Urticária Crônica Espontânea: abordagem clínico-laboratorial e manejo terapêutico

Contexto: Urticária crônica caracteriza-se pela presença de urticas e/ou angioedema, com tempo de evolução superior a 6 semanas. Classifica- se em urticária crônica espontânea (UCE), com causas conhecidas ou não conhecidas e urticária crônica induzida (UCI). Objetivo: Esta revisão de UCE visa abordar os aspectos clínico-laboratoriais e indicações terapêuticas, de acordo com as diretrizes brasileira e internacional. Métodos: para esta revisão de UCE foi realizada pesquisa nas bases de dados PubMed, Embase, Google Acadêmico e Web of Science. Resultados: Foram incluídos artigos em inglês publicados entre 2018 e 2024, de acordo com sua relevância. Discussão: A patogênese da UCE engloba mecanismos imunológicos do tipo I e IIb. O diagnóstico da afecção é clínico, podendo ser realizados exames laboratoriais complementares, incluindo hemograma, VHS, D-dímero, PCR, anticorpos anti-peroxidase tireoidiana e IgE total. O diagnóstico diferencial da UCE apresenta diversas condições clínicas com morfologia semelhante à UCE. O tratamento indicado da UCE envolve medidas como suspensão de eventuais fatores desencadeantes e abordagem farmacológica, com utilização de anti-histamínicos não-sedantes, omalizumabe e uso eventual de ciclosporina. Conclusões: O impacto da UCE para os pacientes e para o sistema de saúde é de extrema relevância e avanços nas pesquisas permitirão um tratamento individualizado, com melhores perspectivas em relação à terapêutica e qualidade de vida dos pacientes.

Knockdown of miR-155 alleviates skin damage in rats with chronic spontaneous urticaria by modulating the JAK/STAT signaling pathway.

OBJECTIVE: The aim of this study was to investigate the role and mechanisms of miR-155 in chronic spontaneous urticaria (CSU). METHODS: The expression level of miR-155 in the skin tissues of patients with CSU and experimental rats were detected by RT-qPCR, followed by the measurement of the histamine release rate in the serum through the histamine release test. Besides, hematoxylin & eosin staining was used to observe the pathological changes of the skin tissues; Corresponding detection kits and flow cytometry to measure the changes of immunoglobulins, inflammatory cytokines and T cell subsets in the serum of rats in each group; and western blot to check the expression level of proteins related to JAK/STAT signaling pathway in the skin tissues. RESULTS: Knockdown of miR-155 reduced the number and duration of pruritus, alleviated the skin damage, and decreased the number of eosinophils in CSU rats. Moreover, knockdown of miR-155 elevated the serum levels of IgG and IgM, decreased the levels of IgA and inflammatory cytokines, and reduced the proportion of CD4 + and CD4 + CD25 + T cells, as well as the CD4+/CD8 + ratio in CSU rats. However, Tyr705 intervention could reverse the effects of knockdown of miR-155 on CSU model rats. Furthermore, we found that knockdown of miR-155 significantly reduced the protein expression of IRF-9, as well as the P-JAK2/JAK2 and P-STAT3/STAT3 ratios in the skin tissues of CSU rats. CONCLUSION: Knockdown of miR-155 can alleviate skin damage and inflammatory responses and relieve autoimmunity in CSU rats by inhibiting the JAK/STAT3 signaling pathway.

Acute Urticaria: Symptoms, Causes, and Evaluation of Phenotypes Prone to Chronicity.

INTRODUCTION: Urticaria is a condition that is characterized by the development of wheals (hives), angioedema, or both. If symptoms persist for less than 6 weeks, it is classified as acute urticaria (AU), and if they persist for longer than 6 weeks, it is classified as chronic urticaria (CU). Disease activity is evaluated using validated patient-reported outcome measures (PROMs) such as the 7-day urticaria activity score (UAS-7) and urticaria control test (UCT). In this study, we aimed to determine whether there was a difference between patients with chronic and recovered urticaria in terms of age, sex, symptoms, disease severity, disease control, and triggering factors by following patients with AU for 6 months. METHODS: The routine tests were requested at the first admission of the patients. If previously examined, anti-thyroid peroxidase (anti-TPO), anti-nuclear antibody, etc., were recorded. After the first examination, the patients were evaluated again using a visual analog scale (VAS), UCT, UAS-7, and medication scores (MSs) in the 1st, 3rd, and 6th months. RESULTS: One hundred nine (F/M: 80/29) patients were included in the study. Twenty-seven patients had a previous history of AU, 22 of these patients were evaluated as having recurrent AU, and five became chronic during follow-up. Urticaria continued in 22 of 82 patients who presented with first-attack AU in the 3rd month and 17 in the 6th month. We had a chronicity rate of 24.7%. It was determined that having positive anti-TPO increased the risk of CU 1.69 times. A statistically significant improvement was found in the mean VAS, UCT, UAS-7, and MSs evaluated in the 1st, 3rd, and 6th months of patients with CU compared with baseline. CONCLUSION: AU is a common disease and usually heals in a short time without becoming chronic. Studies on the causes of chronicity are limited. Testing anti-TPO in patients presenting with AU may be useful in terms of disease course and risk of chronicity.

