Leukotriene receptor antagonists as add-on therapy to antihistamines for urticaria: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: The benefits and harms of adding antileukotrienes to H1-antihistamines for the management of urticaria (hives, itch, and/or angioedema) remain unclear. OBJECTIVE: We sought to systematically synthesize the treatment outcomes of antileukotrienes in combination with H1-antihistamines versus H1-antihistamines alone for acute and chronic urticaria. METHODS: As part of updating American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters urticaria guidelines, we searched MEDLINE, Embase, CENTRAL, LILACS, WPRIM, IBECS, ICTRP, CBM, CNKI, VIP, Wanfang, FDA, and EMA databases from inception to December 18th, 2023 for randomized controlled trials (RCTs) evaluating antileukotrienes and H1-antihistamines versus H1-antihistamines alone in patients with urticaria. Paired reviewers independently screened citations, extracted data, and assessed risk of bias. Random effects models pooled effect estimates for urticaria activity, itch, wheal, sleep, quality of life, and harms. The GRADE approach informed certainty of evidence ratings. Open Science Framework registration: https://osf.io/h2bfx/. RESULTS: Thirty-four RCTs enrolled 3,324 children and adults. Compared to H1-antihistamines alone, the combination of a leukotriene receptor antagonist (LTRA) with H1-antihistamines probably modestly reduces urticaria activity (mean difference: -5.04, 95%CI -6.36 to -3.71; 7-day Urticaria Activity Score) with moderate certainty. We made similar findings for itch and wheal severity, and quality of life. Adverse events were probably not different between groups (moderate certainty), however, no RCT reported on neuropsychiatric adverse events. CONCLUSION: Among patients with urticaria, adding LTRAs to H1-antihistamines probably modestly improves urticaria activity with little to no increase in overall adverse events. The added risk of neuropsychiatric adverse events in this population with LTRAs is small and uncertain.

Topical corticosteroids for hives and itch (urticaria): systematic review and Bayesian meta-analysis of randomized trials.

BACKGROUND: Topical corticosteroids are widely used as a treatment for itch and wheals (urticaria), but their benefits and harms are unclear. OBJECTIVE: To systematically synthesize the benefits and harms of topical corticosteroids for the treatment of urticaria. METHODS: We searched MEDLINE, EMBASE, and CENTRAL from database inception to March 23, 2024, for randomized trials addressing comparing topical corticosteroid to placebo for patients with urticaria (either chronic spontaneous or inducible urticaria or acute urticaria elicited from skin/intradermal allergy testing). Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects meta-analyses addressed urticaria severity, itch severity (numeric rating scale; range 0-10; higher is worse), and adverse events. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed certainty of evidence ratings. PROSPERO registration: CRD42023455182. RESULTS: Nineteen RCTs enrolled 379 participants with a median of mean age of 30.1 years (range 21.1 to 44.0). Compared to placebo, topical corticosteroids may reduce wheal size (ratio of means 0.47, 95%CI 0.38 to 0.59; low certainty) and itch severity (mean difference -1.30, 95%CI -5.07 to 2.46; very low certainty). Topical corticosteroids result in little to no difference in overall adverse events (94 fewer patients per 1000, 95%CrI 172 fewer to 12 more; high certainty). CONCLUSION: Compared to placebo, topical corticosteroids may result in a reduction of wheal size, and result in little to no difference in overall adverse events. Topical corticosteroids may reduce itch severity, but the evidence is very uncertain. Future large, randomized trials addressing the use of topical corticosteroids would further support optimal urticaria management.

