group and 39.14 years in the antihistamines (AH) group. Follow-up ranged from 2 to 18 months between studies. There was no statistically significant difference between groups in terms of TSS level (SMD: -74.82; 95% CI: -222.66 to 73.02; P = 0.32; I2 = 98%), neither in terms of pruritus (MD: -0.07; 95% CI: -0.42 to 0.28; P = 0.70; I2 = 74%). After sensitivity analysis, with the systematic exclusion of each study from the grouped estimates, the result for TSS level did not change. These findings suggest that leukotriene receptor antagonists with antihistamines do not have better outcomes than antihistamines alone regarding TSS and pruritus in patients with CU.

Identification of pyruvic and maleic acid as potential markers for disease activity and prognosis in chronic urticaria

BackgroundPopulation-based studies have highlighted the link between chronic urticaria (CU) and metabolic syndrome, and metabolic alterations have been revealed in CU. However, to our knowledge, a comprehensive metabolomics study on a large cohort of CU patients has not been reported. ObjectiveTo explore the underlying metabolic subtypes and novel metabolite biomarkers for CU diagnosis and therapy. MethodsPlasma samples from 80 CU patients and 82 healthy controls (HCs) were collected for metabolomics quantification and performed bioinformatics analysis. Another independent cohort consisting of 144 CU patients was studied to validate the findings. Bone marrow-derived mast cells (BMMCs) and IgE-induced passive cutaneous anaphylaxis (PCA) mice were utilized for in vitro and in vivo experiments, respectively. ResultsWe observed clear metabolomics difference between CU and HC. Meanwhile, differential metabolites N6-acetyl-l-lysine, L-aspartate, maleic acid and pyruvic acid were used to respectively construct random forest classifiers, and achieved AUCs greater than 0.85, suggesting their potential as diagnostic biomarkers of CU. More importantly, by exploring the underlying metabolic subtypes of CU, we found that the low abundance of pyruvic acid and maleic acid was significantly related to the activity of CU, poor efficacy of second-generation H1-antihistamines (sgAHs), and short relapse-free time. The results were validated in the independent cohort. Moreover, supplementation with pyruvate or maleate could significantly attenuate IgE-mediated mast cells activation in vitro and in vivo. ConclusionsThe combination of plasma pyruvic acid and maleic acid may be effective biomarkers for predicting the disease activity, therapeutic efficacy as well as prognosis for CU patients.

Intravenous Cetirizine Premedication to Mitigate Infusion-Related Reactions

Infusion-related reactions (IRRs) are a recognized concern for chemotherapy, biologic agents, and newer immunotherapies. Antihistamines are frequently recommended to prevent or manage these reactions. For over 60 years, diphenhydramine has been the only H1 antihistamine for intravenous (IV) administration. It has been considered the standard of care as part of premedication regimens to prevent IRRs associated with these therapies despite the lack of a US Food and Drug Administration (FDA)-approved indication and no evidence of efficacy data. Intravenous cetirizine was approved in 2019 for acute urticaria treatment, making it the only second-generation H1 antihistamine that can be administered intravenously. Compared with diphenhydramine, cetirizine has an improved safety profile with less sedation, fewer contraindications, lower incidence of anticholinergic side effects, and minimal risk of adverse events in elderly patients. A head-to-head study demonstrated that IV cetirizine is as effective as IV diphenhydramine in reducing IRRs and may decrease chair time, treatment center visits, and the need for rescue medication. Over the past 3 decades, the FDA has addressed the issue of IRRs by mandating language regarding the requirement or recommendation for premedication in the label of over 50 FDA-approved infusion products. As more therapeutics have premedication required or recommended, IV cetirizine should be considered an antihistamine for preventing and treating IRRs. In this article, we describe a patient whose IRR was successfully managed with IV cetirizine and discuss first- vs. second-generation H1 antihistamines and their use in treating and preventing IRRs.

Targeting histamine receptor 4 in cholinergic urticaria with izuforant (LEO 152020): results from a phase IIa randomized double-blind placebo-controlled multicentre crossover trial.