In chronic spontaneous urticaria, increased Galectin-9 expression on basophils and eosinophils is linked to high disease activity, endotype-specific markers, and response to omalizumab treatment.

BACKGROUND: Galectin-9 (Gal-9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear. OBJECTIVES: To characterize the role and relevance of Gal-9 in the pathogenesis of CSU. METHODS: We assessed 60 CSU patients for their expression of Gal-9 on circulating eosinophils and basophils as well as T cell expression of the Gal-9 receptor TIM-3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal-9 expression by eosinophils and basophils. RESULTS: Our CSU patients had markedly increased rates of circulating Gal-9+ eosinophils and basophils and high numbers of lesional Gal-9+ cells. High rates of blood Gal-9+ eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF-α were positively correlated with circulating Gal-9+ eosinophils/basophils, and TNF-α markedly upregulated Gal-9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal-9+ eosinophils/basophils than non-responders, and omalizumab reduced blood levels of Gal-9+ eosinophils/basophils in responders. Gal-9+ eosinophils/basophils were negatively correlated with TIM-3+TH17 cells. CONCLUSION: Our findings demonstrate a previously unrecognized involvement of the Gal-9/TIM-3 pathway in the pathogenesis CSU and call for studies that explore its relevance.

Paradoxical Worsening of Chronic Spontaneous Urticaria Following Omalizumab Administration: The Missing Link.

Omalizumab, a humanized anti-IgE monoclonal antibody, is commonly employed in the treatment of antihistamine-refractory chronic spontaneous urticaria (CSU), where it significantly reduces free IgE levels, minimizing histamine release from basophils and mast cells. Despite its efficacy, there are concerns regarding its effect on parasitic defense due to IgE's role in combating parasitic infestations. We present a case of a 28-year-old female agriculturist with a six-month history of CSU who experienced a paradoxical exacerbation of her symptoms following an increase in the omalizumab treatment dose. This deterioration coincided with a serologically confirmed parasitic infection with Echinococcus granulosus and Toxocara canis. Despite normal eosinophil counts and IgE levels, which are typically used to identify parasitic infections, the patient's clinical worsening prompted further investigation that led to the identification of the parasitic infection. Treatment with albendazole and omalizumab discontinuation led to the resolution of her CSU, suggesting that the parasitic infection was contributing to the symptom exacerbation. This case highlights the need for careful screening for parasitic infections before initiating omalizumab in antihistamine-refractory CSU patients from endemic regions, or patients who deteriorate clinically on omalizumab, especially when other indicators such as eosinophil count and IgE levels might not suggest infection. It also underscores the importance of considering a tailored approach to managing CSU that balances effective treatment with the potential for adverse effects related to immunomodulation.

Plasma proteins and inflammatory dermatoses: proteome-wide Mendelian randomization and colocalization analyses.

Current genome-wide association studies (GWAS) of plasma proteomes provide additional possibilities for finding new drug targets for inflammatory dermatoses. We performed proteome-wide Mendelian randomization (MR) and colocalization analyses to identify novel potential drug targets for inflammatory dermatoses. We performed MR and colocalization analysis using genetic variation as instrumental variables to determine the causal relationship between circulating plasma proteins and inflammatory dermatoses. 5 plasma proteins were found to be causally associated with dermatitis eczematosa, SLE, urticaria and psoriasis using cis-pQTLs as instrumental variables, but not found in AD and LP. 19 candidate genes with high colocalization evidence were identified. These potential drug targets still require more research and rigorous validation in future trials.

Quality of life measurement in assessing treatment effectiveness in urticaria: European experts position statement.

