Bruton's tyrosine kinase (BTK) is a cytoplasmic signaling protein expressed across a variety of immune cells, terminally differentiated plasma cells, and natural killer cells. Due to the signal potential and targetable nature of BTK, the use of BTK inhibitors (BTKis) has been proposed for the management of several diseases. Currently, the use of BTKis is under investigations for several dermatological conditions such as pemphigus, systemic lupus erythematosus, hidradenitis suppurativa, atopic dermatitis, and chronic spontaneous urticaria (CSU).

The aim of this review is to delve into the use of BTKis in the management of CSU, in order to explore the potential of therapeutic inhibition of BTK in patients with CSU. A thorough analysis of the existing medical literature was conducted across the PubMed, Ovid, Scopus, Embase, and Cochrane Library databases up to 17 August 2024.

BTK use may represent a breakthrough in the management of CSU. Indeed, their use is characterized by oral administration and a favorable mechanism of action that acts on a significant pathogenic pathway rather than a single molecule. However, long-term studies are needed to further investigate safety data, although data from registered trials appear to be reassuring.

Most biological and synthetic target-specific drugs for antihistamine-refractory chronic spontaneous urticaria (CSU) have not been compared head-to-head. This systematic review and network meta-analysis evaluated their relative efficacy and safety.

Searches were conducted on PubMed, Embase, Web of Science and Cochrane library databases to March 25, 2024 for randomized trials. A random-effects model was used to calculate the network estimates reported as mean differences (MD) and odds ratios (OR) with corresponding 95% CIs. Main outcomes included the weekly urticaria activity score (UAS7), adverse events (AEs) and serious adverse events (SAEs).

23 randomized clinical trials with 6933 participants that compared 26 different interventions or dosages and placebos were included. Omalizumab 300 mg [MD -10.07, 95% CI (-11.35; -8.82)] continues to demonstrate superior efficacy compared with placebo. Remibrutinib, at doses of 35 mg once daily [MD -7.80, 95% CI (-12.76; -2.51)], 25 mg twice daily [MD -7.69, 95% CI (-9.85; -5.76)], and 10 mg twice daily [MD -7.61, 95% CI (-12.59; -2.47)], had the best overall performance for efficacy and safety. Dupilumab, fenebrutinib, and rilzabrutinib also showed greater efficacy than placebo. The results were similar for the proportion of patients who achieved UAS7 ≤ 6 or UAS7 = 0. No significant differences were found among all treatment comparisons for AEs and SAEs.

The findings of this study indicate that the biological agent omalizumab 300 mg and the oral small molecule remibrutinib at doses of 35 mg, 25 mg, or 10 mg are recommended for patients with antihistamine-refractory CSU.

PROSPERO: CRD42024516289.

The medical field faces considerable challenges in treating chronic urticaria (CU), which includes both chronic spontaneous urticaria (CSU) and chronic inducible urticaria, owing to its varied nature. The complexity of this condition stems from multiple factors: varying disease mechanisms, different ways in which symptoms manifest, and inconsistent treatment outcomes. Although both forms of CU display hives that persist beyond six weeks, they have distinct causes and progression patterns. This study examines CSU specifically, exploring its various manifestations and associated biological indicators. Currently, there is a pressing need to identify reliable, accessible biomarkers for CSU to enhance diagnosis and develop targeted treatments. Better insights into how specific disease patterns are related to biological markers would significantly improve our understanding of CSU development and enhance patient treatment approaches.

Chronic spontaneous urticaria (CSU) is an inflammatory disorder that manifests with hives, angioedema, or both and lasts more than or equal to 6 weeks. Although certain elements of CSU pathogenesis are well defined, others remain unclear. We discuss our current understanding of the underlying CSU endotypes, distinct clinical phenotypes, and predictive biomarkers. It is increasingly recognized that CSU comprises a spectrum of different underlying pathogenic mechanisms and distinct clinical presentations. Broadly, 2 endotypes that drive CSU pathogenesis have been identified, namely type I (autoallergic) and type IIb (autoimmune). However, a subpopulation shows evidence of both types, and some patients show evidence of neither. Multiple identified biomarkers have been associated with these endotypes or with disease features, such as CSU severity and duration. There is a lack of connectivity among the identified biomarkers, genetic risk loci, phenotypes, and corresponding endotypes, and each of these is frequently considered independently of the others. These identifiable features also have been associated with response, or lack thereof, to available therapies. Future investigations should optimize the endotyping of CSU using point-of-care, noninvasive, accessible biomarkers and assess the differences in response to therapy. With multiple treatments in late-stage development, establishing clearly defined CSU endotypes will facilitate future treatment decision-making and tailored treatment approaches and will inform optimal trial design.

TAS5315 is a Bruton tyrosine kinase (Btk) inhibitor in development for autoimmune and allergic diseases, including rheumatoid arthritis (RA) and chronic spontaneous urticaria (CSU). Two clinical studies evaluated the pharmacology and safety of single and multiple oral doses of TAS5315.

Two phase 1 studies (single ascending-dose [SAD] and multiple ascending-dose [MAD]) assessed the pharmacokinetics (including effect of food), pharmacodynamics (Btk occupancy, inhibition of basophil activation) and safety of TAS5315 (up to 8 mg/day) in healthy males.

TAS5315 showed linear pharmacokinetics over a 0.01-8 mg dose range; maximum plasma concentration and area under the plasma concentration-time curve were reduced by ~40% by food. TAS5315 had dose dependent effects on Btk and basophil activation. In the SAD study, doses ≥2 mg resulted in mean Btk occupancy of almost 100% at 2 and 6 h, and >80% at 24 h, post-administration. TAS5315 1-8 mg/day inhibited basophil activation (mean change from baseline -55% to -89%). TAS5315 was generally tolerable. Although it dose-dependently reduced platelet aggregation (over 2-8 mg in both studies) and prolonged bleeding time (1-8 mg in the MAD study), no relationship between these effects and clinical symptoms was observed. All adverse drug reactions were mild and resolved without treatment; no noteworthy safety concerns were observed in either study.