Cholinergic urticaria (CholU) is a common subtype of chronic inducible urticaria, where signs and symptoms (e.g. pruritic wheals and angioedema) are triggered by sweating due to physical exercise, passive warming and by other sweat-inducing situations. While guidelines recommend treatment with second-generation H1 antihistamines, approximately 90% of patients report uncontrolled disease. Targeting the histamine 4 receptor (H4R) has shown promise in preclinical/clinical studies of allergic/inflammatory diseases. Izuforant (LEO 152020) is a selective oral H4R antagonist with expected dual antipruritic and anti-inflammatory effects. To assess the effects of izuforant in adults with CholU, a common type of chronic urticaria driven by histamine and characterized by high skin levels of H4R expression. This was a phase IIa randomized double-blind placebo-controlled multicentre crossover trial where patients with CholU with an inadequate response to ≥ 1 standard dose of H1 antihistamine received izuforant 100 mg twice daily or placebo (EUCTR2020-004961-38-DE; NCT04853992). The primary endpoint was change from baseline in Urticaria Activity Score. Exploratory endpoints included CholU activity score over 7 days, urticaria control test, Physician Global Assessment, patient global assessment of severity (PGA-S), provocation tests, Dermatology Life Quality Index and CholU quality of life (CholU-QoL). Pharmacokinetic and pharmacodynamic parameters, and serum biomarkers were assessed, as well as safety and tolerability. Nineteen patients were randomized and included in the full analysis set; 18 completed treatment [mean (SD) age 29.5 (9.8) years; mean (SD) CholU duration 8.0 (6.3) years]. The primary and most of prespecified exploratory endpoints were not met; there were significant improvements in PGA-S for izuforant vs. placebo (P = 0.02), and nonsignificant improvements for other endpoints in quality of life and histamine skin prick test. All adverse events (AEs) experienced with izuforant were considered mild. The most frequently reported (> 1 patient) were nausea (three patients) and upper abdominal pain (two patients), occurring more frequently with izuforant vs. placebo (one patient each). There were no treatment-related serious AEs and no patient receiving izuforant discontinued the study. Treatment with izuforant did not cause downregulation of H4R. This is the first study to explore the role of H4R as a therapeutic target in urticaria. Targeting H4R with izuforant was well tolerated but did not demonstrate significant improvements vs. placebo in the primary endpoint and all but one prespecified exploratory endpoint in CholU.

Особливості анестезіологічної допомоги хворим на холодову кропивницю (огляд літератури)

Cold urticaria (CU) is an allergic reaction that manifests itself as hives-like rashes or red spots in response to general or local cooling of the body. Th e disease can be acquired or hereditary, and in the cold season it can affect all segments of the population. Th is pathological condition, at first glance, does not seem to be a very dangerous variant of a local cold injury, but in persons who are prone to exposure to low temperatures, especially with a burdened cold history, it may be accompanied by chronicity of the process and complicated by neurovasculitis, obliterating endarteritis and secondary Raynaud’s syndrome, may decrease the quality of life of the victims and become a cause of disability. The pathophysiology of CU is largely unknown, but it is likely to be related to immunoglobulin E (IgE) and mast cell activation. Cooling has been reported to induce the release of neutrophilic and eosinophilic chemotactic factors, prostaglandin D2, and tumor necrosis factor (TNF-α). Less common immunologic fi ndings in patients with CU include cryoglobulinemia consisting of monoclonal IgG and mixed IgG/IgM and IgG/IgA cryoglobulin types. The mechanisms of development of CU are mainly determined by the formation of cryoglobulins (cold hemolysins) and subsequent degranulation of mast cells. Th e diagnosis of CU depends on the patient’s history and the results of cold provocation tests. Patients with CU are recommended first of all not to overcool, to take warm showers, to wear warm clothes and a hat, and not to consume cold food and drinks. Treatment options include second-generation H1 antihistamines and glucocorticosteroids. New promising option is omalizumab, a humanized monoclonal antibody derived from a recombinant DNA molecule that targets and selectively binds to circulating IgE and affects mast cells function. In patients with CU undergoing general anesthesia, premedication including antihistamines and corticosteroids is recommended, along with strict maintenance of perioperative normotermia.

