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Chronic spontaneous urticaria is an idiopathic syndrome defined by recurring itch, hives, or angioedema (or a combination of these symptoms) for more than 6 weeks. Remibrutinib, an oral, highly selective Bruton's tyrosine kinase inhibitor, showed efficacy and favorable safety in phase 2b trials. Data from phase 3 trials are needed. In the identical, multicenter, double-blind, randomized, placebo-controlled REMIX-1 and REMIX-2 trials, we evaluated the efficacy and safety of remibrutinib in patients with symptomatic chronic spontaneous urticaria after treatment with second-generation H -antihistamines. Patients were randomly assigned in a 2:1 ratio to receive oral remibrutinib at a dose of 25 mg twice daily or placebo. The primary end point was the change from baseline to week 12 in the urticaria activity score during a 7-day period (UAS7), which comprises severity scores for itch and hives during 1 week (scores range from 0 to 42, with higher scores indicating greater severity). Key secondary end points included adverse events and a UAS7 of 6 or lower at weeks 2 and 12 and a UAS7 of 0 at week 12. A total of 470 patients in REMIX-1 and 455 in REMIX-2 were randomly assigned to receive either remibrutinib (313 and 300 patients, respectively) or placebo (157 and 155 patients, respectively). The remibrutinib group had a significantly greater decrease in the UAS7 at week 12 than the placebo group (least-squares mean [±SE] change, -20.0±0.7 vs. -13.8±1.0 [P<0.001] in REMIX-1 and -19.4±0.7 vs. -11.7±0.9 [P<0.001] in REMIX-2), which appeared to be sustained through week 24. At week 12, significantly more patients in the remibrutinib group than in the placebo group had a UAS7 of 6 or lower (REMIX-1, 49.8% vs. 24.8% [P<0.001]; REMIX-2, 46.8% vs. 19.6% [P<0.001]) and a UAS7 of 0 (REMIX-1, 31.1% vs. 10.5% [P<0.001]; REMIX-2, 27.9% vs. 6.5% [P<0.001]). The percentages of patients with any adverse event and with serious adverse events were similar in the remibrutinib group and the placebo group, although a higher percentage of patients in the remibrutinib group than in the placebo group had petechiae (3.8% vs. 0.3% in the combined groups). Treatment with oral remibrutinib resulted in a significant improvement in a composite measure of itching and hives at week 12. (Funded by Novartis Pharmaceuticals; REMIX-1 and REMIX-2 ClinicalTrials.gov numbers, NCT05030311 and NCT05032157, respectively.).

This large, randomized, placebo-controlled trial showed the efficacy of omalizumab, an injectable anti–IgE humanized monoclonal antibody, in the treatment of chronic idiopathic urticaria. Chronic idiopathic urticaria (also called chronic spontaneous urticaria) is defined as itchy hives that last for at least 6 weeks, with or without angioedema, and that have no apparent external trigger. 1 The condition generally has a prolonged duration of 1 to 5 years (persisting for >5 years in 11 to 14% of patients 2 , 3 ) and has a detrimental effect on patients' emotional and physical health-related quality of life. 4 , 5 The impairment accompanying this disorder has been likened to that seen in patients with ischemic heart disease, with patients feeling a similar lack of energy, social isolation, and emotional upset . . .