Efficacy and Safety of Systemic Corticosteroids for Urticaria: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Short courses of adjunctive systemic corticosteroids are commonly used to treat acute urticaria and chronic urticaria flares (both with and without mast cell-mediated angioedema), but their benefits and harms are unclear. OBJECTIVE: To evaluate the efficacy and safety of treating acute urticaria or chronic urticaria flares with versus without systemic corticosteroids. METHODS: We searched the MEDLINE, EMBASE, CENTRAL, CNKI, VIP, Wanfang, and CBM databases from inception to July 8, 2023, for randomized controlled trials of treating urticaria with versus without systemic corticosteroids. Paired reviewers independently screened records, extracted data, and appraised risk of bias with the Cochrane 2.0 tool. We performed random-effects meta-analyses of urticaria activity, itch severity, and adverse events. We assessed certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach. RESULTS: We identified 12 randomized trials enrolling 944 patients. For patients with low or moderate probability (17.5%-64%) to improve with antihistamines alone, add-on systemic corticosteroids likely improve urticaria activity by a 14% to 15% absolute difference (odds ratio [OR], 2.17, 95% confidence interval [CI]: 1.43-3.31; number needed to treat [NNT], 7; moderate certainty). Among patients with a high chance (95.8%) for urticaria to improve with antihistamines alone, add-on systemic corticosteroids likely improved urticaria activity by a 2.2% absolute difference (NNT, 45; moderate certainty). Corticosteroids may improve itch severity (OR, 2.44; 95% CI: 0.87-6.83; risk difference, 9%; NNT, 11; low certainty). Systemic corticosteroids also likely increase adverse events (OR, 2.76; 95% CI: 1.00-7.62; risk difference, 15%; number needed to harm, 9; moderate certainty). CONCLUSIONS: Systemic corticosteroids for acute urticaria or chronic urticaria exacerbations likely improve urticaria, depending on antihistamine responsiveness, but also likely increase adverse effects in approximately 15% more.

Factors Associated With Epinephrine Use in the Treatment of Anaphylaxis in Infants and Toddlers.

BACKGROUND: Undertreatment of anaphylaxis with epinephrine continues to be an unmet need and is a particular challenge among infants and toddlers. OBJECTIVE: To address this gap by identifying barriers and solutions to appropriate and timely administration of epinephrine. METHODS: We conducted a national online survey among primary caregivers of children who experienced a severe food-induced allergic reaction when younger than 36 months. Outcomes of interest included epinephrine use in community and health care settings to treat probable anaphylaxis. RESULTS: Of 264 probable anaphylaxis cases, 39% of infants (aged <12 months) and 61% of toddlers (aged 12-35 months) received epinephrine at any time during the child's most severe allergic reaction (P = .001). A previous diagnosis of a food allergy was reported in 62% of cases where epinephrine was used compared with 26% of cases where epinephrine was not used (P < .001). In children with a previous diagnosis of a food allergy, epinephrine was used in 89% of those who were prescribed an anaphylaxis action plan compared with 50% of those without a plan (P = .001). The adjusted odds ratio for the association between having an anaphylaxis action plan and epinephrine use in cases of probable anaphylaxis was 5.39 (95% confidence interval, 2.18-13.30). CONCLUSIONS: Epinephrine use at any time (including in health care settings) during probable anaphylaxis is more likely in infants and toddlers with a previously diagnosed food allergy than those without diagnosis. The provision of an anaphylaxis action plan is also associated with increased epinephrine use during probable anaphylaxis in this population.

Disparities in Lupus and the Role of Social Determinants of Health: Current State of Knowledge and Directions for Future Research.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. The complex relationships between race and ethnicity and social determinants of health (SDOH) in influencing SLE and its course are increasingly appreciated. Multiple SDOH have been strongly associated with lupus incidence and outcomes and contribute to health disparities in lupus. Measures of socioeconomic status, including economic instability, poverty, unemployment, and food insecurity, as well as features of the neighborhood and built environment, including lack of safe and affordable housing, crime, stress, racial segregation, and discrimination, are associated with race and ethnicity in the US and are risk factors for poor outcomes in lupus. In this scientific statement, we aimed to summarize current evidence on the role of SDOH in relation to racial and ethnic disparities in SLE and SLE outcomes, primarily as experienced in the U.S. Lupus Foundation of America's Health Disparities Advisory Panel, comprising 10 health disparity experts, including academic researchers and patients, who met 12 times over the course of 18 months in assembling and reviewing the data for this study. Sources included articles published from 2011 to 2023 in PubMed, Centers for Disease Control and Prevention data, and bibliographies and recommendations. Search terms included lupus, race, ethnicity, and SDOH domains. Data were extracted and synthesized into this scientific statement. Poorer neighborhoods correlate with increased damage, reduced care, and stress-induced lupus flares. Large disparities in health care affordability, accessibility, and acceptability exist in the US, varying by region, insurance status, and racial and minority groups. Preliminary interventions targeted social support, depression, and shared-decision-making, but more research and intervention implementation and evaluation are needed. Disparities in lupus across racial and ethnic groups in the US are driven by SDOH, some of which are more easily remediable than others. A multidimensional and multidisciplinary approach involving various stakeholder groups is needed to address these complex challenges, address these diminish disparities, and improve outcomes.