Therapeutics of urticaria: Results from a hospital-based multicenter study in China

Background: Therapeutics of urticaria in Chinese outpatients remain to be illustrated. Objectives: To investigate clinical treatment of outpatients with urticaria, and provide real-world evidence for selection of medication regimens. Methods: In this hospital-based multicenter study, urticaria outpatients filled in a questionnaire at initial visit and were followed-up (once per week, for 4 weeks). Results: We recruited 1715 urticaria outpatients and 647 completed 4 week’s follow-up. Their total UAS7 was reduced (27.44 at baseline, 16.87 in 1 week, 12.39 in 2 weeks, 7.21 in 3 weeks, 4.2 in 4 weeks). 71.8% patients recovered from urticaria (therapy was highly effective in 11%, whereas effective in 14.2%). The second-generation H1 antihistamines (sgAHs) (at conventional dose) were the most commonly prescribed drugs, with ebastine, levocetirizine and olopatadine being the leading ones (41.1%, 36.2%, and 16%, respectively). Combinations of several antihistamines (649 cases, 37.8%) at conventional dose were far more common than a single drug at escalated dose (59 cases, 3.4%). The combination of ebastine with levocetirizine was the most frequent options (18.25%, 313 cases), followed by combination of ebastine with compound glycyrrhizin (18.2%, 312 cases). The usage rates of tripterygium glycoside (19.6%), hydroxychloroquine (17.2%) and system application glucocorticoids (5.5%) in angioedema were much higher than in symptomatic dermographism and chronic spontaneous urticaria. Conclusions: This study identifies curative therapy for Chinese outpatients with urticaria. The sgAHs, especially ebastine, are the most commonly prescribed drugs. Olopatadine has fast-acting and curative effects. Compound glycyrrhizin holds potential as a versatile collaborator. Combinations of several antihistamines at conventional dose is common.

Safety of omalizumab in chronic urticaria during pregnancy: a real-life study.

Managing a pregnant patient with chronic spontaneous urticaria (CSU) is often challenging. Recent data have shown that most CSU treatments in pregnant patients are second-generation H1 antihistamines (sgAHs), while data on the safety of omalizumab are scant. To evaluate, in a routine clinical practice setting, the efficacy and safety of omalizumab in patients with severe CSU refractory to sgAHs who either became pregnant during treatment or who started the drug during pregnancy. We conducted a retrospective study of women aged ≥ 18 years who were pregnant, who received one or more doses of omalizumab at any time during their pregnancy or who were taking omalizumab at the time of, or in the 8 weeks before, conception. Twenty-nine pregnant patients were evaluated: 23 (79%) conceived a child while taking omalizumab (group A), while 6 (21%) started omalizumab treatment during pregnancy (group B). Among patients in group A, we observed 23 births (21 liveborn singletons and 1 liveborn twin pair) and 1 miscarriage. Fifteen (65%) patients discontinued omalizumab after confirming their pregnancy, while eight (35%) were exposed to omalizumab during their entire pregnancy. In group B, omalizumab was introduced at a mean (SD) 10.83 (3.60) weeks' gestation and all patients were exposed to it until the end of pregnancy. In this group, there were seven liveborn infants (five singletons and one twin pair). No adverse events, pregnancy complications or congenital anomalies in newborns were recorded in either group. Omalizumab for CSU treatment before and during pregnancy does not appear to have negative effects on maternal or fetal outcomes.

Role of Bilastine in Allergic Rhinitis: A Narrative Review.