Background Iron deficiency is the primary cause of anemia in children. Intravenous (IV) iron formulations circumvent malabsorption and rapidly restore hemoglobin. Methods This Phase 2, non-randomized, multicenter study characterized the safety profile and determined appropriate dosing of ferric carboxymaltose (FCM) in children with iron deficiency anemia. Patients aged 1–17 years with hemoglobin <11 g/dL and transferrin saturation <20% received single IV doses of undiluted FCM 7.5 mg/kg ( n  = 16) or 15 mg/kg ( n  = 19). Results The most common drug-related treatment-emergent adverse event was urticaria (in three recipients of FCM 15 mg/kg). Systemic exposure to iron increased in a dose-proportional manner with approximate doubling of mean baseline-corrected maximum serum iron concentration (157 µg/mL with FCM 7.5 mg/kg; and 310 µg/mL with FCM 15 mg/kg) and area under the serum concentration–time curve (1901 and 4851 h·µg/mL, respectively). Baseline hemoglobin was 9.2 and 9.5 g/dL in the FCM 7.5 and 15 mg/kg groups, respectively, with mean maximum changes in hemoglobin of 2.2 and 3.0 g/dL, respectively. Conclusions In conclusion, FCM was well tolerated by pediatric patients. Improvements in hemoglobin were greater with the higher dose, supporting use of the FCM 15 mg/kg dose in pediatric patients (Clinicaltrials.gov NCT02410213). Impact This study provided information on the pharmacokinetics and safety of intravenous ferric carboxymaltose for treatment of iron deficiency anemia in children and adolescents. In children aged 1–17 years with iron deficiency anemia, single intravenous doses of ferric carboxymaltose 7.5 or 15 mg/kg increased systemic exposure to iron in a dose-proportional manner, with clinically meaningful increases in hemoglobin. The most common drug-related treatment-emergent adverse event was urticaria. The findings suggest that iron deficiency anemia in children can be corrected with a single intravenous dose of ferric carboxymaltose and support use of a 15 mg/kg dose.

Introduction Delayed allergy to red meat, also termed alpha-gal syndrome, is increasingly reported in adults and African communities, while pediatric cases remain rare. Case presentation Here, we report on a 7-year-old Caucasian boy presenting with recurrent wheals since the age of 5 years old. Episodes with hives occurred around every 3 weeks, mainly in the evening. One of these episodes was also associated with angioedema. No clear trigger was identified. At the first visit, after excluding an infection and autoimmune thyroiditis, chronic spontaneous urticaria was suspected and symptomatic treatment with antihistamines was prescribed. Six months later, the boy presented at the emergency room with generalized urticaria, dyspnoea, and emesis. Symptoms resolved after administration of epinephrine and antihistamines. A detailed medical history after this event revealed that he had eaten three sausages as well as jelly beans containing gelatine several hours prior to this episode. More precisely, after eating the sausages and jelly beans during the day, he had shown some hives before going to bed, and later developed the other symptoms in the middle of the night, suggesting alpha-gal syndrome. In his history, several tick bites are reported. Immunoglobulin E levels for alpha-gal were clearly elevated, confirming the diagnosis of a delayed-appearing immunoglobulin E-mediated allergic reaction to alpha-gal. Emergency medication was prescribed and avoidance of red meat and gelatine-containing foods was recommended. Under this exclusion diet, the boy remained asymptomatic, with the exception of two accidents in the follow up of 3 years, one developing during a barbecue and the second after exceptionally eating marshmallows. Conclusion A detailed clinical history led to the diagnosis of alpha-gal syndrome. Although alpha-gal syndrome is typically seen in adults, our case illustrates that children can also present with this potentially life-threatening allergy. Since alpha-gal syndrome is rare in Europe, the disease is not well known and often overlooked for several years, especially in children.

Celiac disease (CD) is an immune-mediated, gluten-induced enteropathy that affects predisposed individuals of all ages. Many patients with CD do not report gastrointestinal symptoms making it difficult to reach an early diagnosis. On the other hand, CD is related to a wide spectrum of extra-intestinal manifestations, with dermatitis herpetiformis (DH) being the best characterized. These associated conditions may be the clue to reaching the diagnosis of CD. Over the last few years, there have been multiple reports of the association between CD and several cutaneous manifestations that may improve with a gluten-free diet (GFD). The presence of some of these skin diseases, even in the absence of gastrointestinal symptoms, should give rise to an appropriate screening method for CD. The aim of this paper is to describe the different cutaneous manifestations that have been associated with CD and the possible mechanisms involved.

