Non-Skin-Related Symptoms are Common in Chronic Spontaneous Urticaria and Linked to Active and Uncontrolled Disease: Results from CURE.

BACKGROUND: Chronic spontaneous urticaria (CSU) can present with non-skin-related symptoms (NSRS), including recurrent unexplained fever, joint/bone/muscle pain (JBMP), and malaise, which also occur in other conditions that manifest with wheals (e.g., urticarial vasculitis or autoinflammatory disorders) or without wheals (e.g., infection). OBJECTIVE: We sought to determine the rate of patients with CSU affected by fever, JBMP and malaise, their trigger factors, links with clinical and laboratory characteristics, and their impact on everyday life and treatment responses. METHODS: We analyzed baseline data from the Chronic Urticaria Registry (CURE) of 2,521 patients with CSU who were ≥16 years old. RESULTS: One-third of CSU patients (31.2%, 786/2,521) had ≥1 NSRS, including recurrent fever (5.3%), JBMP (19.1%), and/or malaise (18.6%). In a multivariable analysis, having ≥1 of these NSRS correlated with food and infection as trigger factors of urticaria (adjusted odds ratio [aOR]=1.7 and 1.5), wheals of ≥24 hours duration (aOR=2.5), sleep disturbance (aOR=2.4), anxiety (aOR=2.8), comorbid atopic dermatitis (aOR=2.1), gastrointestinal disease (aOR=1.8), elevated leukocytes (aOR=1.7) and erythrocyte sedimentation rate (aOR=1.5). In a bivariate analysis, these NSRS were additionally associated with higher disease activity (UAS7, median: 21 vs. 14, p=0.009), longer disease duration (years, median: 2 vs. 1, p=0.001), presence of angioedema (74.6% vs. 58.7%, p<0.001), worse quality of life (CU-Q2oL, median: 42 vs. 29, p<0.001) and more frequent poor control of CSU (78% vs. 69%, p<0.001). CONCLUSION: The presence of NSRS in a subpopulation of CSU patients points to a need for better control of the disease, exclusion of comorbid conditions and/or exclusion of urticarial vasculitis and urticarial autoinflammatory diseases.

Patient-Reported Outcome Measures in Atopic Dermatitis and Chronic Urticaria are Underused in Clinical Practice.

BACKGROUND: Patient-reported outcome measures (PROMs) are validated and standardized tools that complement physician evaluations and guide treatment decisions. PROMs 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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". AD and CU PROM usage is associated with being female, younger, and a dermatologist. POSCORAD and UAS were the most utilized 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. AD and CU PROM users would like training in selecting the proper PROM. CONCLUSION: Even though 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.

Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases.

Chronic urticaria (CU) is a mast cell (MC)-dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE-mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation-including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators-strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid-binding immunoglobulin-like lectin8 -[Siglec-8] [lirentelimab/AK002], Siglec-6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on- or off-target, immunosuppressive adverse effects.

In the skin lesions of patients with mycosis fungoides, the number of MRGPRX2-expressing cells is increased and correlates with mast cell numbers.

Background: Mycosis fungoides (MF) is an indolent T-cell lymphoma that mainly affects the skin and presents with itch in more than half of the patients. Recently, the expression of Mas-related G protein-coupled receptor X2 (MRGPRX2), a receptor of mast cell (MC) responsible for the IgE-independent non-histaminergic itch, has been shown in lesional skin of patients with pruritic skin diseases, including chronic urticaria, prurigo, and mastocytosis. As of yet, limited knowledge exists regarding the MRGPRX2 expression in the skin of patients with MF. Objectives: To investigate the number of MRGPRX2-expressing (MRGPRX2+) cells in the skin of patients with MF and its correlation with clinical and laboratory characteristics of the disease. Methods: MRGPRX2 was analyzed in lesional and non-lesional skin of MF patients and healthy skin tissues by immunohistochemistry. Co-localization of MRGPRX2 with the MC marker tryptase was assessed by immunofluorescence. Public single-cell RNAseq data was reanalyzed to identify the MRGPRX2 expression on the distinct cell types. Results: In lesional skin of MF patients, MRGPRX2+ cell number was higher than in non-lesional skin and healthy control skin (mean:15.12 vs. 6.84 vs. 5.51 cells/mm2, p=0.04), and correlated with MC numbers (r=0.73, p=0.02). MC was the primary cell type expressing MRGPRX2 in MF patients. The ratio of MRGPRX2+ MCs to MRGPRX2+ cells in lesional and non-lesional skin correlated with the severity of disease (r=0.71, p=0.02 and r=0.67, p=0.03, respectively). Conclusions: Our findings point to the role of MRGPRX2 and MC in the pathogenesis of MF that should be investigated in further studies.