Allergic rhinitis (AR) is considered a trivial disease and is often self-treated with over-the-counter drugs and home remedies. However, AR is a contributing risk factor for asthma associated with complications, including chronic cough, eosinophilic esophagitis, and otitis media with effusion. In AR, inflammation is primarily mediated by histamines. Guidelines advise using second-generation oral H1 antihistamines as the primary treatment for AR. Second-generation H1 antihistamines strongly prefer the H1 receptor, limiting their ability to enter the central nervous system. Thus, they have minimal adverse effects. Among these H1 antihistamines, bilastine is highly specific for H1 receptors with a slight affinity for other receptors. It has a rapid and prolonged action, which reduces the need for frequent dosing and has better compliance. In the long term, bilastine is well-tolerated with minimal adverse effects. It is not associated with drug interactions, so dosage adjustment is unnecessary. Bilastine does not penetrate the brain and is nonsedating at 80 mg once daily. The low possibility of drug-drug interactions and pharmacokinetics of bilastine makes it suitable for elderly patients, even with compromised hepatic and renal function, without dose adjustment. This review comprehensively discusses the guidelines and the role of bilastine in treating AR. How to cite this article: Tiwaskar M, Vora A, Tewary K, et al. Role of Bilastine in Allergic Rhinitis: A Narrative Review. J Assoc Physicians India 2023;71(11):58-61.

Remibrutinib demonstrates favorable safety profile and sustained efficacy in chronic spontaneous urticaria over 52 weeks

Remibrutinib (LOU064), an oral, highly selective Bruton tyrosine kinase inhibitor, offers fast disease control in patients with chronic spontaneous urticaria (CSU) who remain symptomatic despite treatment with second-generation H1 antihistamines. It is currently in phase 3 development for CSU. We sought to evaluate long-term safety and efficacy of remibrutinib in patients with CSU inadequately controlled with H1 antihistamines. In this phase 2b extension study, patients who completed the core study and had a weekly Urticaria Activity Score (UAS7) ≥16 at the beginning of the extension study received remibrutinib 100 mg twice daily for 52 weeks. The primary objective was to assess long-term safety and tolerability. Key efficacy end points included change from baseline in UAS7 and proportion of patients with complete response to treatment (UAS7= 0) and well-controlled disease (UAS7 ≤6) at week 4 and over 52 weeks. Overall, 84.3% (194/230) of patients entered the treatment period and received ≥1 doses of remibrutinib. The overall safety profile of remibrutinib was comparable between the extension and core studies. Most treatment-emergent adverse events were mild to moderate and considered unrelated to remibrutinib by investigators. The 3 most common treatment-emergent adverse events by system organ class were infections (30.9%), skin and subcutaneous tissue (26.8%), and gastrointestinal disorders (16.5%). At week 4 and 52, mean± SD change from baseline in UAS7 was -17.6± 13.40 and -21.8± 10.70; UAS7= 0 (as observed) was achieved in 28.2% and 55.8% and UAS7 ≤6 (as observed) was achieved in 52.7% and 68.0% of patients, respectively. Remibrutinib demonstrated a consistent favorablesafety profile with fast and sustained efficacy for up to 52 weeks in patients with CSU.

Comparative analysis of clinical efficacy and safety of omalizumab biosimilar in the treatment of patients with chronic spontaneous urticaria

BACKGROUND: Importance of optimizing strategy for treatment of chronic spontaneous urticaria is highly becoming relevance for the clinicians. Nowadays monoclonal antibodies are preferred option of treatment the refractory chronic spontaneous urticaria, main of that is omalizumab.
 AIM: to establish comparative analysis of the efficacy and safety of Genolair (JSC Generium, Russia) and Xolair (Novartis Pharma AG, Switzerland) in the treatment of patients with chronic spontaneous urticaria.
 MATERIALS AND METHODS: A 36-week, open parallel-group study was conducted. Were included 43 adult patients with chronic spontaneous urticaria who were resistant to ongoing therapy with standard and escalated doses of second-generation H1-antihistamines. All patients were divided into 2 groups: the main group (MG; n=18) ― patients who administrated Genolair; the comparison group (CG; n=25) ― patients who firstly administrated Xolair and then switching therapy to Genolair. Throughout the study period, patients completed questionnaires on the assessment of disease activity (UAS 7), urticaria control (UCT), quality of life index (DLQI). Additionally, the level of total IgE in blood serum was assessed. For statistical data processing, EXCEL 2010 and STATISTICA 7.0 software packages were used.
 RESULTS: After 4 weeks from the start of monoclonal antibody therapy, patients in both groups were responders to omalizumab. At the same time, there were no significant differences when comparing scores on the UAS 7, UCT scale between patients of the MG and the CG during the entire observation period (p 0.05). The change in treatment paradigm in CG also did not have a statistically significant effect on the indicators of urticaria activity and disease control (p 0.05). At the same time, the quality of everyday life changed more positively in the MG, which was reflected in a more pronounced change in the DLQI index at the time of the control assessment since 20 weeks of therapy (p=0.032). An increase in the level of total IgE in the blood serum of all patients with chronic spontaneous urticaria after the initiation of a course of immunobiological therapy was demonstrated, while there were no statistically significant intergroup differences in relation to changes in this laboratory parameter (p 0.05).
 CONCLUSION: During the treatment of patients with severe chronic spontaneous urticaria, resistant to ongoing therapy with standard and escalated doses of second-generation H1-antihistamines, comparable clinical efficacy and safety of the study drug Genolair and the reference drug Xolair were shown.