These data indicate TAS5315 has potential as a novel therapeutic for immunological diseases associated with aberrant Btk signalling, including RA and CSU. Further evaluation of TAS5315 is warranted.

Chronic spontaneous urticaria (CSU) presents as a persistent and distressing condition, with varying treatment responses. Omalizumab, a monoclonal anti-IgE antibody, has shown efficacy in managing antihistamine (AH1)-refractory CSU, but its varied response patterns and associated factors remain understudied, particularly in India.

We conducted a retrospective study involving 81 antihistamine-resistant CSU patients treated with omalizumab at a tertiary care center in Northern India between 2018 and 2023. Baseline characteristics, treatment response, and adverse effects were analyzed. Patients were categorized into various response groups based on treatment timelines and biomarker correlations.

We observed 65% achieved symptom cessation (group 1) following a single omalizumab dose, while 21% responded between second and third doses (group 2). A subset (7.4%) necessitated increased dosing frequency (group 3) for symptom control. Additionally, 6.2% showed persistent symptoms despite increased dosing frequency (group 4), exhibiting distinctive biomarker profiles indicative of an autoimmune endotype. Notably, 27.1% experienced exacerbations during treatment, emphasizing the need for tailored management approaches and response expectations.

Omalizumab demonstrated remarkable efficacy in the treatment of AH1-refractory CSU, with a good safety profile. This study highlights the complexity of treatment response to omalizumab and the potential utility of biomarkers in guiding personalized therapeutic strategies. Further research into biomarker-based endotypes is warranted to optimize CSU management.

Tezepelumab, an mAb inhibiting thymic stromal lymphopoietin, is an upstream-targeted therapy with potential to inhibit multiple pathways in chronic spontaneous urticaria (CSU).

We sought to evaluate tezepelumab efficacy and safety in patients with CSU despite treatment with second-generation H1 antihistamines.

This phase 2b study randomized 183 patients (125 anti-IgE therapy-naive; 58 anti-IgE therapy-experienced) to placebo every 2 weeks, tezepelumab 210 mg every 4 weeks, tezepelumab 420 mg every 2 weeks, or omalizumab 300 mg every 4 weeks (anti-IgE-naive only) for 16-week treatment. The primary end point was change from baseline in weekly Urticaria Activity Score (UAS7) at week 16. Safety and exploratory end points were evaluated through week 32.

The 16-week primary end point was not met. In the overall population, tezepelumab 210 mg and 420 mg did not significantly improve UAS7 versus placebo (least squares mean [SE]: -13.5 [1.6] and -14.7 [1.5], respectively, vs -13.6 [1.6], P = .99, nominal and P = .60, nominal, respectively). Greater improvement in UAS7 versus placebo was observed in the anti-IgE-naive tezepelumab-treated populations (nominal significance); a trend toward significance was observed with omalizumab. In the anti-IgE-naive population, there was delayed, sustained, 32-week off-treatment improvement in UAS7 versus placebo with tezepelumab 210 mg (nominally significant) and 420 mg (trend), but not with omalizumab. This effect was larger in patients with lower baseline IgE levels and longer CSU duration and accompanied sustained IL-5 and IL-13 reductions. Tezepelumab and placebo safety findings were balanced.

Although the 16-week primary end point was not met, tezepelumab showed post-treatment reductions in CSU activity through week 32, suggesting a delayed, sustained, thymic stromal lymphopoietin blockade treatment effect.

Patient-reported outcome measures (PROMs) help to assess disease control and quality of life (QoL) in chronic spontaneous urticaria (CSU) and recurrent angioedema (RA). This study aimed to assess the correlation between two different concepts: disease control and QoL, using disease-specific PROMs.

We analyzed data from 445 CSU and 330 RA patients who completed both a disease control and QoL PROM as part of the clinical routine. We included the UCT and CU-Q2oL for CSU and AECT and AE-QoL for RA.

In CSU and RA, disease control scores positively correlated with QoL scores (Spearman's rho correlation coefficient (CR) -0.757, -0.735; p < 0.001) with better disease control corresponding to better quality of life. However, 5.9% of CSU patients and 28% of RA patients with complete disease control had impaired QoL. In CSU, QoL was impaired in 69.2% of patients based on the CU-Q2oL and in 62.7% of patients based on a single numeric question from the UCT, with a mismatch in 89/445 patients. In RA, QoL was impaired in 58.5% using the AE-QoL and in 52.7% using a single numeric question from the AECT30mo, with a mismatch in 69/330 patients. Different domains of the QoL PROMs showed different degrees of influence on disease control, with "Itching/Embarrassment" showing the strongest correlation with the UCT (CR -0.804; p < 0.001) and "Functioning" with the AECT3mo (CR -0.824; p < 0.001).

Although most patients with controlled disease have better quality of life, unexpectedly, quality of life remains impaired in up to one-fourth of patients with completely controlled CSU and RA. Reasons behind this should be investigated in further studies.

Background/Objectives: Human β-defensin 2 (HBD2) is a protein that plays an important role in activating the immune system by modulating spinal pathways and the inflammatory response. According to previous research, HBD2 was proven to be important in chronic spontaneous urticaria (CSU) (their values were significantly elevated in CSU patients, with a significant correlation between HBD2 levels and the percentage of peripheral basophils, suggesting that elevated HBD2 levels may be a potential marker of basophil and mast cell activation), which led us to additional research on the HBD2 molecule in isolated chronic angioedema. The aim of this research is to examine HBD2 values in the saliva and serum of patients with isolated angioedema, as a potential biomarker of the disease. Methods: This cross-sectional study involved a total of 102 participants, involving three groups: 33 patients with isolated chronic non-hereditary angioedema (AE) (defined as sudden onset of localized edema without chronic urticaria), 33 patients with angioedema associated with chronic urticaria (CU+AE), and 35 healthy participants (controls, CTRL). They provided a saliva sample to determine HBD2 levels using an ELISA (Enzyme-Linked Immunosorbent Assay). Subsequently, a peripheral blood sample (serum) was taken from the participants to determine HBD2 levels using the same ELISA. Results: Salivary HBD2 levels were significantly higher in those with CU+AE than in the CTRL (p = 0.019). While salivary HBD2 values differed between those with angioedema and CTRL, the serum HBD2 values did not. Also, no correlation between the levels of HBD2 in saliva and serum was found. Conclusions: Since we found that salivary HBD2 values were significantly higher in those with CU+AE than in CTRL, this points to a possible role of the HBD2 molecule in pathogenesis of AE (namely, that it induces degranulation in mast cells and vascular permeability, and has antimicrobial properties) Therefore, more research is needed to determine how reliable salivary HBD2 measurement is, as well as its significance.

