Antihistamine resistance in chronic urticaria
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Antihistamine Resistance in Chronic Urticaria: Prevalence and Clinical Predictors
Antihistamine resistance is a significant challenge in the management of chronic urticaria (CU), with studies showing that more than 50% of patients with chronic spontaneous urticaria (CSU) do not respond adequately to standard or even up to fourfold doses of second-generation H1-antihistamines 379. Clinical predictors of antihistamine resistance include a low quality of life, high baseline urticaria activity scores, the presence of chronic inducible urticaria, autoimmune comorbidities, and higher body mass index (BMI). There is an inverse correlation between BMI and symptom control, suggesting that overweight and obesity may contribute to poorer responses to antihistamines .
Mechanisms and Pathophysiology: Inflammation and Gut Microbiota
The underlying mechanisms of antihistamine resistance in CU are not fully understood, but evidence points to a pro-inflammatory phenotype. Patients with antihistamine-resistant CSU often have higher levels of systemic inflammation markers, such as C-reactive protein and interleukin-6, and show altered gut microbiota profiles. Specifically, these patients have increased abundance of certain bacteria (Prevotella, Megamonas, Escherichia) and decreased levels of others (Blautia, Alistipes, Anaerostipes, Lachnospira), which may contribute to persistent inflammation and reduced treatment response .
Alternative and Add-On Treatments for Antihistamine-Resistant Chronic Urticaria
Biologic Therapies: Omalizumab and Ligelizumab
For patients who do not respond to antihistamines, biologic agents such as omalizumab and ligelizumab have shown significant efficacy. Omalizumab, an anti-IgE monoclonal antibody, is recommended for antihistamine-resistant CSU and has demonstrated moderate to large beneficial effects in reducing urticaria symptoms 46. Ligelizumab, another monoclonal antibody, has shown even greater efficacy in some studies, with both agents being well-tolerated and effective for patients who have failed antihistamine therapy .
Lirentelimab: Targeting Mast Cells and Eosinophils
Lirentelimab, an anti–sialic acid–binding immunoglobulin-like lectin 8 monoclonal antibody, has demonstrated activity in patients with various forms of antihistamine-refractory CU, including those who are omalizumab-naive or omalizumab-refractory. Treatment with lirentelimab led to significant improvements in urticaria control and symptom reduction, with a favorable safety profile .
Leukotriene Receptor Antagonists and Other Add-On Therapies
Leukotriene receptor antagonists, such as montelukast, may provide additional benefit for a small subset of patients with severe, antihistamine-resistant CU, though the overall effect is limited and not consistent across all patients 210. The combination of H2 antihistamines with H1 antihistamines has also been explored, but the evidence for their effectiveness remains unclear .
Novel and Adjunctive Treatments
Adjunctive therapies, such as Ziziphus jujube syrup, have shown promise in improving urticaria activity and sleep quality when added to antihistamine regimens in resistant cases, suggesting a potential role for complementary treatments .
Personalized Medicine and Future Directions
The management of antihistamine-resistant CU is moving toward personalized approaches, taking into account clinical predictors, biomarkers, and patient-specific factors such as BMI and comorbidities 39. Ongoing research aims to identify reliable biomarkers and develop more targeted therapies to improve outcomes for patients who do not respond to standard antihistamine treatment .
Conclusion
Antihistamine resistance in chronic urticaria is common and associated with specific clinical and inflammatory profiles. Biologic agents like omalizumab and ligelizumab, as well as newer therapies such as lirentelimab, offer effective alternatives for patients with refractory disease. Personalized treatment strategies, informed by clinical predictors and emerging biomarkers, are essential for optimizing care in this challenging patient population 1346+2 MORE.
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