In this study, the European Academy of Dermatology and Venereology (EADV) Task Forces on Quality of Life and Patient-Oriented Outcomes and Urticaria and Angioedema has examined the Health-Related Quality of Life (HRQoL) measurement in the treatment of urticaria. The Dermatology Life Quality Index was the most frequently used HRQoL instrument in clinical trials on urticaria. Many reports of clinical trials of urticaria gave no exact numeric results related to HRQoL changes, making clear conclusions and comparisons with other studies impossible. The interpretation of HRQoL impairment data is more difficult when assessed by instruments without severity stratification systems. The minimal clinically significant difference (MCID) is a more clinically oriented and relevant parameter than depending on statistically significant changes in HRQoL scores. Therefore, using HRQoL instruments with established MCID data in clinical trials and clinical practice is preferred.

Scorpion sting and allergic reaction to scorpion venom: A case-based review.

OBJECTIVE: To describe a young patient with scorpion sting (SS) with typical lesions of urticaria besides the local SS clinical picture. MATERIALS AND METHODS: A systematic screening of articles dating from 1966 to 2021 was conducted in the main databases. All articles included the association between SS and urticaria. A new case report is added to the published list. RESULTS: The literature search found 5 articles with 29 patients with SS and urticaria/allergic reactions. We performed our analysis by adding our present case, resulting in a total of 30 cases. Most were male, and their ages varied from 29 to 48 years. Regarding SS severity, most were mild or moderate. In two articles, patients had more than one sting. The allergic reaction varied from urticaria, pruritus, flushing, angioedema, wheezing, rhinorrhea, sneezing, consciousness alterations, and gastrointestinal and cardiovascular alterations. In 5/6 (83%) articles, the patients were alive at the study time. One subject died from anaphylactic shock. CONCLUSION: The present article systematically reviewed all published cases of SS and allergic reactions to scorpion venom. It is an infrequent association; most patients are male and in the productive age, and reaction may vary from mild to severe, including death.

Prevalence of Blastocystis in Patients Referred to Bushehr Medical Centers and Its Relationship with Urticaria.

Objective: Recent studies determined that the amoeboid form of Blastocystis acts as a factor in stimulating the host's immune responses and ultimately results in urticaria and other skin disorders. The present study was conducted in order to determine the prevalence of Blastocystis in people referred to Bushehr city health centers and the relationship of this parasite with urticaria. Methods: Fecal samples were collected from 180 males and females referred to Bushehr health centers and a questionnaire containing demographic information was completed for each person. Samples were examined by preparing direct smear (wet mount) and then formalin-detergent sedimentation techniques. Data were analyzed using SPSS 22.0 software and chi-square test. Results: The results showed that 11.1% of cases infected with Blastocystis and 55% of patients with Blastocystis had various gastrointestinal symptoms. Statistical analysis showed that there was no significant relationship between infection with some demographic factors such as sex, age, literacy level and residence, but this was significant with some clinical symptoms such as itching and urticaria. Conclusion: Despite the existence of conflicting information and many ambiguities about the Blastocystis, this emerging pathogen is very important in terms of causing allergic and skin disorders in sufferers, therefore, it is necessary that patients with urticaria be evaluated for Blastocystis along with other diagnostic procedures and physicians should request a test before any medical intervention. Thus, diagnosis and treatment of these people can play an important role in improving the health of society.

Severity of papular urticaria in children is associated with specific IgG4 anti-salivary gland antigens from Aedes aegypti.

Summary: Background. Papular Urticaria (PU) is a cutaneous hypersensitivity disorder triggered by hematophagous arthropod bites. Despite being a common condition, especially in tropical environments, many knowledge gaps are observed for this disease. The main objective of this study was to investigate the patterns of humoral immune response to mosquito antigens in children with PU and establish a correlation between this response and the severity of clinical symptoms. Methods. An analytical cross-sectional observational study was carried out. Clinical and sociodemographic data and children's blood samples were collected to measure the specific antibodies from: 1. A. aegypti salivary gland antigens; 2. A. aegypti whole body antigens (both produced in the laboratory of the Center for Health Sciences at the Federal University of Rio de Janeiro). A PU severity score based on clinical data is proposed to correlate disease severity with antibody reactivity signatures. Results. According to the clinical data, 58.9% of children received high severity scores. A significant statistical correlation was found between patients with high PU severity score and the development of symptoms before the age of two (p = 0.0326) and high IgG4 anti-salivary gland antigens concentration (p less than 0.05). Conclusion. It is suggested that PU severity in children is associated with a high concentration of IgG4 anti-salivary gland antigens from Aedes aegypti. Further studies are recommended to deepen the understanding of the mechanisms involved.

