Optimizing CSU care
New directions in CSU guidelines and therapies
Chronic spontaneous urticaria (CSU) has a large impact on patients' quality of life and requires long-term, often individualized management.1 Fortunately, treatment options are expanding, and healthcare professionals could soon be in a position to offer highly personalized care and disease control.2
A stepwise algorithm
The dose of second-generation H1-antihistamines may be increased up to fourfold for patients with uncontrolled CSU1
As outlined in Figure 1, the core treatment strategy for CSU in adults remains a three-step approach, beginning with second-generation H1-antihistamines, then escalating to omalizumab and then, if required, cyclosporine.
Figure 1. Treatment algorithm recommended in the international guidelines1 and a potential positioning of novel medications within an updated treatment strategy.2 CSU, chronic spontaneous urticaria; CU, chronic urticaria; H1-AH, H1-antihistamine; IgE, Immunoglobulin E; IL-17, interleukin 17; IL-23, interleukin 23; IL-5, interleukin 5; IL-5Rα, interleukin 5 receptor alpha. Image licensed under Creative Commons license 4.0 by Zuberbier et al.1,2
Of note, not all second-generation H1-antihistamines have been tested specifically in chronic urticaria. Current evidence supports the use of bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, and rupatadine.1
A key point in the current guidance is the advice to increase the dose of antihistamines up to fourfold if patients do not achieve symptom control with the standard dose.1
Omalizumab remains the preferred next-line treatment after high-dose antihistamines fail1
If symptoms still are not under control with a high dose of second-generation H1-antihistamines, it is time to consider adding omalizumab – usually after 2–4 weeks, or even earlier if symptoms are particularly difficult to manage. For adults with CSU who remain unresponsive, cyclosporine (used alongside H1-antihistamines) becomes a third-line option. Although cyclosporine is off-label, it offers a more favorable risk/benefit ratio compared with long-term use of steroids and steps in when omalizumab is not sufficient.1
Noteworthy, according to the 2021 guideline, long-term use of systemic glucocorticosteroids should be avoided in patients with chronic urticaria due to potential safety concerns. However, short courses may be considered for managing acute exacerbations.1
Monitoring tools: UCT and AECT
The Angioedema Control Test (AECT) can support angioedema-specific disease monitoring1
Regular assessment of disease activity, quality of life (QoL), and treatment response remains central to CSU management.1
To support this approach, the guideline recommends using the Urticaria Control Test (UCT) for patients with hives (wheals), and the AECT for those who experience angioedema with or without hives. It emphasizes consistent reassessment at each visit and encourages the use of QoL measures, such as the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) or the Dermatology Life Quality Index (DLQI) to support individualized care.1
Treatment approach in children
While the management of CSU in children generally aligns with adult treatment principles, there are key differences in how care is adapted for pediatric patients.
For children, guidelines advise beginning treatment with second-generation H1-antihistamines, and approaching the escalation steps more cautiously, considering the child's age, weight, and overall health1
Firstly, the second-generation H1-antihistamines recommended for children include the same drugs as for the adult population apart from ebastine.1
Secondly, treatment escalation is approached more cautiously due to limited safety data in children.1 Clinicians may consider dose escalation of second-generation antihistamines, but carefully individualized based on age, weight, and response. However, there is evidence that children may respond more favorably to antihistamines compared with adults, which may reduce the need for further escalation in many cases.3
On the horizon: Advancing options beyond the current algorithm
As shown in Figure 1, current treatment recommendations for CSU include second-generation H1-antihistamines, followed by adding on omalizumab or cyclosporine for patients whose symptoms remain uncontrolled.1,2 Yet, for patients who do not respond to these therapies, several novel agents are under investigation, with some already in late-stage trials.