The early excitatory action of striatal cholinergic-GABAergic microcircuits conditions the subsequent GABA inhibitory shift.

Cholinergic interneurons of the striatum play a role in action selection and associative learning by activating local GABAergic inhibitory microcircuits. We investigated whether cholinergic-GABAergic microcircuits function differently and fulfill a different role during early postnatal development, when GABAA actions are not inhibitory and mice pups do not walk. We focused our study mainly on dual cholinergic/GABAergic interneurons (CGINs). We report that morphological and intrinsic electrophysiological properties of CGINs rapidly develop during the first post-natal week. At this stage, CGINs are excited by the activation of GABAA receptors or GABAergic synaptic inputs, respond to cortical stimulation by a long excitation and are linked by polysynaptic excitations. All these excitations are replaced by inhibitions at P12-P15. Early chronic treatment with the NKCC1 antagonist bumetanide to evoke premature GABAergic inhibitions from P4 to P8, prevented the GABA polarity shift and corticostriatal pause response at control postnatal days. We propose that early excitatory cholinergic-GABAergic microcircuits are instrumental in the maturation of GABAergic inhibition.

The Multidimensional Burden of Atopic Dermatitis Among Adults: Results From a Large National Survey.

Importance: Atopic dermatitis (AD) is long term and burdensome. Studies investigating disease burden in adults are limited in scope with gaps in understanding of the adult patient lived experience. Objective: To describe the multidimensional burden of AD among mainly US adults. Design, Setting, and Participants: This survey study for an externally led patient-focused drug development meeting with the US Food and Drug Administration on adult patients with AD was conducted between August 1, 2019, and October 11, 2019. Data were analyzed betwean March 26, 2021, and June 29, 2021. Main Outcomes and Measures: We used multivariable ordinal regression to assess associations between demographic and clinical variables and patient-reported overall AD impact scores (ordinal scale from 1 [no impact] to 5 [significant impact]). Results: Among 1065 survey respondents, 114 (11%) were aged 18 to 24 years, 235 (22%) were 25 to 34 years, 242 (23%) were 35 to 50 years, 288 (27%) were 51 to 64 years, and 186 (17%) were aged 65 years or older; 881 (83%) were women. Four hundred eighty-nine (46%) participants reported low-moderate AD impact scores (2-3), 544 (51%) reported high-significant impact scores (4-5), whereas 32 (3%) reported no association of AD with disease burden (impact score, 1). Variables strongly associated with overall impact scores were current AD severity (moderate: OR, 4.13; 95% CI, 2.94-5.79; severe: OR, 13.63; 95% CI, 8.65-21.50 vs mild), and time spent managing AD (11-20 hours: OR, 2.67; 95% CI, 1.77-4.03, ≥21 hours: OR, 5.34; 95% CI, 3.22-8.85, vs <5 hours). Conclusions and Relevance: In this survey study, AD severity and time spent managing symptoms showed the strongest associations with disease burden. This analysis highlights the multidimensional burden of AD in adults and emphasizes the need for more effective treatment strategies that reduce the time patients spend managing their AD.

Prenatal reduction of E14.5 embryonically fate-mapped pyramidal neurons in a mouse model of autism.