Time-course and dose-effect of omalizumab in treating chronic idiopathic urticaria/chronic spontaneous urticaria.

PURPOSE: Several studies have shown that subcutaneous injections of omalizumab can treat chronic idiopathic/spontaneous urticaria (CIU/CSU) patients by only assessing the efficacy on specific endpoints. This study aimed to quantitatively analyze different doses of omalizumab in CIU/CSU and compare it with ligelizumab. METHODS: Literature searches were performed in PubMed, Embase, and Web of Science databases. A model-based meta-analysis (MBMA) was utilized to develop a model incorporating time since the initiation of treatment and dose for omalizumab, with the change from baseline in Urticaria Activity Score (CFB-UAS7) as the primary efficacy endpoint. The time-course and dose-effect relationship throughout the omalizumab treatment period was analyzed, and the findings were compared with those of the investigational ligelizumab. RESULTS: The model equation for the CFB-UAS7 was established as E = -Emax × time/(ET50 + time) × (b0 + b1 × dose). The estimated values of the model parameters E max , ET 50 , b 0 , and b 1 were -1.16, 1.26 weeks, -9.90, and -0.0361 mg-1, respectively. At week 12 after the first dose, the model-predicted CFB-UAS7 for 150 mg and 300 mg of omalizumab were -16.0 (95% CI, -17.2 to -14.8) and -21.7 (95% CI, -22.9 to -20.5), respectively. In the PEARL-1 trial, the CFB-UAS7 for 72 mg and 120 mg of ligelizumab were -19.4 (95% CI, -20.7 to -18.1) and -19.3 (95% CI, -20.6 to -18.0), respectively. In the PEARL-2 trial, these values were -19.2 (95% CI, -20.5 to -17.9) and -20.3 (95% CI, -21.6 to -19.0), respectively. CONCLUSION: Omalizumab showed a significant dose-dependent effect in the treatment of CSU. Both 72 mg and 120 mg ligelizumab might have the potential to outperform 150 mg (but not 300 mg) omalizumab.

Inhibition of Mast Cell Degranulation by Novel Small Molecule MRGPRX2 Antagonists.

BACKGROUND: Mas-related G-protein coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell-mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identified, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo. OBJECTIVE: We identified and characterized novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell-mediated disease. METHODS: Antagonists were identified using multiple functional assays in cell lines overexpressing human MRGPRX2, LAD2 mast cells, human peripheral stem cell-derived mast cells, and isolated skin mast cells. Skin mast cell degranulation was evaluated in Mrgprb2em(-/-) knockout (KO) and Mrgprb2em(MRGPRX2) transgenic human MRGPRX2 knock-in (KI) mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples. RESULTS: MRGPRX2 antagonists potently inhibited agonist-induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested, in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist-induced degranulation and resulting vascular permeability in MRGPRX2 KI mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin. CONCLUSION: MRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation.

Treatment of patients with evidence of mast cell-mediated itch in the absence of hives with omalizumab.

PURPOSE: The presence of wheals or hives has been viewed as a hallmark symptom of urticaria, a highly debilitating disease. This study explores our experience with omalizumab in patients with apparent mast-cell mediated pruritus in the absence of hives. MATERIALS AND METHODS: This is a retrospective case series examining all patients with mast cell-mediated pruritus in the absence of hives from April 2022 to May 2024 at a tertiary referral clinic at Icahn School of Medicine at Mount Sinai in New York. Peak pruritus-numerical rating scale (PP-NRS) itch score changes over time were recorded and analyzed. RESULTS: Six patients (67% women; mean [SD] age, 47.67 [13.52] years) were included in the analysis. The median [IQR] pruritus PP-NRS itch score before omalizumab injection was 9 [6 - 10] and the final median [IQR] PP-NRS itch score was 2.5 [0 - 5]. The mean [SD] reduction in the PP-NRS itch score was 6 [3.16]. CONCLUSIONS: This study suggests that patients with evidence of mast cell-mediated pruritus can be identified based on clinical features and may benefit from omalizumab therapy.

One-month daily and three-month weekly rifapentine plus isoniazid are comparable in completion rate and safety for latent tuberculosis infection in non-HIV Population: A randomized controlled trial.