Dupilumab and remibrutinib may expand treatment options for patients experiencing refractory CSU2,4
On April 18, 2025, the US Food and Drug Administration (FDA) approved dupilumab as the first new targeted therapy in over a decade for adolescents (aged 12 years and older) and adults with H1-antihistamine-refractory CSU.5
Dupilumab, an IL-4 and IL-13 receptor antagonist with an established safety profile in type 2 inflammatory conditions such as asthma,2,4 was approved based on positive results from the phase 3 LIBERTY-CUPID trials, which demonstrated significant clinical benefit compared with placebo.5
However, in February 2025, the European Medicines Agency (EMA) withdrew their approval application for dupilumab in CSU.6
In addition, remibrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor, demonstrated significant improvements in itch and hive symptoms compared with placebo in the completed phase 3 REMIX-1 and REMIX-2 trials in patients with antihistamine-refractory CSU.7
Autoantibody profiles may help predict response to biologic treatment8
As treatment options expand, biomarkers may help guide clinicians to the optimal medication for a patient. For example, a 2023 study found that patients with both immunoglobulin (Ig)G and IgE autoantibodies targeting FcεRIα (high-affinity IgE receptor) tended to respond slowly or not at all to omalizumab, highlighting the potential for biomarker-driven treatment decisions in the future.8
Other emerging treatments
Other therapies at earlier stages of clinical development include those targeting cytokines involved in pruritus and epithelial inflammation. Agents targeting thymic stromal lymphopoietin (TSLP), interleukin (IL)-31, and oncostatin M are currently in phase 2 trials, and have attracted interest due to their roles in itch signaling and barrier dysfunction.2 These cytokine pathways may be especially relevant for patients whose CSU overlaps with other type 2 inflammatory conditions.
Mast cell-targeting approaches are also advancing. Given the central role mast cells play in CSU, early-phase trials of mast cell-depleting therapies are exploring whether direct modulation of mast cell populations could offer disease control.2 Although still in development, these therapies represent a novel mechanism that may complement the existing treatment algorithm.
Meanwhile, other biologics, such as those targeting IL-5, IL-17, and IL-23, are being explored off-label. These are typically used in patients with comorbid type 2 or eosinophilic conditions and remain investigational in CSU.2
While none of these therapies are yet part of formal guideline recommendations, they reflect the field’s broader shift toward more targeted treatment options for patients with CSU who do not respond to currently approved therapies.
Regional variations in guidelines
The international guideline sets a global standard, but national guidelines provide some variation. For example, the UK and Australian–New Zealand guidelines9 suggest considering the addition of montelukast alongside second-generation H1-antihistamines during first-line treatment, a recommendation not included in the European Academy of Allergy and Clinical Immunology (EAACI) guidance.1,10 This is based on limited clinical evidence suggesting that montelukast combined with a second-generation H1‐antihistamines may improve symptom control.10
The same guidelines also suggest the use of first-generation H1-antihistamines as a third-line option in combination with second-generation agents, whereas the EAACI guideline strongly advises against this due to safety concerns and an unfavorable risk/benefit profile.1,10 These differences underline the importance of context-specific practice and clinician judgment.
When increased doses of second-generation antihistamines are not sufficient to control symptoms, the UK and Australian–New Zealand guidelines recommend the addition of montelukast alongside second-generation H1-antihistamines during first-line treatment9,10
References
- Zuberbier, 2022. The international EAACI/GA(2)LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. https://www.doi.org/10.1111/all.15090
- Zuberbier, 2024. Chronic urticaria: Unmet needs, emerging drugs, and new perspectives on personalised treatment. https://www.doi.org/10.1016/S0140-6736(24)00852-3
- Özçeker, 2023. Differences between adult and pediatric chronic spontaneous urticaria from a cohort of 751 patients: Clinical features, associated conditions and indicators of treatment response. https://www.doi.org/10.1111/pai.13925
- Agache, 2020. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma: A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. https://www.doi.org/10.1111/all.14235
- Regeneron Pharmaceuticals. 2025. Dupixent® (dupilumab) approved in the U.S. as the first new targeted therapy in over a decade for chronic spontaneous urticaria (CSU). https://www.globenewswire.com/news-release/2025/04/18/3064133/0/en/Dupixent-dupilumab-Approved-in-the-U-S-as-the-First-New-Targeted-Therapy-in-Over-a-Decade-for-Chronic-Spontaneous-Urticaria-CSU.html
- EMA. 2025. Dupixent - withdrawal of application for variation to marketing authorisation. https://www.ema.europa.eu/en/medicines/human/variation/dupixent-0
- Metz, 2025. Remibrutinib in chronic spontaneous urticaria. https://www.doi.org/10.1056/NEJMoa2408792
- Maronese, 2023. IgG and IgE autoantibodies to IgE receptors in chronic spontaneous urticaria and their role in the response to omalizumab. https://www.doi.org/10.3390/jcm12010378
- ASCIA, 2020. Position paper-chronic spontaneous urticaria (CSU). https://www.allergy.org.au/images/stories/pospapers/ASCIA_HP_Position_Paper_CSU_2020.pdf
- Sabroe, 2022. British Association of Dermatologists guidelines for the management of people with chronic urticaria 2021. https://www.doi.org/10.1111/bjd.20892
Randomized controlled trials (RCTs), although critical to assess the efficacy of novel treatments, often exclude large groups of patients and do not reflect real-world clinical settings.1 Researchers therefore turn to real-world data (RWD) – generated during routine clinical practice – to fill the gap and obtain critical information to help healthcare professionals (HCPs) obtain the best possible outcomes for their patients.