Osteoporosis (OP) is defined as a generalized skeletal disease characterized by low bone mass and an alteration of the microarchitecture that lead to an increase in bone fragility and, therefore, an increased risk of fractures. It must be considered today as a true public health problem and the most widespread metabolic bone disease that affects more than 200 million people worldwide. Under physiological conditions, there is a balance between bone formation and bone resorption necessary for skeletal homeostasis. In pathological situations, this balance is altered in favor of osteoclast (OC)-mediated bone resorption. During chronic inflammation, the balance between bone formation and bone resorption may be considerably affected, contributing to a net prevalence of osteoclastogenesis. Skin diseases are the fourth cause of human disease in the world, affecting approximately one third of the world’s population with a prevalence in elderly men. Inflammation and the various associated cytokine patterns are the basis of both osteoporosis and most skin pathologies. Moreover, dermatological patients also undergo local or systemic treatments with glucocorticoids and immunosuppressants that could increase the risk of osteoporosis. Therefore, particular attention should be paid to bone health in these patients. The purpose of the present review is to take stock of the knowledge in this still quite unexplored field, despite the frequency of such conditions in clinical practice.

Chronic urticaria is characterized by recurrent wheals and/or angioedema lasting for more than 6 weeks. Chronic urticaria is an extremely disabling disease limiting daily activities, compromising patient quality of life, and frequently associated with psychiatric comorbidities (depression and/or anxiety). Unfortunately, there are still gaps in the knowledge regarding treatment in special populations, especially in older patients. Indeed, there are no specific recommendations for the management and treatment of chronic urticaria in older people; therefore, recommendations for the general population are used. However, the utilization of some medications may be complicated by potential concerns of comorbidities or polypharmacy. Currently, the diagnostic and therapeutic procedures for chronic urticaria in the older patient are the same as those indicated for other age groups. In particular, there is a limited number of blood chemistry investigations for spontaneous chronic urticaria and specific tests for inducible urticaria. With regard to therapy, second-generation anti-H1 antihistamines are used and, in recalcitrant cases, omalizumab (an anti-IgE monoclonal antibody) and possibly cyclosporine A are additional choices. Nonetheless, it should be underlined that in older patients the differential diagnosis can be more difficult, owing to the lower frequency of chronic urticaria and the likelihood of other pathologies that are peculiar for this age group and that can be included in the chronic urticaria differential diagnosis. As far as therapy is concerned, the physiological characteristics of these patients, the possible comorbidities, and the intake of other medications often require a very attentive drug selection for chronic urticaria compared with other age groups. The purpose of this narrative review is to provide an update on the epidemiology, clinical characteristics, and management of chronic urticaria in older patients.

Although allergic rhinitis (AR) and chronic spontaneous urticaria (CSU) share overlapping immunological pathways, their distinct clinical manifestations imply the involvement of unique underlying mechanisms. This study aimed to investigate the metabolomic differences between patients with AR alone and those with concurrent AR and CSU (AR_CSU, defined as patients simultaneously presenting with both conditions). An untargeted metabolomic analysis was performed on serum samples from 53 AR patients and 14 AR_CSU patients using ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (LC-MS/MS). Multivariate statistical analyses, including partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), were employed to identify differential metabolites and metabolic pathways. A total of 209 significantly different metabolites were identified between the AR and AR_CSU groups (p < 0.05). Distinct metabolic patterns were observed through PLS-DA and OPLS-DA analyses, with no overlap between the two groups. Twenty metabolites exhibited high diagnostic potential (AUC > 0.75), among which Fasciculic acid C and Biotin-XX-Hydrazide showed particularly strong discriminatory power (AUC ≈ 0.8). Pathway analysis highlighted significant alterations in linoleic acid, fatty acid, and arachidonic acid metabolism. Notably, fatty acid elongation pathways were upregulated in AR_CSU patients, whereas primary bile acid biosynthesis and Fc gamma R-mediated phagocytosis were downregulated. This study represents the first comprehensive metabolomic comparison between AR and AR_CSU, identifying distinct metabolic signatures and potential biomarkers. These findings advance our understanding of the pathophysiological differences between these conditions and could inform the development of targeted therapeutic strategies.

Although placebo contributes to the effects of treatment for various symptoms and conditions, its effect on itch has rarely been investigated. In this meta-analysis, the magnitude of the placebo effect on itch was systematically investigated in clinical trials including patients with chronic itch due to atopic dermatitis, psoriasis, or chronic idiopathic urticaria. From searches in four databases, 34 articles were included in the quantitative analyses. Placebo treatment significantly decreased itch (1.3 out of 10, 95% confidence interval 1.02–1.61) compared with baseline itch (effect size 0.55), indicating that placebo effects have a considerable role in these patients’ treatment.

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.