Chronic spontaneous urticaria—status quo and future

AbstractChronic spontaneous urticaria (CsU) is a chronic inflammatory dermatosis whose etiology is not yet fully understood. In affected patients, it is often associated with a high limitation of health-related quality of life, which necessitates effective therapeutic management. Different immune cell populations such as mast cells, eosinophilic and basophilic granulocytes, and T cells are involved in the pathogenesis of CsU, whereby mast cells playing a key role. In addition, type I autoallergic reactions with auto IgE antibodies or type IIb autoimmune reactions with auto IgG antibodies have been identified in a proportion of patients. The current international guideline initially recommends the use of second-generation H1 antihistamines, first in standard, then in off-label quadruple dosing. Subsequently, the anti-IgE antibody omalizumab should be added. However, this therapy algorithm does not lead to freedom from manifestations in all patients. Therefore, various targeted therapies are currently being evaluated for their efficacy in CsU, such as off-label use of the anti-interleukin receptor alpha (IL4Rα) antibody dupilumab, the anti-IL-17A antibody secukinumab, or interleukin‑5 blockade using mepolizumab, reslizumab, or benralizumab. In addition, new promising compounds such as the Bruton tyrosine kinase (BTK) inhibitors remibrutinib and fenebrutinib, the anti-cKIT antibody barzolvolimab, the anti-SIGLEC8 antibody lirentelimab, the anti-TSLP antibody tezepelumab, the anti-C5aR1 antibody advoralimab, or the topical application of Syk kinase inhibitors are being tested, which were developed according to new insights into the pathogenesis of CsU. The BTK inhibitor fenebrutinib is currently not being pursued due to a less favorable side effect profile compared to remibrutinib, as well as the anti-IgE antibody ligelizumab, which was inferior to omalizumab therapy in a phase 3 study. Overall, there is a high need for new therapeutic strategies to better treat CsU both symptomatically and curatively. This requires a more comprehensive understanding of pathogenesis of the disease in order to develop new targeted therapies.

Comparative Safety Profiles of Individual Second-Generation H1-Antihistamines for the Treatment of Chronic Urticaria: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

The comparative safety and/or dosing regimens of individual second-generation H1-antihistamines (sgAHs) in patients with chronic urticaria (CU) remain poorly elucidated. To compare the safety profiles of individual sgAHs and/or dosing regimens in adolescents or adult patients with CU using a systematic review and network meta-analysis of all available evidence. With limited English publications, electronic databases and gray literature were searched for randomized clinical trials from inception, with searches last updated on January 20, 2023. Relevant safety outcomes included treatment unacceptability (all-cause discontinuation), tolerability (discontinuation due to any adverse events), adverse events, serious adverse events, central nervous system (CNS) side effects, and anticholinergic side effects. Regarding the network estimates, the probability of being associated with the highest adverse outcome risk was estimated for each treatment comparison. Fifty-one randomized clinical trials with 14 individual sgAHs and different dosing regimens, involving 7502 participants, were included. On the basis of the findings from network meta-analyses, variations in sgAH treatment comparisons were observed regarding the unacceptability of treatment, tolerability, adverse events, and CNS side effects. There were no statistically significant differences between the results of sgAH treatment for serious adverse events and those for anticholinergic side effects. On the basis of the ranking of safety profiles, emedastine 4 mg, mizolastine 10 mg, and cetirizine 10 mg were the top 3 ranked treatments with unfavorable safety profiles associated with CNS side effects and any adverse events. These findings suggest evidence of variations in safety profiles among sgAHs for CU treatment, particularly in terms of adverse events and CNS side effects.