RWE: Actionable insights for personalized CSU care
Studies based on RWD generate real-world evidence (RWE), which can help researchers to understand the effectiveness and tolerability of treatments in everyday clinical practice across diverse patient populations.1 RWD also play a key role in ongoing monitoring of risk–benefit profiles by allowing researchers to identify long-term or rare safety signals.1
RWE can therefore inform regulatory decision-making and support treatment decisions in the clinic and the development of guidelines, beyond simply enhancing the understanding of disease epidemiology and burden.1
A key source of RWD is large-scale registries, such as the Chronic Urticaria Registry (CURE), which collects extensive, longitudinal patient data that offer insights into chronic spontaneous urticaria (CSU) prevalence, demographic trends, and disease progression across diverse populations.2
Researchers have used CURE data to help identify distinct patient subgroups, treatment predictors, and symptom patterns that may inform individualized management approaches.3 A few of the findings to date include:
- Patients with comorbid chronic inducible urticaria have earlier disease onset than those without, as well as greater quality-of-life impairment and fewer features typically associated with autoimmune CSU, pointing to an autoallergic mechanism4
- Eosinopenia and elevated neutrophil-to-lymphocyte ratio may be associated with autoimmune CSU5
- A poor response to omalizumab could potentially be predicted by immunoglobulin (Ig)E levels <30 IU/L and a high systemic inflammation response index5
- Patients presenting with both wheals and angioedema have the highest disease burden and are more likely to have psychiatric or autoimmune comorbidities, suggesting these factors may be relevant during patient assessment6
- Approximately one-third of people with CSU experience symptoms such as joint pain, fever, and fatigue, which may indicate uncontrolled disease or alternative diagnoses, such as urticarial vasculitis or autoinflammatory syndromes7
These findings illustrate how RWD may help HCPs to offer personalized support for patients with CSU.
The power of PROMs
An important complement to routine clinical data is patient-reported outcome measures (PROMs). These are valuable tools in personalized management, as they capture important aspects of treatment efficacy that are not reflected in clinical assessments or objective markers.8 They can help clinicians assess treatment effects across different domains and enhance communication with patients.8
In CSU, tools such as the EuroQol 5-Dimension questionnaire (EQ-5D), Dermatology Life Quality Index (DLQI), Work Productivity and Activity Impairment questionnaire (WPAI), and Jenkins Sleep Evaluation Questionnaire (JSEQ) may offer a broader picture of disease impact, including sleep, work productivity, and emotional wellbeing.9 They also offer a more complete picture of treatment response; for example, patients reported reduced impairment across these domains after treatment with omalizumab.9
Incorporating PROMs can help clinicians better communicate with patients, supporting better treatment adherence and patient retention8
For specific assessment in chronic urticaria, there is also the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), developed to assess quality of life across areas particularly relevant to this condition, such as sleep, appearance, and daily functioning.10
Other validated PROM tools in CSU include the Urticaria Control Test (UCT) and the Patient Activation Measure-13 (PAM-13), which can be used to assess disease control and patients’ knowledge, skills, and confidence in managing their health.11 This can uncover important issues, such as poor disease control and low confidence among patients in managing their treatment.11
Similarly, a study using UCT scores and UAS7 (weekly Urticaria Activity Score) highlighted a misalignment between physician and patient perspectives on the status of disease control.12 The same study revealed that patients who achieve full disease control (UCT=16) report better sleep quality and health-related quality of life (HRQoL).12
These examples show how PROMs may help surface important insights that could otherwise go unrecognized.
