Chronic spontaneous urticaria (CSU) is a debilitating condition that goes far beyond skin symptoms, significantly impairing patients’ quality of life.¹ Research indicates that CSU is associated with increased all-cause mortality and a higher incidence of suicidal ideation—underscoring the immense mental health burden.¹ At the EAACI Hong Kong Allergy School 2025, global experts from China, Japan, and Germany emphasized the substantial impact of CSU on patients and outlined the latest treatment options for the disease. CSU is increasingly recognized as a systemic disease that demands comprehensive and effective management. 

CSU is characterized by intense, persistent itching and the unpredictable appearance of wheals or angioedema, lasting longer than 6 weeks, severely disrupting sleep, diet, work, and personal relationships.^1,2 CSU affects an estimated 30 million adults in mainland China alone.¹ The presentation and prevalence of urticaria subtypes also show notable regional variations.³ For instance, cholinergic urticaria appears more commonly in Asia, and patients with CSU tend to have a lower incidence of associated angioedema.³ However, regardless of location, the burden of CSU is not to be underestimated.² It is linked to a more than twofold increase in patient mortality, a statistic primarily driven by a threefold higher risk of suicide.²

There was a consensus on a fundamental problem in CSU management.^1-3 There is a significant perception gap, where physicians often underestimate the disease's impact on the patient, leading to undertreatment and prolonged patient suffering.^2,3 Patients often face a delay of about two years before receiving a correct diagnosis for chronic urticaria, during which extensive and unnecessary allergy tests are conducted, as many physicians mistakenly believe their condition to be an allergy.¹ As a result, failure or delay to implement guidelinerecommended therapies is common globally.^1,3

The standard of care for CSU follows a step-wise international guideline, aiming for complete symptom control.² Treatment typically begins with second-generation antihistamines, escalating to up-dosing if control is not achieved.² If symptoms remain uncontrolled, biologic agents such as omalizumab may be considered, with cyclosporine reserved for the most refractory cases.² Tools such as the urticaria control test (UCT) help guide stepping up or down.² However, despite good responses in most patients treated with omalizumab, therapeutic options remain limited for those who do not respond.¹

The initial understanding of CSU pathology and omalizumab mechanism of action points to mast cell immunoglobulin E (IgE) release as the primary mechanism of urticaria. Recent research has expanded our understanding beyond the mast cell, implicating other pathways that help explain its complexity and treatment resistance.³ The “omalizumab paradox" highlights this gap in understanding disease pathology and treatment options.³ Omalizumab is effective in over 80% of patients, yet only about 60% of CSU cases are thought to be driven by classical autoimmunity.³ Furthermore, its rapid onset of action is faster than the time it takes to reduce mast cell receptors, pointing to additional, less understood mechanisms of action.³ Basophils are now recognized as crucial contributors; in CSU patients, they show higher spontaneous histamine release, and their migration into skin tissue is a key inflammatory step.³ Additionally, the coagulation cascade is often activated in severe urticaria, creating a pro-inflammatory feedback loop that can perpetuate the condition.³

This evolving understanding of CSU pathology has paved the way for a new generation of upcoming targeted therapies, which show promise by targeting other inflammatory pathways.^2,3 Dupilumab prevents inflammatory cells from migrating into the skin.³ BTK inhibitors like remibrutinib provide rapid, potent control by blocking mast cell activation and are effective even in patients who failed omalizumab.² Finally, anti-c-Kit antibodies such as barzolvolimab deplete mast cells directly, leading to profound and long-lasting symptom relief that can persist after treatment stops, suggesting a potential for disease modification.² These advanced therapies are moving the field toward the ultimate goal of achieving complete and sustained control—“treating the disease until it is gone“—offering new hope for even the most difficult-to-treat patients worldwide.

In summary, CSU is a systemic disease that severely impacts patients' QoL and mental health, with significant mortality risks.^1-3 Experts emphasized the need for improved recognition and management, as many patients face misdiagnosis and inadequate treatment.^1-3 While current guidelines recommend antihistamines and biologics, gaps remain in care.^1-3 Ongoing research reveals complex mechanisms behind CSU, paving the way for targeted therapies that promise better symptom control and a goal of complete disease resolution.^1-3 
 

Below are highlights consolidated from the panel discussion session: 

1. Is it safe to keep patients on antihistamines for years if needed? 

   It is generally regarded as safe to maintain patients on second-generation antihistamines long-term, even for up to 20 years, especially in settings where biologics are not accessible. 

2. How should doctors choose between various biologics targeting different pathways?

   The choice should be a shared decision with the patient. Key factors include comorbid health conditions (e.g. a patient with atopic dermatitis may benefit more from IL4/IL13 inhibition), the desired speed of symptom relief, and the medication's track record (Omalizumab has a long history of safety and efficacy). 

3. What are the long-term safety concerns for the newest drugs like BTK and C-kit inhibitors? ​​​​​​​

   Based on data of up to two years, these novel therapies appear very safe, especially compared to older immunosuppressants like cyclosporine. They do not cause a complete depletion of B-cells or mast cells, and long-term infection rates in trials are low. 

4. Do biologic treatments just control symptoms, or can they modify the disease itself? ​​​​​​​

   While their primary role is symptom control, consistent, effective treatment can modify the long-term course of the disease based on clinical experience and observation. 

5. ​​​​​​​What is the role of co-factors like stress and diet? 
   
   ​​​​​​​Co-factors are very important triggers. Stress in particular is a major factor in causing flares. While patients often believe food is the cause, this is usually incorrect and requires careful counselling from their doctor.