Although several observations suggest that the constitutive biological, genetic or physiological changes leading to autism spectrum disorders (ASD) start in utero, their early impact on the number and density of neurons in the brain remains unknown. Using genetic fate mapping associated with the immunollabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO) clearing method we identified and counted a selective population of neocortical and hippocampal pyramidal neurons in the in utero valproate (VPA) mouse model of autism. We report that 1 day before birth, the number of pyramidal neurons born at E14.5 in the neocortex and hippocampus of VPA mice is smaller than in age-matched controls. VPA also induced a reduction of the neocortical-but not hippocampal-volume 1 day before birth. Interestingly, VPA mice present an increase in both neocortical and hippocampal volumes 2 days after birth compared with controls. These results suggest that the VPA-exposed hippocampus and neocortex differ substantially from controls during the highly complex perinatal period, and specially 1 day before birth, reflecting the early pathogenesis of ASD.

Asthma care during COVID-19: differences in attitudes and expectations between physicians and patients.

OBJECTIVE: The aim of this study was to explore differences in attitudes, behaviors and expectations related to COVID-19 between physicians and patients with asthma. METHODS: An anonymous survey was distributed through email and social media to adult patients with asthma during a three-week period in April-May 2020. A separate survey was sent to physicians. The surveys asked about demographic information, specific challenges and concerns due to COVID-19, and attitudes/behaviors during this time. RESULTS: A total of 1171 patients and 225 physicians completed the surveys. Overall, patients with asthma and physicians had large differences in expectations related to COVID-19. Patients were more likely than physicians to believe that individuals with asthma are at a higher risk to get COVID-19 (37.5% vs. 12.0%, p < 0.001), have increased anxiety due to COVID-19 (79.6% vs 70.0%, p = 0.002), and should not go to work (62.7% vs 11.9%, p < 0.001). Neither patients nor physicians felt confident they could distinguish COVID-19 symptoms from asthma (61.2% and 74.5% did not feel confident, respectively). Patients with severe asthma were significantly more impacted by the pandemic (e.g., became unemployed [OR 2.15], had difficulty getting asthma medications [OR 2.37]) compared to those with nonsevere asthma. CONCLUSION: Patients with asthma and their physicians have markedly different attitudes and opinions regarding care during the COVID-19 pandemic. Such differences have important implications when providing patient-centered care.Supplemental data for this article can be accessed at publisher's website.

Food allergy treatment value: Child caregiver and patient perspectives.

BACKGROUND: Food allergy is a major health problem that significantly impacts quality of life (QoL). There is growing focus to evaluate food allergy-related QoL and treatment options' value beyond the clinical effectiveness perspective by engaging patients and caregivers. We aimed to identify and prioritize outcomes important to food allergy parents of children and patients allergic to milk, egg, and/or peanut, to guide comparative effectiveness research (CER) that focuses on evaluating food allergy treatment decisions. METHODS: We conducted a modified 3-round Delphi study to identify and derive consensus on priority treatment outcomes for parents of children and adult patients with diagnosed allergies to at least one of three major allergenic foods (milk, egg, and peanut) from across the United States. RESULTS: Round 1 yielded 44 statements for round 2, and 39 statements reached the agreement level for round 3 ranking. Statements were organized under 4 sections: 1) food allergy problems, 2) treatment experiences, 3) important treatment outcomes, and 4) value of different treatment options. CONCLUSION: Food allergy parents and patients face several social, psychological, medical, healthcare, financial, food selection, and awareness challenges. The areas of consensus on important treatment outcomes revealed shared priority for reducing the risk of potentially fatal allergic reactions and having reliable treatments. The most valued treatment options reflect hope for permanent cure and fear of serious allergic reactions.

Caregiver-Reported Presentation of Severe Food-Induced Allergic Reactions in Infants and Toddlers.