The diagnostic workup for systemic mastocytosis differs from consensus recommendations: Results of a worldwide survey.

Objective: Mastocytosis is a complex disorder affecting various organs. The diagnostic workup can be challenging and requires a multidisciplinary approach including the use of uncommon tests. To assess mastocytosis management around the globe, we conducted the first worldwide online survey for physicians. Methods: A 21-item questionnaire was sent out to the members of the World Allergy Organization (WAO), the Global Allergy and Asthma European Network (GA2LEN), the Urticaria (UCARE) and Angioedema (ACARE) Centers of Reference and Excellence, the German Society of Allergology and Clinical Immunology (DGAKI), and the European Mast Cell and Basophil Research Network (EMBRN) in April-June 2021. Results: Across 628 respondents from 79 countries 87.7% and 9.7% of physicians were allergists/clinical immunologists and/or dermatologists. Participating physicians were from all regions of the world (Europe, EU: 41.6%; North America, NA: 24.8%; Latin America, LA: 14.5%; Asia-Pacific, AP: 12.6%; and Africa/Middle East, AME: 6.5%). Only 2.2% of respondents worked at Specialized Mastocytosis Centers (SMCs) in North America or European Union. Physicians reported caring for 4 patients with mastocytosis per year, with higher numbers in European Union and Asia Pacific (5/year) compared to Latin America (2/year). Dermatologists and physicians who work at SMCs reported higher patient numbers (15/year and 80/year, respectively). Suspicion of mastocytosis in the allergology and dermatology community is commonly driven by anaphylaxis (82.9%), mastocytosis skin lesions (82.1%), or elevated tryptase levels (76.6%). Osteoporosis and gastrointestinal symptoms less often prompted suspicion of mastocytosis (21.4% and 49.9%, respectively). World Health Organisation (WHO)-diagnostic criteria and classification, regardless of the region, are only used by about 50% of physicians, with higher rates for SMCs (83.3%). Serum tryptase, bone marrow biopsy, and KIT D816V mutation analysis are included in the diagnostic workup by 90.9%, 61.5%, and 58.4% of physicians, respectively. The biggest challenges for the management of mastocytosis are the lack of more effective treatment options (51.1%), missing multidisciplinary networks (47.1%), and the lack of experience of specialists from other disciplines (39.0%). Conclusions: The diagnostic workup for mastocytosis differs from consensus recommendations and varies between regions. This may be improved by establishing active multidisciplinary networks, increasing access to diagnostic procedures, consistently applying WHO criteria, and developing new Mastocytosis Centers of Reference and Excellence.

Global disparities in availability of epinephrine auto-injectors.

Background: Anaphylaxis is the most severe clinical presentation of acute systemic allergic reactions and can cause death. Given the prevalence of anaphylaxis within healthcare systems, it is a high priority public health issue. However, management of anaphylaxis - both acute and preventative - varies by region. Methods: The World Allergy Organization (WAO) Anaphylaxis Committee and the WAO Junior Members Steering Group undertook a global online survey to evaluate local practice in the diagnosis and management of anaphylaxis across regions. Results: Responses were received from WAO members in 66 countries. While intramuscular epinephrine (adrenaline) is first-line treatment for anaphylaxis, some countries continue to recommend alternative routes in contrast to guidelines. Epinephrine auto-injector (EAI) devices, prescribed to individuals at ongoing risk of anaphylaxis in the community setting, are only available in 60% of countries surveyed, mainly in high-income countries. Many countries in South America, Africa/Middle-East and Asian-Pacific regions do not have EAI available, or depend on individual importation. In countries where EAIs are commercially available, national policies regarding the availability of EAIs in public settings are limited to few countries (16%). There is no consensus regarding the time patients should be observed following emergency treatment of anaphylaxis. Conclusion: This survey provides a global snapshot view of the current management of anaphylaxis, and highlights key unmet needs including the global availability of epinephrine for self-injection as a key component of anaphylaxis management.

Differential diagnosis between urticarial vasculitis and chronic spontaneous urticaria: An international Delphi survey.

