Treatments and Targets to Achieve Disease Control in Chronic Spontaneous Urticaria: Current and Emerging Therapeutic Options

Clara Emilie Syrene Østergaard,1 Simon Francis Thomsen,1,2 Ditte Georgina Zhang1 1Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark; 2Department of Biomedical Sciences, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Clara Emilie Syrene Østergaard, Department of Dermato-Venereology & Wound Healing Centre Bispebjerg Hospital, Bispebjerg Bakke 23, Copenhagen, NV, 2400, Denmark, Tel +4540106382, Email [email protected]: Chronic spontaneous urticaria (CSU) is a common and often debilitating inflammatory skin disease characterized by recurrent pruritic wheals, angioedema, or both, persisting for ≥ 6 weeks. Symptoms are unpredictable, with sudden onset and resolution, fluctuating severity, variable duration, and inconsistent responses to treatment, which may substantially impair patients’ quality of life. This underscores the complexity of clinical management and the need for effective therapies to achieve disease control. According to international guidelines, first-line therapy consists of second-generation H1-antihistamines, which may be up-dosed to fourfold in patients with inadequate response. Less than half of patients on standard doses achieve disease control, increasing to 63% with up-dosing. Patients who remain uncontrolled after 2– 4 weeks may escalate to add-on therapy with omalizumab, which provides complete disease control in approximately 70% of antihistamine-refractory cases. Omalizumab has transformed CSU management and is well-established as safe and effective. However, up to one third of patients, particularly those with autoimmune (type IIb) CSU, do not achieve adequate disease control. For patients refractory to antihistamines and omalizumab, recently approved add-on therapies, including remibrutinib and dupilumab, provide additional options. Cyclosporine may be considered for severe, refractory cases, particularly in type IIb CSU, though its use is limited by potential serious adverse effects. Off-label therapies, such as leukotriene receptor antagonists and short courses of systemic corticosteroids, may also be used when guideline-recommended treatments are insufficient. Additional therapeutic targets are continuously under development. Emerging treatments include Tyrosine kinase (KIT) inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, TSLP inhibitors, Janus kinase (JAK) inhibitors, Mas-related G protein-coupled receptor X2 (MRGPRX2) antagonists, and interleukin 2 (IL-2), which may provide effective options for refractory patients while enhancing understanding of CSU pathophysiology. Collectively, these therapies support a shift toward more personalized and targeted management strategies, aiming to achieve faster and more efficient disease control.Keywords: biologic therapy, chronic spontaneous urticaria, disease control, emerging treatments, endotypes