Background: In the world, approximately 1% of the population suffers from chronic spontaneous urticaria (CSU), burdening patients' quality of life and challenging clinicians in terms of treatment. Recent scientific evidence has unveiled the potential role of a family of molecules known as "alarmins" in the pathogenesis of CSU. Methods: Papers focusing on the potential pathogenetic role of alarmins in CSU with diagnostic (as biomarkers) and therapeutic implications, in English and published in PubMed, Scopus, Web of Science, as well as clinical studies registered in ClinicalTrials.gov and the EudraCT Public website, were reviewed. Results: The epithelial-derived alarmins thymic stromal lymphopoietin and IL-33 could be suitable diagnostic and prognostic biomarkers and possible therapeutic targets in CSU. The evidence on the role of non-epithelial-derived alarmins (heat shock proteins, S-100 proteins, eosinophil-derived neurotoxin, β-defensins, and acid uric to high-density lipoproteins ratio) is more heterogeneous and complex. Conclusions: More homogeneous studies on large cohorts, preferably supported by data from international registries, will be able to elucidate the intriguing and complex pathogenetic world of CSU.

Omalizumab, a monoclonal antibody targeting immunoglobulin E (IgE), is approved for adults and adolescents (12 years or older) with chronic spontaneous urticaria (CSU) that does not respond to high-dose antihistamines. In Korea, there is limited research on predictive biomarkers for omalizumab response in CSU patients.

This retrospective, single-institution study aimed to identify clinical parameters predicting omalizumab response in Korean CSU patients.

We analyzed records of CSU patients aged 19 or older starting omalizumab between January 2017 and October 2019. Omalizumab efficacy was assessed using the Urticaria Activity Score summed over 7 days (UAS7), categorized as well-controlled, mild, moderate, or severe. Ninety CSU patients participated in this study.

Among these, improvements in UAS7 categories from baseline to 12 weeks of treatment were observed in 78 patients, while 12 patients showed no significant efficacy. The present study identified potential biomarkers that could predict a patient's response to omalizumab, including disease duration and total serum IgE levels (p=0.022, p=0.046). Notably, a significant correlation was observed between higher detection rates in multiple antigen simultaneous test (MAST) food testing and lower treatment responses (p=0.033).

Shorter disease duration of CSU and elevated initial serum total IgE level may serve as potential predictive biomarkers for the responsiveness to omalizumab. Furthermore, a higher MAST food detection rate seemed to correlate with a less favorable treatment response, suggesting patients with a high MAST food detection rate might benefit from a food evaluation in addition to omalizumab treatment.

The etiology and pathophysiology of vaccine-associated chronic urticaria (CU) remain unclear, particularly during the coronavirus disease 2019 (COVID-19) pandemic. Thus, this study aimed to comprehensively investigate the global burden and long-term trends of vaccine-associated CU, with a focus on the associated vaccines and the distribution of cases across different age groups and sexes.

Using data from the World Health Organization international pharmacovigilance database (VigiBase), which encompasses reports from 156 countries and territories between 1968 and 2023, we systematically analyzed the global burden and long-term trends in vaccine-associated CU reports (total individual case safety reports = 131,255,418). We estimated the global and regional reports, information component (IC) with IC0.25 using disproportionality analyses, and reporting odds ratio (ROR) with 95% confidence interval (CI) to investigate the potential associations between 27 vaccines and CU.

Among the 3,474 reports of all-cause CU, 1,898 vaccine-associated CU reports were identified between 2010 and 2023. A dramatic surge in vaccine-associated CU reports has been observed since 2020, primarily driven by the COVID-19 mRNA vaccines. The COVID-19 mRNA vaccines were associated with the most CU reports (ROR, 26.52 [95% CI, 24.33-28.90]; IC, 3.18 [IC0.25, 3.10]), followed by papillomavirus (ROR, 4.23 [95% CI, 2.55-7.03]; IC, 1.93 [IC0.25, 1.06]), influenza (ROR, 3.09 [95% CI, 2.16-4.43]; IC, 1.57 [IC0.25, 0.96]), Ad5-vectored COVID-19 (ROR, 2.82 [95% CI, 2.40-3.31]; IC, 1.42 [IC0.25, 1.16]), and zoster vaccines (ROR, 2.28 [95% CI, 1.32-3.93]; IC, 1.12 [IC0.25, 0.18]). These increased risks were particularly pronounced for males and older adults. No fatal outcomes have been reported in vaccine-associated CU.

This study underscores the importance of clinicians considering the potential risk factors associated with vaccine-associated CU, especially in the context of COVID-19-related vaccines. Ongoing pharmacovigilance efforts facilitated by robust reporting systems are required to further validate our findings.

The latest international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for urticaria recommends limited laboratory testing for chronic spontaneous urticaria (CSU) and selective testing for only certain chronic inducible urticaria (CIndU) subtypes, though the rationale for these recommendations is poorly explained. This study aimed to improve the understanding of CIndU subtypes by comprehensively comparing their demographic, clinical, and laboratory characteristics with those of the better-characterized CSU.