An international Delphi study on the burden of allergic rhinoconjunctivitis and urticaria and the role of bilastine among current treatment options

ABSTRACT Background Allergic rhinoconjunctivitis and chronic urticaria are common histamine-driven diseases, exerting detrimental effects on cognitive functions, sleep, daily activities, and quality of life. Non-sedating second-generation H1-antihistamines are the first-line treatment of choice. Aim of the study was to define the role of bilastine among second-generation H1-antihistamines in the treatment of allergic rhinoconjunctivitis and urticaria in patients of different ages. Methods An international Delphi study was carried out to assess consensus among experts from 17 European and extra-European countries on three main topics: 1) Burden of disease; 2) Current treatment options; 3) Specific characteristics of bilastine among second-generation antihistamines. Results Here, we present the results obtained for a selection of 15 out of 27 consensus statements, focused on disease burden, role of second-generation antihistamines and bilastine profile. The rate of concordance was ≥98% for 4 statements, ≥ 96% for 6, ≥ 94% for 3, and ≥90% for 2. Conclusions The high degree of agreement obtained suggests a wide awareness of the burden of allergic rhinoconjunctivitis and chronic urticaria among experts from all over the world and reflects a broad consensus on the role of second-generation antihistamines in general and of bilastine in particular for their management.

Effect of second-generation antihistamines on nighttime sleep and daytime sleepiness in patients with allergic rhinitis.

The daytime tiredness experienced by the vast majority of allergic rhinitis (AR) sufferers is directly related to the fact that they experience disrupted sleep at night. This study compared the effects of recently marketed second-generation H1 antihistamines (SGAs) on nighttime sleep and daytime sleepiness in patients with AR, with patients grouped into those taking non-brain-penetrating antihistamines (NBP group) and those taking brain-penetrating antihistamines (BP group). Patients with AR completed self-administered questionnaire-based surveys to determine Pittsburgh Sleep Quality Index (PSQI) before and after taking SGAs. Statistical analysis was performed on each evaluation item. Of 53 Japanese patients with AR between 6 and 78years old, median (SD) agewas 37.0 (22.4) years old and 21 weremen (40%). Of the 53 patients, 34 were the NBP group and 19 were the BP group. In the NBP group, mean (SD) subjective sleep quality score after medication was 0.76 (0.50), which was significantly lower (better) than the score of 0.97 (0.52) before medication (p = 0.020). In the BP group, mean (SD) subjective sleep quality score after medication was 0.79 (0.54), which was not significantly different from the score of 0.74 (0.56) before medication (p = 0.564). In the NBP group, mean (SD) global PSQI score was 3.47 (1.71) after medication, which was significantly lower (better) than the score of 4.35 (1.92) before medication (p = 0.011). In the BP group, mean (SD) global PSQI score was 2.47 (2.39) after medication, which was not significantly different from the score of 3.00 (2.71) before medication (p = 0.125). Subjective sleep quality and global PSQI score were improved only in the group taking non-brain-penetrating SGAs.

The efficacy and safety of high-dose nonsedating antihistamines in chronic spontaneous urticaria: a systematic review and meta-analysis of randomized clinical trials