BACKGROUND: Urticarial vasculitis (UV) should be differentiated from chronic spontaneous urticaria (CSU) in patients initially presenting with recurrent wheals, although criteria for differential diagnosis remain ill-defined. OBJECTIVES: To set the goals, define criteria and unmet needs in UV diagnosis and differential diagnosis with CSU, and explore the possibility of coexistence of both diseases. METHODS: Thirteen experts experienced in UV research participated in a Delphi survey of European Academy of Allergy and Clinical Immunology taskforce. This Delphi survey involved three rounds of anonymous responses to n = 32 questions with the aim to aggregate the experts' opinions and to achieve consensus. Urticaria specialists (n = 130, most from Urticaria Centers of Reference and Excellence) evaluated the consensus statements and recommendations in the fourth and final round. RESULTS: The panel agreed that essential criteria to guide a skin biopsy in patients with recurrent wheals should include at least one of the following features: wheal duration >24 h, bruising/postinflammatory hyperpigmentation, and systemic symptoms. Leukocytoclasia and fibrin deposits were identified as a minimum set of UV histological criteria. As agreed by the panel members, CSU and normocomplementemic UV (NUV) may coexist in some patients. CONCLUSIONS: The use of established criteria for the diagnosis and differential diagnosis of UV in patients with recurrent wheals can help guide the diagnostic approach and prompt earlier treatment. Further studies should investigate whether CSU and NUV are different entities or part of a disease spectrum.

Type 2 chronic inflammatory diseases: targets, therapies and unmet needs.

Over the past two decades, significant progress in understanding of the pathogenesis of type 2 chronic inflammatory diseases has enabled the identification of compounds for more than 20 novel targets, which are approved or at various stages of development, finally facilitating a more targeted approach for the treatment of these disorders. Most of these newly identified pathogenic drivers of type 2 inflammation and their corresponding treatments are related to mast cells, eosinophils, T cells, B cells, epithelial cells and sensory nerves. Epithelial barrier defects and dysbiotic microbiomes represent exciting future drug targets for chronic type 2 inflammatory conditions. Here, we review common targets, current treatments and emerging therapies for the treatment of five major type 2 chronic inflammatory diseases - atopic dermatitis, chronic prurigo, chronic urticaria, asthma and chronic rhinosinusitis with nasal polyps - with a high need for targeted therapies. Unmet needs and future directions in the field are discussed.

Patients With Chronic Spontaneous Urticaria Who Have Wheals, Angioedema, or Both, Differ Demographically, Clinically, and in Response to Treatment-Results From CURE.

BACKGROUND: Patients with chronic spontaneous urticaria (CSU) have spontaneous wheals (W), angioedema (AE), or both, for longer than 6 weeks. Clinical differences between patients with standalone W, standalone AE, and W and AE (W+AE) remain incompletely understood. OBJECTIVE: To compare W, AE, and W+AE CSU patients regarding demographics, disease characteristics, comorbidities, disease burden, and treatment response. METHODS: Baseline data from 3,698 CSU patients in the ongoing, prospective, international, multicenter, observational Chronic Urticaria REgistry (CURE) were analyzed (data cut: September 2022). RESULTS: Across all CSU patients, 59%, 36%, and 5% had W+AE, W, and AE, respectively. The W+AE patients, compared with W and AE patients, showed the lowest male-to-female ratio (0.33), higher rates of concomitant psychiatric disease (17% vs 11% vs 6%, respectively), autoimmune disease (13% vs 7% vs 9%, respectively), and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (9% vs 5% vs 2%, respectively) and the highest disease impact. The W patients, compared with W+AE and AE patients, showed the lowest rates of concomitant hypertension (15% vs 21% vs 40%, respectively) and obesity (11% vs 16% vs 17%, respectively), the highest rate of concomitant inducible urticaria (24% vs 22% vs 6%, respectively), and shorter W duration. The AE patients, compared with W+AE and W patients, were older at disease onset, showed longer AE duration, and the best response to increased doses of H1-antihistamines (58% vs 24% vs 31%, respectively) and omalizumab (92% vs 67% vs 60%, respectively). CONCLUSIONS: Our findings provide a better understanding of CSU phenotypes and may guide patient care and research efforts that aim to link them to pathogenic drivers.

How Infection and Vaccination Are Linked to Acute and Chronic Urticaria: A Special Focus on COVID-19.

Since more than a century ago, there has been awareness of the connection between viral infections and the onset and exacerbation of urticaria. Our knowledge about the role of viral infection and vaccination in acute and chronic urticaria improved as a result of the COVID-19 pandemic but it has also highlighted knowledge gaps. Viral infections, especially respiratory tract infections like COVID-19, can trigger the onset of acute urticaria (AU) and the exacerbation of chronic urticaria (CU). Less frequently, vaccination against viruses including SARS-CoV-2 can also lead to new onset urticaria as well as worsening of CU in minority. Here, with a particular focus on COVID-19, we review what is known about the role of viral infections and vaccinations as triggers and causes of acute and chronic urticaria. We also discuss possible mechanistic pathways and outline the unmet needs in our knowledge. Although the underlying mechanisms are not clearly understood, it is believed that viral signals, medications, and stress can activate skin mast cells (MCs). Further studies are needed to fully understand the relevance of viral infections and vaccinations in acute and chronic urticaria and to better clarify causal pathways.