We conducted a retrospective analysis of 567 patients (median age 41 years, 67% female) diagnosed with CSU, symptomatic dermographism (SD), cold urticaria (ColdU), cholinergic urticaria (CholU), and delayed pressure urticaria (DPU).

Our findings revealed that patients with SD, ColdU, and CholU had lower levels of C-reactive protein (CRP), higher total serum immunoglobulin E (IgE) levels, and higher basophil counts compared to CSU patients. These subtypes also had distinct demographic and clinical features, such as a younger age of onset and a longer disease duration. In contrast, patients with DPU had significantly higher CRP levels and neutrophil counts compared to those with CSU.

These findings highlight the heterogeneity among chronic urticaria subtypes, suggesting that a tailored approach to laboratory testing may be more effective. The distinct immunological and clinical features observed in CIndU subtypes suggest a need for subtype-specific diagnostic and therapeutic guidelines.

Mast cells (MCs) are known to have a pathological impact in a variety of settings, in particular in allergic conditions. There is also limited evidence implicating MCs in diabetes, raising the possibility that MC function may be influenced by alterations in glucose levels. However, it is not known whether MCs are directly affected by elevated glucose concentrations. Moreover, it is not known which glucose transporters that are expressed by MCs, and whether MCs are dependent on glucose transporters for activation. Here we addressed these issues. We show that MCs express high levels of both glucose transporter 1 (GLUT1/Slc2A1) and GLUT3 (Slc2A3). Further, we show that the inhibition of either GLUT1 or GLUT3 dampens both MC degranulation and cytokine induction in response to IgE receptor crosslinking, and that combined GLUT1 and GLUT3 inhibition causes an even more pronounced inhibition of these parameters. In contrast, the inhibition of GLUT1 or GLUT3, or combined GLUT1 and GLUT3 inhibition, had less impact on the ability of the MCs to respond to activation via compound 48/80. Elevated glucose concentrations did not affect MC viability, and had no stimulatory effect on MC responses to either IgE receptor crosslinking or compound 48/80. Altogether, these findings reveal that MCs are strongly dependent on glucose transport via GLUT1 and/or GLUT3 for optimal responses towards IgE-mediated activation, whereas MC functionality is minimally affected by elevated glucose levels. Based on these findings, antagonists of GLUT1 and GLUT3 may be considered for therapeutic intervention in allergic conditions.

Chronic spontaneous urticaria (CSU) is a debilitating, inflammatory skin condition characterized by infiltrating immune cells. Available treatments are limited to improving the signs and symptoms. There is an unmet need to develop therapies that target disease-driving pathways upstream of mast cell activation to inhibit or delay the progression of CSU and associated comorbidities. Here, we aim to define disease modification due to a treatment intervention and criteria that disease-modifying treatments (DMTs) must meet in CSU. We have defined disease modification in CSU as a favorable treatment-induced change in the underlying pathophysiology and, therefore, the disease course, which is clinically beneficial and enduring. A DMT must fulfil the following criteria: (1) prevents or delays the progression of CSU, (2) induces long-term, therapy-free clinical remission, which is the sustained absence of CSU signs and symptoms without the need for treatment, and (3) affects the underlying mechanism of CSU, as demonstrated by an effect on disease-driving signals and/or a biomarker. DMTs in CSU should slow disease progression, achieve long-lasting disease remission, target disease-driving mechanisms, reduce mast cell-activating IgE autoantibodies, target cytokine profile polarization, and normalize the gut microbiome and barrier. Treating CSU at the immune system level could provide valuable alternatives to pharmacotherapy in CSU management. Specific DMTs in CSU are yet to be developed, but some show potential benefits, such as inhibitors of Bruton's Tyrosine Kinase, IL-4 and IL-13. Future therapies could prevent CSU signs and symptoms, achieve long-term clinical benefits after discontinuing treatment, and prevent associated concomitant disorders.

The review article explores the evolving role of Bruton's tyrosine kinase (BTK) inhibitors in immune-mediated dermatological conditions, addressing significant gaps in current treatment approaches.

The review comprehensively discusses the mechanisms of action of BTK inhibitors, including irreversible and reversible inhibitors. Clinical applications of BTK inhibitors in dermatological diseases such as pemphigus, chronic spontaneous urticaria (CSU), hidradenitis suppurativa (HS), systemic lupus erythematosus (SLE), and atopic dermatitis are explored, highlighting recent advancements and ongoing clinical trials. Potential advantages of BTK inhibitors over existing therapies and challenges in translating preclinical findings to clinical outcomes are discussed.

BTK inhibitors represent a promising therapeutic avenue for immune-mediated dermatological conditions, offering oral administration, targeted pathway inhibition, and a favorable safety profile compared to biologic therapies. Ongoing research and clinical trials hold the potential to address unmet needs and reshape the therapeutic landscape in dermatology.

Chronic urticaria is a common and debilitating mast cell-driven skin disease presenting with itchy wheals, angio-oedema, or both. Chronic urticaria is classified as spontaneous (without definite triggers) and inducible (with definite and subtype-specific triggers; eg, cold or pressure). Current management guidelines recommend step-up administration of second-generation H1-antihistamines to four-fold the approved dose, followed by omalizumab and ciclosporin. However, in many patients, chronic urticaria does not respond to this linear approach due to heterogeneous underlying mechanisms. A personalised endotype-based approach is emerging based on the identification of autoantibodies and other drivers of urticaria pathogenesis. Over the past decade, clinical trials have presented promising options for targeted treatment of chronic urticaria with the potential for disease modification, including Bruton's tyrosine kinase inhibitors, anti-cytokine therapies, and mast cell depletion. This Therapeutics article focuses on the evidence for these novel drugs and their role in addressing an unmet need for personalised management of patients with chronic urticaria.

Patient-reported outcome measures (PROMs) are validated and standardized tools that complement physician evaluations and guide treatment decisions. They are crucial for monitoring atopic dermatitis (AD) and chronic urticaria (CU) in clinical practice, but there are unmet needs and knowledge gaps regarding their use in clinical practice.