BackgroundStandard doses of second-generation H1-antihistamines (sgAHs) as first-line treatment are not always effective in treating chronic spontaneous urticaria (CSU), and hence an increase in the dose of sgAHs is recommended. However, literature evaluating the efficacy and safety of this treatment remains inconclusive, highlighting the need for a systematic review and meta-analysis. The aim of this systematic review and meta-analysis was to evaluate the efficacy and safety of high-dose sgAHs compared with standard-dose sgAHs in treating CSU.MethodsA systematic literature search of double-blind, randomized controlled trials (RCT) utilizing multiple doses of sgAHs was performed by searching the electronic databases Medline, Embase, PsycInfo, Cochrane databases, and Web of Science. Bibliographies were also manually searched. The Cochrane Risk of Bias Tool for assessing risk of bias was used to assess the quality of randomized controlled trials (RCTs). Two reviewers screened studies, extracted data, and evaluated the risk of bias independently. The response rate, the number of adverse events, somnolence, and withdrawal due to adverse events were extracted from each article. The data were combined and analyzed to quantify the safety and efficacy of the treatment. RevMan (V5.3) software was used for data synthesis.ResultsA total of 13 studies were identified, seven of which met the eligibility criteria for the meta-analysis. Our pooled meta-analyses showed that high-dose sgAHs was associated with a significantly higher response rate than standard-dose (RR 1.13, 95% CI 1.02 to 1.26; P = 0.02). Conversely, high doses of sgAHs were associated with significantly higher somnolence rates than standard dose (RD 0.05, 95% CI 0.01 to 0.09; P = 0.02). There was no significant difference in adverse events or withdrawal due to adverse events between standard- and high-dose treatments.ConclusionsOur analyses showed that a high dose of sgAHs (up to two times the standard dose) might be more effective than a standard dose in CSU treatment. High-dose and standard-dose sgAHs showed similar adverse events, except for somnolence, where incidence was found to be dose-dependent in some studies. However, given the limited number of studies, our meta-analysis results should be interpreted with caution.

Stepping Down Treatment in Chronic Spontaneous Urticaria: What We Know and What We Don't Know.

In chronic spontaneous urticaria (CSU), wheals, angioedema, or both appear spontaneously for >6 weeks. Current recommended treatment options for urticaria target mast cell mediators such as histamine, or activators, such as autoantibodies. The goal of CSU treatment is to treat the disease until it is gone as effectively and safely as possible. As no cure is available for CSU as of now, the treatment is aimed at continuously suppressing disease activity, with complete control of the disease and a normalization of quality of life. To achieve this, pharmacological treatment should be continued until no longer needed. Treatment of CSU should follow the basic principles of treating as much as needed and as little as possible taking into consideration that the activity of the disease may vary. Since CSU is a disease with spontaneous remission, it is hard to tell, in patients with complete control and no signs or symptoms, when medication is no longer needed. The current international guideline for urticaria suggests that the treatment can be stepped down once a patient is free of signs and symptoms. Other reasons for stepping down the treatment of CSU patients include safety concerns or issues, pregnancy or wanting to become pregnant, and economic factors. As of now, it is unclear over which period, with what intervals and with which dosages CSU treatment should be stepped down. Guidance on this is needed for all recommended therapies: (i) standard-dosed second-generation H1-antihistamine (sgAH), (ii) higher than standard-dosed sgAH, (iii) standard-dosed omalizumab, (iv) higher than standard-dosed omalizumab, and (v) cyclosporine. However, there is a lack of controlled trials on the step down and discontinuation of these treatments. Here, we aim to provide a summary of what is known and what needs to be investigated in further studies, based on our own experience and real-world evidence.

Chronic recurrent wheals - If not chronic spontaneous urticaria, what else?

Chronic urticarial rash, mostly due to chronic spontaneous urticaria (CSU), is seen in up to 1-4% of the general population. Urticarial vasculitis (UV) and autoinflammatory syndromes, i.e., cryopyrin-associated periodic syndromes (CAPS) and Schnitzler syndrome (SchS), can mimic CSU-like rash but represent rare disorders with systemic symptoms including fever, headache, conjunctivitis, and arthralgia. Clinical and laboratory features can point to the presence of any of these diseases in patients initially presenting with chronic urticarial rash. These include long-lasting wheals (> 24 hours), lesional burning, systemic symptoms, and/or increase in inflammatory markers (e.g., C-reactive protein, serum amyloid A, and/or S100A8/9). Lesional skin biopsy usually demonstrates leukocytoclastic vasculitis (UV) or neutrophil-rich infiltrate (CAPS and SchS). In contrast to CSU, where second-generation H1 antihistamines and omalizumab allow to control symptoms in most patients, systemic immunosuppression and anti-interleukin (IL)-1 therapies are needed in case of UV and autoinflammatory diseases, respectively. The rarity and low awareness of CSU differential diagnoses may be related to the longer delays in diagnosis and therapy in those affected with UV, CAPS, and SchS. Knowledge of the differential diagnoses of CSU is important because only correct diagnosis allows adequate therapy. Complications such as the development of lymphoproliferative disease in SchS and amyloidosis in CAPS, and the presence of comorbid diseases, such as systemic lupus erythematosus in UV, must be considered and monitored.