OBJECTIVES: The 3HP regimen, consisting of 12 doses of weekly rifapentine plus isoniazid, improves completion rate of latent tuberculosis infection (LTBI) treatment, but flu-like symptoms are common. The novel 1HP regimen, involving daily rifapentine plus isoniazid for 28 days, has demonstrated low toxicity in Human Immunodeficiency Virus (HIV)-infected populations. We aimed to investigate whether 1HP has a lower incidence rate of systemic drug reaction (SDR) compared with 3HP during treatment in non-HIV populations. METHODS: This randomised, multicentre trial compared the completion rate and risks of SDRs of 1HP and 3HP in aged ≥13-years non-HIV subjects with LTBI between September 2019 and September 2023 (ClinicalTrials.gov: NCT04094012). We also investigated associations between SDRs and plasma levels of drugs and their metabolites. RESULTS: A total of 251 and 239 individuals were randomised to 1HP and 3HP groups, respectively, with completion rates of 82.9% (208/251) and 84.5% (202/239), respectively. Among them, 12.7% (32/251) and 10.9% (26/239) of 1HP and 3HP groups experienced SDRs, respectively (p=0.522), predominantly urticaria in 1HP group (59.4% [19/32]) and flu-like syndrome in 3HP group (80.8% [21/26]). Among participants experiencing SDRs, 43.8% (14/32) and 34.6% (9/26) in 1HP and 3HP groups, respectively, completed treatment (p=0.470). Cutaneous reactions were more common in 1HP than 3HP group (32.7% [82/251] vs. 13.0% [31/239], p<0.001). In 1HP group, urticaria was associated with a higher plasma desacetyl-rifapentine level (ug/mL) at both 2 (median [interquartile range]: 36.06 [17.46-50.79] vs. 22.94 [14.67-31.65], p=0.018) and 6 hours (26.13 [15.80-53.06] vs. 29.83 [18.13-34.01], p=0.047) after dosing. CONCLUSIONS: In non-HIV population, the incidence rate of SDR under 1HP is not lower than 3HP. Notably, urticaria, rather than flu-like syndrome, was the predominant SDR associated 1HP. The findings of this study underscore the feasibility of 1HP regimen in non-HIV populations with a high completion rate exceeding 80%.

Adrenergic Urticaria: An Updated Review.

It can be difficult to delineate the cause of urticarial eruptions, and in chronic cases, it can be a challenging condition to effectively treat. Several forms of urticarial eruptions are well documented and established. Our review focuses on a form of urticaria that is less commonly reported: adrenergic urticaria. In this review, we aim to consolidate the literature in the hopes that this urticarial subtype is considered in urticarial differentials, as well as highlight potential gaps in the research and future directions in treatment options.

Multisystem Involvement in a Pediatric Patient With Hypermobile Ehlers-Danlos Syndrome: A Case Report of the Diagnostic Complexity and Management Challenges.

Ehlers-Danlos syndrome (EDS) is a collection of genetic disorders caused by abnormalities in collagen and typified by hyperflexible joints, hyperextensible skin, and a tendency for easy bruising and tissue injuries. Hypermobile Ehlers-Danlos syndrome (hEDS), the most common subtype, presents a diagnostic challenge due to the lack of specific genetic markers. This case report describes a 13-year-old girl with hEDS, presenting with hypermobility, thoracolumbar scoliosis, constipation, glucosuria, microscopic hematuria, urticaria, and intermittent episodes of bilateral hand and feet swelling. Genetic testing revealed a variant of uncertain significance in the COL9A2 gene. An echocardiogram showed a mildly dilated aortic root. The complexity of her presentation underscores the challenges in diagnosing and managing hEDS with multisystem involvement.

Effects of hot bath therapy on cholinergic urticaria with hypohidrosis or anhidrosis.

Cholinergic urticaria with hypohidrosis or anhidrosis (CUHA) can impair quality of life due to itching, tingling, and reduced sweating. Current treatment options for CUHA include antihistamines, pulsed steroids, and sweat-promoting therapies such as exercise or hot baths. However, the efficacy of these therapies, particularly hot bath therapy, has yet to be established. We evaluated the efficacy of hot bath therapy in patients with CUHA. We enrolled eight patients who underwent hot bath therapy between January 2010 and August 2022. Patients had a half-body bath in a bathtub filled with hot water (40-43°C) for 30-60 minutes daily for 3-7 days. After treatment, pain improved in three (42.9%) patients, urticaria improved in four (50%) patients, and anhidrosis improved in five (62.5%) patients without any severe adverse events. Because hot bath therapy is easily performed, it should be considered a treatment option for patients with CUHA.