We investigated the global real-world use of AD and CU PROMs in allergology and dermatology clinics as well as their associated local and regional networks.

Across 72 specialized allergy and dermatology centers and their local and regional networks, 2,534 physicians in 73 countries completed a 53-item questionnaire on the use of PROMs for AD and CU.

Of 2,534 physicians, 1,308 were aware of PROMs. Of these, 14% and 15% used PROMs for AD and CU, respectively. Half of physicians who use PROMs do so only rarely or sometimes. Use of AD and CU PROM is associated with being female, younger, and a dermatologist. The Patient-Oriented Scoring Atopic Dermatitis Index and Urticaria Activity Score were the most common PROMs for AD and CU, respectively. Monitoring disease control and activity are the main drivers of the use of PROMs. Time constraints were the primary obstacle to using PROMs, followed by the impression that patients dislike PROMs. Users of AD and CU PROM would like training in selecting the proper PROM.

Although PROMs offer several benefits, their use in routine practice is suboptimal, and physicians perceive barriers to their use. It is essential to attain higher levels of PROM implementation in accordance with national and international standards.

Solar urticaria is a rare photodermatosis characterized by rapid-onset sunlight-induced urticaria, but its pathophysiology is not well understood.

We sought to define cutaneous cellular and molecular events in the evolution of solar urticaria following its initiation by solar-simulated UV radiation (SSR) and compare with healthy controls (HC).

Cutaneous biopsy specimens were taken from unexposed skin and skin exposed to a single low (physiologic) dose of SSR at 30 minutes, 3 hours, and 24 hours after exposure in 6 patients with solar urticaria and 6 HC. Biopsy specimens were assessed by immunohistochemistry and bulk RNA-sequencing analysis.

In solar urticaria specimens, there was enrichment of several innate immune pathways, with striking early involvement of neutrophils, which was not observed in HC. Multiple proinflammatory cytokine and chemokine genes were upregulated (including IL20, IL6, and CXCL8) or identified as upstream regulators (including TNF, IL-1β, and IFN-γ). IgE and FcεRI were identified as upstream regulators, and phosphorylated signal transducer and activator of transcription 3 expression in mast cells was increased in solar urticaria at 30 minutes and 3 hours after SSR exposure, suggesting a mechanism of mast cell activation. Clinical resolution of solar urticaria by 24 hours mirrored resolution of inflammatory gene signature profiles. Comparison with available datasets of chronic spontaneous urticaria showed transcriptomic similarities relating to immune activation, but several transcripts were identified solely in solar urticaria, including CXCL8 and CSF2/3.

Solar urticaria is characterized by rapid signal transducer and activator of transcription 3 activation in mast cells and involvement of multiple chemotactic and innate inflammatory pathways, with FcεRI engagement indicated as an early event.

Chronic urticaria (CU) is characterized by persistent skin hives, redness, and itching, enhanced by immune dysregulation and inflammation. Our main objective is identifying key genes and molecular mechanisms of chronic urticaria based on bioinformatics. We used the Gene Expression Omnibus (GEO) database and retrieved two GEO datasets, GSE57178 and GSE72540. The raw data were extracted, pre-processed, and analyzed using the GEO2R tool to identify the differentially expressed genes (DEGs). The samples were divided into two groups: healthy samples and CU samples. We defined cut-off values of log2 fold change ≥1 and p < .05. Analyses were performed in the Kyoto Encyclopaedia of Genes and Genomes (KEGG), the Database for Annotation, Visualization and Integrated Discovery (DAVID), Metascape, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and CIBERSOFT databases. We obtained 1613 differentially expressed genes. There were 114 overlapping genes in both datasets, out of which 102 genes were up-regulated while 12 were down-regulated. The biological processes included activation of myeloid leukocytes, response to inflammations, and response to organic substances. Moreover, the KEGG pathways of CU were enriched in the Nuclear Factor-Kappa B (NF-kB) signaling pathway, Tumor Necrosis Factor (TNF) signaling pathway, and Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway. We identified 27 hub genes that were implicated in the pathogenesis of CU, such as interleukin-6 (IL-6), Prostaglandin-endoperoxide synthase 2 (PTGS2), and intercellular adhesion molecule-1 (ICAM1). The complex interplay between immune responses, inflammatory pathways, cytokine networks, and specific genes enhances CU. Understanding these mechanisms paves the way for potential interventions to mitigate symptoms and improve the quality of life of CU patients.

The purpose of this study was to assess the clinical effectiveness and safety profile of omalizumab as a therapeutic intervention for chronic urticaria (CU).

From March 1, 2023, to September 30, 2023, data on a cohort comprising 96 patients with CU, who underwent treatment with omalizumab at our medical institution's allergy clinic, were systematically compiled. Subsequent to the administration of omalizumab, the therapeutic efficacy was assessed utilizing the 7-day urticaria activity score and the urticaria control test.

Based on the statistical analysis, the mean duration of therapeutic intervention was 2.4 ± 1.3 months, with a corresponding mean cumulative dosage of 765 ± 450 mg. Of the subset of 42 patients with CU who were subjected to a follow-up period exceeding 3 months, it was observed that the treatment led to complete symptom remission, and no instances of recurrence were documented. Notably, there were statistically significant differences in the treatment duration and the cumulative dosage between patients who experienced co-morbid conditions and those who did not (p < 0.01, 95% CI: 0.280-1.326; p < 0.01, 95% CI: 0.597-2.997). Furthermore, there were significant differences in the treatment duration and cumulative dosage between patients in the combined allergic rhinitis group and those in the non-combined allergic rhinitis group (p < 0.01, 95% CI: 0.204-1.305; p = 0.01, 95% CI: 0.326-2.860).

Omalizumab demonstrates efficacy in the management of CU among Chinese patients by exerting effective symptom control and facilitating the regression of skin lesions. The assessment of its therapeutic efficacy typically requires a 12-week treatment period. Moreover, the co-occurrence of CU with other allergic disorders serves as a pertinent consideration for the adjustment of omalizumab dosing regimens.