BACKGROUND: Recognizing anaphylaxis in infants and toddlers can be challenging for health care providers and caregivers, and current diagnostic criteria and anaphylaxis action plans do not specifically address this younger population. OBJECTIVE: To describe symptoms and signs observed by primary caregivers of infants and toddlers during severe food-induced allergic reactions. METHODS: We conducted a national online survey among primary caregivers of children who experienced a severe food-induced allergic reaction when less than 36 months of age. Respondents who were present during the child's most severe reaction were asked to report symptoms and signs observed. The survey asked about infant- and toddler-specific symptoms and signs in lay language for caregivers. Data were compared with patient-reported data from past studies to identify distinct patterns among the younger population. RESULTS: The survey was completed for 374 children (193 infants, 181 toddlers). The most common symptoms and signs reported were skin reactions (90%), facial and extremity swelling (59%), gastrointestinal issues (51%), and coughing/wheezing (45%). Infants (aged <12 months) more frequently experienced skin reactions, skin mottling, and ear pulling/scratching or putting fingers in ears, as compared with toddlers (aged 12-35 months). Toddlers experienced throat itching and coughing/wheezing more frequently than infants. CONCLUSIONS: Anaphylaxis presentation demonstrates similarities and differences in infants and toddlers. Modifying the terminology used in the current criteria allowed for reporting of symptoms and signs of anaphylaxis that are more common in infants and toddlers. Diagnostic criteria, clinical guidelines, and anaphylaxis action plans may be enhanced to address this young, often nonverbal, population.

Asthma Disparities During the COVID-19 Pandemic: A Survey of Patients and Physicians.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has demonstrated significantly worse outcomes for minority (black and Hispanic) individuals. Understanding the reasons for COVID-19-related disparities among patients with asthma has important public health implications. OBJECTIVE: To determine factors contributing to health disparities in those with asthma during the COVID-19 pandemic. METHODS: An anonymous survey was sent through social media to adult patients with asthma, and a separate survey was sent to physicians who provide asthma care. The patient survey addressed demographic information including socioeconomic status, asthma control, and attitudes/health behaviors during COVID-19. RESULTS: A total of 1171 patients (10.1% minority individuals) and 225 physicians completed the survey. Minority patients were more likely to have been affected by COVID-19 (eg, became unemployed, lived in a community with high COVID-19 cases). They had worse asthma control (increased emergency visits for asthma, lower Asthma Control Test score), were more likely to live in urban areas, and had a lower household income. Initial differences in attitudes and health behaviors disappeared after controlling for baseline demographic features. Institutional racism was demonstrated by findings that minority individuals were less likely to have a primary care physician, had more trouble affording asthma medications due to COVID-19, and were more likely to have lost health insurance because of COVID-19, and that 25% of physicians found it more challenging to care for black individuals with asthma during COVID-19. CONCLUSIONS: Differences in socioeconomic status and the effects of institutional racism, but not health behaviors, sources of information, or attitudes, are playing a role in disparities seen for patients with asthma during COVID-19.

Perspectives on Living with Chronic Spontaneous Urticaria: From Onset through Diagnosis and Disease Management in the US.

Chronic spontaneous urticaria is challenging to manage and substantially affects quality of life. This US, non-interventional qualitative study examined patients' clinical journeys and emotional burden from symptom onset through disease management. Chronic spontaneous urticaria patients participated in interviews and completed diaries focusing on disease and treatment history/perspectives, impact on personal/family life, and relationships with physicians/other healthcare providers. Physicians were interviewed about their views on disease management and patient care. Twenty-five patients, previously or currently receiving chronic spontaneous urticaria treatment(s), and 12 physicians participated. Key stages following symptom onset were identified: Crisis (associated with feelings of torment/disorientation/shock); Searching for answers (puzzlement/frustration/anxiety); Diagnosis (relief/satisfaction/fear/isolation); and Disease management (frustration/hope/powerlessness). Findings revealed patients' perceptions and experiences of chronic spontaneous urticaria, including living with a 'skinemy', experiencing their 'own personal hell' and feeling 'like an experiment'. Awareness of unmet needs in patient care/management identified in this study may ultimately improve patient support and enhance physicians' understanding of disease burden.

Enhanced Glutamatergic Currents at Birth in Shank3 KO Mice.