Positive Basophil Tests Are Linked to High Disease Activity and Other Features of Autoimmune Chronic Spontaneous Urticaria: A Systematic Review.

BACKGROUND: Chronic spontaneous urticaria (CSU) is believed to be Autoimmune (aiCSU) (type IIb CSU) in at least 8% of patients, associated with mast cell-activating IgG autoantibodies. Basophil tests such as the basophil activation test (BAT) and basophil histamine release assay (BHRA) are considered the best single tests for an aiCSU diagnosis. To date, the strength of associations among a positive BAT and/or BHRA (BAT/BHRA+) and CSU features, patient demographics, and response to treatment remains poorly characterized. OBJECTIVE: To evaluate the strength of current evidence on basophil tests as parameters for CSU characteristics. METHODS: We performed a systematic literature search and review to assess the relationship between BAT/BHRA+ and clinical and laboratory parameters of CSU. Of 1,058 records found in the search, 94 studies were reviewed by experts in urticaria and 42 were included in the analysis. RESULTS: In CSU patients, BAT/BHRA+ showed a strong level of evidence for an association with high disease activity and low levels of total IgE. A weak level of evidence was shown for the association of BAT/BHRA+ and the presence of angioedema, and basopenia. CONCLUSIONS: Our results suggest that aiCSU defined by BAT/BHRA+ is more active or severe and is linked to other aiCSU markers such as low total IgE/basopenia. Basophil tests should be standardized and implemented in routine clinical care to improve the diagnosis and treatment of patients with aiCSU.

Urticarial Vasculitis Differs From Chronic Spontaneous Urticaria in Time to Diagnosis, Clinical Presentation, and Need for Anti-Inflammatory Treatment: An International Prospective UCARE Study.

BACKGROUND: Chronic spontaneous urticaria (CSU) and urticarial vasculitis (UV) share several clinical features including the occurrence of wheals. As of yet, the criteria for differentiating the 2 disorders are not clearly defined. OBJECTIVE: Here, we aimed to identify differences, similarities, and the likelihood for specific clinical features in patients with UV versus those with CSU. METHODS: Across 10 Urticaria Centers of Reference and Excellence, 106 patients with skin biopsy-confirmed UV and 126 patients with CSU were prospectively recruited to complete a questionnaire on the clinical features, course, and response to treatment of their disease. RESULTS: As compared with CSU, patients with UV more often experienced postinflammatory skin hyperpigmentation, wheals of ≥24-hour duration, eye inflammation, and fever (6.9, 4.0, 3.6, and 2.4 times, respectively). Clinical features that increased the risk for UV diagnosis when present at the onset of disease included wheals of ≥24-hour duration (7.3-fold), pain of the skin (7.0-fold), postinflammatory hyperpigmentation (4.1-fold), and fatigue (3.1-fold). The diagnostic delay was markedly longer for normocomplementemic UV as compared with hypocomplementemic UV and CSU (21 vs 5 vs 6 months, respectively). Oral corticosteroids and omalizumab were the most effective treatments in patients with UV and CSU, respectively. Patients with UV showed a higher need for immunosuppressive and anti-inflammatory therapies than patients with CSU. CONCLUSIONS: Long wheal duration, skin pain and hyperpigmentation, and systemic symptoms point to UV rather than CSU as the underlying disease and should prompt further diagnostic workup including a skin biopsy.

Chronic urticaria and the pathogenic role of mast cells.

The signs and symptoms of chronic urticaria (CU) are caused by the activation and degranulation of skin mast cells (MCs). Recent studies have added to our understanding of how and why skin MCs are involved and different in CU. Also, novel and relevant mechanisms of MC activation in CU have been identified and characterized. Finally, the use of MC-targeted and MC mediator-specific treatments has helped to better define the role of the skin environment, the contribution of specific MC mediators, and the relevance of MC crosstalk with other cells in the pathogenesis of CU. Here, we review these recent findings and their impact on our understanding of CU, with a focus on chronic spontaneous urticaria (CSU). Also, we highlight open questions, issues of controversy, and unmet needs, and we suggest what studies should be performed moving forward.