The treatment options for chronic spontaneous urticaria (CSU) primarily include second generation non-sedative antihistamine (SGAHs). Bilastine is a newer, nonsedating SGAH approved for urticaria in February 2019 by the Drugs Controller General of India. Its major advantages are in terms of superior efficacy, lack of drug interactions and adverse effects, including sedation, compared to conventional SGAHs. The role of cytokines in the pathogenesis of CSU is well known. However, there is a shortage of data regarding the change in serum levels of proinflammatory cytokines following H1 antihistamines. We conducted this trial to evaluate the role of bilastine in cytokine modulation and autoimmunity, thereby explaining its role in modifying the disease process in CSU.

This prospective study was conducted in a tertiary institute in Kolkata on patients aged 12 years and above with a CSU >6 months. These patients had an unsatisfactory response, as per the Urticaria Activity Score 7 (UAS7), to previous antihistamine therapies in standard doses. Treatment effectiveness was determined by comparing the UAS7 at baseline with that at weeks 4, 8 and 12. Also, baseline serum interleukin-6 (IL-6) and IL-17 were compared with those at the end of the study, that is, 12 weeks.

Thirty patients who matched the inclusion criteria and signed informed consent were included in the study. At the end of 12 weeks, 10% of patients (n = 3) achieved a complete treatment response (UAS = 0), whereas 43.33% of patients (n = 13) were labelled as having well-controlled urticaria (UAS <6). At 12 weeks, the mean UAS7 score (6.47 ± 4.45) was statistically significant compared to the baseline score (25.47 ± 7.74). The mean values of serum IL-6 (pg/ml) and IL-17 (pg/ml) at baseline were 5.96 ± 5.24 pg/ml and 6.96 ± 5.97 pg/ml, respectively. At the end of treatment, that is, 3 months, the mean values were reduced to 4.61 ± 4.56 pg/ml and 5.08 ± 3.87 pg/ml. The reduction was statistically significant for both serum IL-6 (P < 0.001) and IL-17 (P < 0.0001).

We conclude that bilastine at a once-daily continuous dose of 40 mg for 3 months is safe and effective in CSU patients who are refractory to treatment at the standard doses of SGAHs. Improved symptomatic control with bilastine was also associated with better control over the inflammatory process, as suggested by the lowering of mean cytokine levels in our study.

Chronic inducible urticaria (CIndU) is a subtype of chronic urticaria (CU) which require specific physical or non-physical triggers to occur. They may be isolated or may coexist with chronic spontaneous urticaria (CSU). Despite their frequent appearance in dermatology clinics, there is scarce information on the distinguishing features among the most common subtypes of CIndU as well as isolated CIndU versus CSU plus CIndU.

To compare clinical and laboratory characteristics, and comorbid conditions among the most common CIndU types and isolated CIndU versus CSU plus CIndU.

We retrospectively analysed CIndU patients and compared patients' demographic, clinical and laboratory characteristics across isolated CIndU, CSU plus CIndU, symptomatic dermographism (SD), cold urticaria (ColdU) and cholinergic urticaria (ChoU).

A total of 423 patients (~70% isolated CIndU, ~30% CSU plus CIndU, ~5% mixed CIndU subtypes) were included in the study. The most frequent CIndU subtypes were SD (68.6%; 290/423), ColdU (11.4%; 48/423) and ChoU (10.9%; 46/423). Isolated CIndU patients were younger than CSU plus CIndU (33.74 ± 12.72 vs. 37.06 ± 11.84, p = 0.010). Angioedema, emergency referrals, need for systemic steroids, comorbid systemic disorders were more frequent and baseline urticaria control test scores were lower in CSU plus CIndU patients (vs. CIndU, p < 0.001, p = 0.008, p < 0.001, p = 0.031, p = 0.036, respectively). Among CIndU subtypes, ChoU patients were younger (24.9 ± 12.2 vs. 34.47 ± 12.12 vs. 31.38 ± 14.95; p < 0.001) and had male predominance (p < 0.001) while SD patients had no angioedema (p < 0.001) and had higher frequency of increased total IgE levels (p = 0.006).

Isolated CIndU and CSU plus CIndU seems to be different endotypes of CU where CSU plus CIndU presents a more severe and refractory course. There are distinctive features of each CIndU subtype. These suggest involvement of different pathomechanistic pathways in these subtypes that need to be clarified in future studies.

This study delves into the critical role of alarmins in chronic spontaneous urticaria (CSU), focusing on their impact on disease severity and the quality of life (QoL) of patients. We investigated the alterations in alarmin levels in CSU patients and their correlations with the Urticaria Activity Score (UAS7) and the Dermatology Life Quality Index (DLQI). We analyzed serum levels of interleukin-25 (IL-25), interleukin-33 (IL-33), and thymic stromal lymphopoietin (TSLP) in 50 CSU patients, comparing these to 38 healthy controls. The study examined the relationship between alarmin levels and clinical outcomes, including disease severity and QoL. Elevated levels of IL-33 and TSLP in CSU patients (p < 0.0001) highlight their potential role in CSU pathogenesis. Although IL-25 showed higher levels in CSU patients, this did not reach statistical significance (p = 0.0823). Crucially, IL-33's correlation with both UAS7 and DLQI scores underscores its potential as a biomarker for CSU diagnosis and severity assessment. Of the alarmins analyzed, IL-33 emerges as particularly significant for further exploration as a diagnostic and prognostic biomarker in CSU. Its substantial correlation with disease severity and impact on QoL makes it a compelling candidate for future research, potentially serving as a target for therapeutic interventions. Given these findings, IL-33 deserves additional investigation to confirm its role and effectiveness as a biomarker and therapeutic target in CSU.

Patients with chronic spontaneous urticaria (CSU) can have comorbid inducible urticaria (CIndU). How comorbid CIndU affects patients and their CSU is largely unclear.

To compare patients with CSU with and without comorbid CIndUs for differences in demographic features, clinical characteristics, and laboratory markers.