Autism spectrum disorders (ASD) are neurodevelopmental disorders induced by genetic and environmental factors. In our recent studies, we showed that the GABA developmental shifts during delivery and the second postnatal week are abolished in two rodent models of ASD. Maternal treatment around birth with bumetanide restored the GABA developmental sequence and attenuated the autism pathogenesis in offspring. Clinical trials conducted in parallel confirmed the usefulness of bumetanide treatment to attenuate the symptoms in children with ASD. Collectively, these observations suggest that an alteration of the GABA developmental sequence is a hallmark of ASD. Here, we investigated whether similar alterations occur in the Shank3 mouse model of ASD. We report that in CA3 pyramidal neurons, the driving force and inhibitory action of GABA are not different in naïve and Shank3-mutant age-matched animals at birth and during the second postnatal week. In contrast, the frequency of spontaneous excitatory postsynaptic currents is already enhanced at birth and persists through postnatal day 15. Therefore, in CA3 pyramidal neurons of Shank3-mutant mice, glutamatergic but not GABAergic activity is affected at early developmental stages, hence reflecting the heterogeneity of mechanisms underlying the pathogenesis of ASD.

Brain Derived Neurotrophic Factor Modification of Epileptiform Burst Discharges in a Temporal Lobe Epilepsy Model.

INTRODUCTION: Transforming Growth Factor-Beta 1 (TGF-ß1) is a pleiotropic cytokine with potent anti-inflammatory property, which has been considered as an essential risk factor in the inflammatory process of Ischemic Stroke (IS), by involving in the pathophysiological progression of hypertension, atherosclerosis, and lipid metabolisms. -509C/T TGF-ß1 gene polymorphism has been found to be associated with the risk of IS. The aim of this meta-analysis was to provide a relatively comprehensive account of the relation between -509C/T gene polymorphisms of TGF-ß1 and susceptibility to IS. METHODS: Male Wistar rats were divided into sham (receiving phosphate buffered saline within dorsal hippocampus), pilocarpine (epileptic model of TLE), single injection BDNF (epileptic rats which received single high dose of BDBF within dorsal hippocampus), and multiple injections BDNF (epileptic rats which received BDNF in days 10, 11, 12, and 13 after induction of TLE) groups. Their electrocorticogram was recorded and amplitude, frequency, and duration of spikes were evaluated. RESULTS: Amplitude and frequency of epileptiform burst discharges were significantly decreased in animals treated with BDNF compared to pilocarpine group. CONCLUSION: Our findings suggested that BDNF may modulate the epileptic activity in the animal model of TLE. In addition, it may have therapeutic effect for epilepsy. More studies are necessary to clarify the exact mechanisms of BDNF effects.

Fluoxetin upregulates connexin 43 expression in astrocyte.

INTRODUCTION: Recent studies have shown that astrocytes play major roles in normal and disease condition of the central nervous system including multiple sclerosis (MS). Molecular target therapy studies in MS have revealed that connexin-43 (Cx43) and Aquaporin-4 (AQP4) contents of astrocytes undergo expression alteration. Fluoxetine had some effects in MS patients unrelated to its known antidepressant effects. Some of fluoxetine effects were attributed to its capability of cAMP signaling pathway stimulation. This study aimed to investigate possible acute effects of fluoxetine on Cx43 and AQP4 expression in astrocyte. METHODS: Astrocytoma cells were treated for 24 hours with fluoxetine (10 and 20 µg/ml) with or without adenyl cyclase (AC) and protein kinase A (PKA) inhibition. Cx43 expression at both mRNA and protein levels and AQP4 expression at mRNA level were evaluated. RESULTS: Acquired results showed that fluoxetine with and without AC and PKA inhibition resulted in Cx43 up-regulation both in mRNA and protein levels, whereas AQP4 expression have not changed. DISCUSSION: In conclusion, data showed that fluoxetine alone and in the absence of serotonin acutely up-regulated Cx43 expression in astrocytes that can be assumed in molecular target therapy of MS patients. It seems that cAMP involvement in fluoxetine effects need more researches.

Response to Comment on "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring".

Bambini-Junior et al. questioned whether our treatment in two rodent models of autism has a long-lasting effect into adulthood. In response, we show that bumetanide treatment around delivery attenuates autistic behavioral features in adult offspring. Therefore, the polarity of γ-aminobutyric acid (GABA) actions during delivery exerts long-lasting priming actions after birth.