Expert opinion on the role of bilastine and bilastine-montelukast combination in the management of allergic rhinitis: An Indian perspective

In India, the burden of allergic rhinitis (AR) is enormous, comprising 55% of all patients with allergies. Intranasal corticosteroids are the recommended first-line therapy for patients with moderate-to-severe AR, particularly when nasal congestion is the predominant symptom. However, second-generation antihistamines are the first line of treatment in mild AR and effectively improve symptoms, such as sneezing, itching, and rhinorrhoea. Bilastine is a second-generation H1-antihistamine indicated for the symptomatic treatment of allergic rhinoconjunctivitis in adults and adolescents over 12 years of age. Though it is an effective individual molecule for the management of AR, studies have shown that synergistic combination therapy of bilastine-montelukast has a dual action on early- and late-phase allergic reactions in AR patients with concomitant asthma. An advisory board meeting was conducted (on a virtual platform) to gain insights from Indian experts on the following: (i) burden of AR and AR with concomitant asthma in Indian settings; (ii) current unmet needs; and (iii) role and positioning of bilastine and bilastine plus montelukast combination in the management of AR and AR with concomitant asthma in adults and adolescents over 12 years of age. The experts shared their opinions based on the available scientific evidence and/or clinical expertise or experience. In this article, we have summarized the highlights of the expert panel discussion and available evidence for each of these topics.

Clinical experience of a specialized urticaria outpatient clinic from a Portuguese UCARE.

Background. Chronic urticaria (CU) is a frequent disease, with a prevalence of at least 1%. It is characterized by pruritic wheals, angioedema or both for a period longer than 6 weeks. Objective. Identify the demographic, clinical, laboratory and therapeutic profile of patients treated in a Portuguese Urticaria Center of Reference and Excellence (UCARE) and compare it with international series. Methods. Retrospective analysis of database of patients observed in a specialized urticaria outpatient clinic, from January 2017 through September 2019, of a UCARE center in Portugal. Demographic and clinical features, laboratory findings and pharmacological treatment were obtained from the records. Descriptive analyses were performed for all variables. Chi square and fisher's exact tests were applied to analyze the independence of variables and the fit of distribution. P less than 0.05 was considered significant. Results. During this period, 477 patients were observed, of whom 429 (90%) were diagnosed with chronic urticaria. Mean age (years) at the onset of symptoms was 43.7 (standard deviation (SD) 17.6, range 6-88) and at diagnosis 46.7 (SD 17.8, range 6-88) resulting in an average diagnostic delay of 3 years (range 0-25). Median follow-up period since first attendance in the specialized outpatient clinic was 1.7 years (interquartile range (IQR) 0.79, range 0.1-2.75) . Concerning the whole group of CU patients, 347 (81%) had chronic spontaneous urticaria (CSU) - 79% female, 39 (9%) had isolated chronic inducible urticaria (CIndU) and 43 (10%) had CSU with CIndU. Autologous serum skin test (ASST) was done in 76 patients (positive in 24 (32%)) and basophil activation test (BAT) was done in 38 (positive in 13 (34%)). At the moment of study, 204 (48%) of CU patients were medicated with a second-generation H1-antihistamine (sgAH) daily (first-line therapy), 99 (23%) with sgAH up to four times the standard dose (second-line therapy) and 126 (29%) with omalizumab (third-line therapy). Additionally, 7 (2%) patients were completing a short course of systemic corticosteroids for management of disease exacerbation. Disease control was achieved in 316 of CSU patients (81%). Conclusions. Referral to a specialized urticaria outpatient clinic is important for a proper assessment of the disease and adequately symptom control.