We analyzed 708 patients with CSU of our Urticaria Center of Reference and Excellence enrolled in CURE, the chronic urticaria registry. CURE data collected until October 2022 were used to compare patients with and without comorbid CIndU for their demographic characteristics, disease onset, activity, impact, and control, as well as concomitant allergic and autoimmune diseases and laboratory parameters associated with autoimmune CSU.

Of 708 patients with CSU, 247 (35%) had comorbid CIndU. Compared with patients with standalone CSU, patients with CSU with comorbid CIndU were significantly younger, had earlier disease onset, longer disease duration, higher impact on quality of life, and a higher rate of concomitant allergic diseases. Moreover, patients with CSU with comorbid CIndU less often had features linked to autoimmune CSU such as angioedema, concomitant autoimmune diseases, eosinopenia, low levels of total IgE, and low total IgE combined with elevated anti-thyroid peroxidase IgG.

Autoimmune CSU may be less common in patients with comorbid CIndU than without, and comorbid CIndU may point to autoallergic CSU.

Chronic spontaneous urticaria (CSU) is a debilitating affliction that affects diverse quality of life (QoL) parameters such as sleep, self-esteem, and daily activities. Second-generation antihistamines, such as desloratadine, are more effective and safer in managing CSU. Desloratadine is a nonsedating, potent, and highly selective H1 receptor antagonist. At its daily dose of 5 mg, almost half of CSU patients do not show symptomatic improvement. European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum (EDF) (EuroGuiDerm)/Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI) guidelines recommend increasing the dosage to up to four times in such nonresponsive patients. However, there is insufficient clinical evidence in Indian settings.

We evaluated the efficacy and safety of 10 mg desloratadine (OD) in 256 nonresponsive patients with moderate to severe CSU. The primary outcome was the change in Urticaria Activity Score (UAS7) from baseline to four weeks. Additionally, change in Chronic Urticaria Quality of Life (CU-Q2oL) scores during the course of treatment was also evaluated.

The mean UAS7 scores showed a significant reduction from 31.9 ± 4.8 at baseline to 18.2 ± 8.1 at the end of the study (p < 0.0001). The use of a higher dose of desloratadine also decreased the CU-Q2oL scores significantly from 59.8 ± 14.7 at baseline to 35.4 ± 10 at four weeks (p < 0.0001). The incidence of adverse events (AEs) possibly linked to the drug was low (1.6%), and no serious adverse events were reported.

Results indicated improvements in the disease severity as well as its positive impact on participants' QoL. This study confirms the efficacy and safety of daily use of a twofold dose of desloratadine in nonresponsive moderate to severe CSU patients.

Chronic spontaneous urticaria (CSU) is unpredictable and can severely impair patients' quality of life. Patients with CSU need a convenient, user-friendly platform to complete patient-reported outcome measures (PROMs) on their mobile devices. CRUSE® , the Chronic Urticaria Self Evaluation app, aims to address this unmet need.

CRUSE® was developed by an international steering committee of urticaria specialists. Priorities for the app based on recent findings in CSU were defined to allow patients to track and record their symptoms and medication use over time and send photographs. The CRUSE® app collects patient data such as age, sex, disease onset, triggers, medication, and CSU characteristics that can be sent securely to physicians, providing real-time insights. Additionally, CRUSE® contains PROMs to assess disease activity and control, which are individualised to patient profiles and clinical manifestations.

CRUSE® was launched in Germany in March 2022 and is now available for free in 17 countries. It is adapted to the local language and displays a country-specific list of available urticaria medications. English and Ukrainian versions are available worldwide. From July 2022 to June 2023, 25,710 observations were documented by 2540 users; 72.7% were females, with a mean age of 39.6 years. At baseline, 93.7% and 51.3% of users had wheals and angioedema, respectively. Second-generation antihistamines were used in 74.0% of days.

The initial data from CRUSE® show the wide use and utility of effectively tracking patients' disease activity and control, paving the way for personalised CSU management.

Chronic urticaria (CU) is the recurring development of wheals (aka "hives" or "welts"), angioedema, or both for more than 6 weeks. Wheals and angioedema occur with no definite triggers in chronic spontaneous urticaria, and in response to known and definite physical triggers in chronic inducible urticaria. Approximately 1.4% of individuals globally will have CU during their lifetime. The itching and physical discomfort associated with CU have a profound impact on daily activities, sexual function, work or school performance, and sleep, causing significant impairment in a patient's physical and mental quality of life. CU also places a financial burden on patients and healthcare systems. Patients should feel empowered to self-advocate to receive the best care. The voice of the patient in navigating the journey of CU diagnosis and management may improve patient-provider communication, thereby improving diagnosis and outcomes. A collaboration of patients, providers, advocacy organizations, and pharmaceutical representatives have created a patient charter to define the realistic and achievable principles of care that patients with CU should expect to receive. Principle (1): I deserve an accurate and timely diagnosis of my CU; Principle (2): I deserve access to specialty care for my CU; Principle (3): I deserve access to innovative treatments that reduce the burden of CU on my daily life; Principle (4): I deserve to be free of unnecessary treatment-related side-effects during the management of my CU; and Principle (5): I expect a holistic treatment approach to address all the components of my life impacted by CU. The stated principles may serve as a guide for healthcare providers who care for patients with CU and translate into better patient-physician communication. In addition, we urge policymakers and authors of CU treatment guidelines to consider these principles in their decision-making to ensure the goals of the patient are achievable.

Anti-heat shock protein (HSP) autoantibodies are detected in autoimmune diseases. We sought to ascertain whether anti-HSP10 IgG is present in patients with CSU and to elucidate the role of HSP10 in CSU pathogenesis.

Using a human proteome microarray, six potential autoantibodies had higher expression in 10 CSU samples compared with 10 normal controls (NCs). Among them, HSP10 IgG autoantibody was quantified by immune dot-blot assay in sera from 86 CSU patients and 44 NCs. The serum levels of HSP10 and microRNA-101-5p were measured in CSU patients and NCs. The effects of HSP10 and miR-101-5p on mast cell degranulation in response to IgE, compound 48/80, and platelet-activating factor (PAF) were investigated.

CSU patients had higher IgG positivity to HSP10 (40.7% vs. 11.4%, p = .001), lower serum HSP10 levels (5.8 ± 3.6 vs. 12.2 ± 6.6 pg/mL, p < .001) than in NCs, and their urticaria severity was associated with anti-HSP10 IgG positivity, while HSP10 levels were related to urticaria control status. MiR-101-5p was increased in CSU patients. PAF enhanced IL4 production in PBMCs from CSU patients. IL-4 upregulated miR-101-5p and reduced HSP10 expression in keratinocytes. Transfection of miR-101-5p reduced HSP10 expression in keratinocytes. MiR-101-5p promoted PAF-induced mast cell degranulation, while HSP10 specifically prevented it.

A new autoantibody, anti-HSP10 IgG was detected in CSU patients, which showed a significant correlation with UAS7 scores. A decreased serum HSP10 level was associated with upregulation of miR-101-5p due to increased IL-4 and PAF in CSU patients. Modulation of miR-101-5p and HSP10 may be a novel therapeutic approach for CSU.

Urticaria is a skin-condition characterized by sudden-onset pruritic wheals with/without angioedema. Urticaria can be acute or chronic. Chronic urticaria may be spontaneous or inducible, based on absence/presence of specific triggers. Chronic spontaneous urticaria is most frequent (∼80%). Urticaria is primarily a mast-cell mediated histaminergic-disorder. Recently, other inflammatory cells and pro-inflammatory cytokines have been implicated. Deeper understanding has unmasked two endotypes - IgE-mediated type I autoimmunity/autoallergy and IgG-mediated type IIb autoimmunity. Current treatment recommendation involving second-generation H1-antihistamines, omalizumab and cyclosporine is effective in 60-80% patients. So, newer treatment options are being explored based on emerging targets. Despite being non-lethal, urticaria considerably impairs patient's quality-of-life and may be associated with extra-cutaneous comorbidities. Several "patient reported outcome measures" have been proposed to evaluate disease-activity, impact and control, for effective treatment modulation till complete disease control. This review discusses the current understanding about urticaria and its future directions, to facilitate optimum evidenced-based care.

The purpose of this review is to provide an overview of the recent advancements and relevance of the autoimmune theories in chronic spontaneous urticaria (CSU).

Two primary types of autoimmunity, Type I and Type IIb, have emerged as major contributors to CSU, characterized by immunoglobulin E (IgE) and immunoglobulin G (IgG) autoantibodies, respectively. Genetic evidence supports the notion that CSU shares more similarities with other autoimmune diseases rather than atopic diseases. Novel autoallergens such as FcεRI and tissue transglutaminase have been identified, contributed to our understanding of autoimmune mechanisms. Furthermore, the potential overlap between Type I and Type IIb autoimmunity has been recognized. Evaluating the autoimmune status of CSU patients through biomarkers and understanding their clinical implications is vital for effective management. For instance, CSU patients with Type IIb autoimmunity, with or without coexisting Type I autoimmunity, may exhibit resistance to H1-antihistamines and omalizumab treatment but could potentially respond well to cyclosporine or Bruton's tyrosine kinase inhibitors.

Further investigations are needed to explore new autoallergens and autoantibodies in CSU, establishing their connection to the development of autoimmunity. The efficacy of novel drugs targeting different mechanisms should be examined to determine their responses in both autoimmune CSU and nonautoimmunity-related CSU.

Atopic dermatitis and asthma are two diseases whose pathogenesis is largely attributable to the activation, at least in the initial stages, of T helper (Th)-2 Lymphocytes, the related cytokine axis, and B lymphocytes with antibody production. Psoriasis is conversely a pathology resulting from a recruitment of Th-17 and Th-1 lymphocytes, after an initial role of innate immunity. Mepolizumab is a humanized monoclonal antibody directed against interleukin (IL)-5, a central cytokine in the Th-2 axis, therefore involved in the pathogenesis of asthma. Several authors have described the appearance of psoriatic lesions in patients with asthma or atopic dermatitis following the therapy with dupilumab, a monoclonal antibody that blocks the interleukin (IL)-4, another Th-2 cytokine.

We present the case of a 59-year-old patient who developed psoriasiform lesions on the palms after mepolizumab therapy for asthma, for the activation of the parallel cytokine cascade after the blockade of IL-5. We successfully treated the patient with a topical calcipotriol and betamethasone ointment.

We should investigate with further attention the possible impact on the human immunological ecosystem put in place by the inhibition of the activity of individual inflammatory mediators, so as to be able to recognize the initial adverse effects early.

Omalizumab is effective in chronic spontaneous urticaria unresponsive to antihistamines. Of the licensed dosing schedules, Korean patients prefer a low dose, of 150 mg/month, for financial reasons. However, real-world experiences of low-dose omalizumab consumption have not been reported. The aim of this retrospective study was to assess the treatment outcomes and long-term clinical course of patients with chronic spontaneous urticaria who were treated with low-dose omalizumab. The study included 179 patients aged ≥ 20 years who were treated with omalizumab 150 mg/month for ≥ 12 weeks. Baseline disease activity was mild, moderate, and severe in 54.7%, 35.2%, and 10.1% of patients, respectively. A complete response was observed in 133 patients at 12 weeks, among whom 88 patients showed early responses within 4 weeks. Overall, 158 patients finally achieved a complete response. Multivariate analyses revealed that baseline disease activity is more likely to be mild in patients who experience early and final complete responses. The absence of atopic comorbidities correlated with an early response. Smoking was associated with a final complete response. This study shows that low-dose omalizumab provides favourable treatment outcomes in antihistamine-refractory chronic spontaneous urticaria. Disease severity, atopic comorbidity, and smoking may be predictive factors for studying the response to omalizumab.