Keeping healthcare on track
CSU is associated with delayed diagnosis, poor symptom control despite treatment, and significant emotional and social burden, highlighting the need for early diagnosis and patient-centered management.11
RWD can help uncover important issues, such as treatment inertia or poor awareness of guidelines. For example, researchers found that more than 80% of patients currently using antihistamines had poorly controlled CSU (UCT <12), suggesting that many may benefit from treatment review or escalation.11 An earlier analysis identified widespread use of systemic corticosteroids for CSU, despite these not being recommended as routine treatment.13 Although systemic corticosteroids are included in guidelines for rapid control of severe disease flares, their long-term use is discouraged due to severe side effects.14
HCPs can also use RWD to identify unmet needs in individual patients, increasingly assisted by digital tools. One example is the CRUSE® mobile app, which enables patients to log symptoms, treatment responses, and QoL metrics in real time. This can help clinicians monitor CSU between visits and adjust care based on real-world patterns.15
References
- Berger, 2017. Good practices for real-world data studies of treatment and/or comparative effectiveness: Recommendations from the joint ISPOR-ISPE special task force on real-world evidence in health care decision making. https://www.doi.org/10.1002/pds.4297
- Weller, 2021. The chronic urticaria registry: Rationale, methods and initial implementation. https://www.doi.org/10.1111/jdv.16947
- CURE: Key facts about the registry. https://urticaria-registry.com/key-facts/
- Kovalkova, 2024. Comorbid inducible urticaria is linked to non-autoimmune chronic spontaneous urticaria: CURE insights. https://www.doi.org/10.1016/j.jaip.2023.11.029
- Bakay, 2024. What can be learned from real-world data about chronic spontaneous urticaria? https://www.doi.org/10.2500/aap.2024.45.240041
- Buttgereit, 2023. Patients with chronic spontaneous urticaria who have wheals, angioedema, or both, differ demographically, clinically, and in response to treatment—Results from CURE. https://www.doi.org/10.1016/j.jaip.2023.08.020
- Pyatilova, 2024. Non-skin related symptoms are common in chronic spontaneous urticaria and linked to active and uncontrolled disease: Results from the chronic urticaria registry. https://www.doi.org/10.1016/j.jaip.2024.04.027
- Kluzek, 2022. Patient-reported outcome measures (PROMs) as proof of treatment efficacy. https://www.doi.org/10.1136/bmjebm-2020-111573
- Seetasith, 2024. Real-world outcomes in patients with chronic spontaneous urticaria receiving omalizumab: Insights from a clinical practice survey. https://www.doi.org/10.1080/03007995.2024.2354534
- Shah, 2022. Comparative assessment of quality of life in chronic spontaneous urticaria receiving second generation anti histamines: A real world study. https://www.doi.org/10.25259/IJSA_2_2021
- Weller, 2025. Urticaria voices: Real-world experience of patients living with chronic spontaneous urticaria. https://www.doi.org/10.1007/s13555-025-01348-8
- Kolkhir, 2023. The benefit of complete response to treatment in patients with chronic spontaneous urticaria—CURE results. https://www.doi.org/10.1016/j.jaip.2022.11.016
- Weller, 2022. Epidemiology, comorbidities, and healthcare utilization of patients with chronic urticaria in Germany. https://www.doi.org/10.1111/jdv.17724
- Friedman, 2024. A practical approach to diagnosing and managing chronic spontaneous urticaria. https://www.doi.org/10.1007/s13555-024-01173-5
- Neisinger, 2024. CRUSE®—An innovative mobile application for patient monitoring and management in chronic spontaneous urticaria. https://www.doi.org/10.1002/clt2.12328
Patient case studies
Gain clinical insights from real-world case discussions:
- Sophia Neisinger shares experience with the CRUSE app for patient-reported outcomes (PROs)
- Karsten Weller presents a case of isolated angioedema and the diagnostic approach
- Ana Maria Giménez-Arnau discusses a case study identifying the treatment of CSU with antihistamines
The CRUSE app has been transforming CSU management for several years now – something the pandemic made very clear. Neisinger describes how real-time symptom tracking has proven essential in helping clinicians deliver more precise, responsive care. View transcript.
Catch up with the essential diagnostic tools and evidence-based treatment pathways that effectively address angioedema, in this case study presented by Weller. View transcript.
“It is essential to tailor treatment plans not only to individual patients but also to the various stages of their disease.” Giménez-Arnau discusses management of CSU with antihistamines. View transcript.
Optimizing clinical management of CSU
What’s driving change in chronic spontaneous urticaria (CSU) care? New therapies, treatment escalation, and gaps in current practice are reshaping disease management. Read our updates below and hear from Gülseren Tuncay (Charité – Universitätsmedizin, Berlin) on how the latest developments and drug approvals will help healthcare providers to offer more effective, personalized care to people with CSU.
Introducing timely alternatives in CSU management
Fewer than 10% of patients with CSU achieve complete control with standard doses of second-generation H1-antihistamines,1 underscoring the need for timely evidence-based treatment escalation. Patients with moderate-to-severe CSU often remain symptomatic despite antihistamine use, highlighting a persistent unmet need.1
As outlined by the American Academy of Allergy, Asthma & Immunology (AAAAI), there is a notable lack of high-quality evidence supporting cycling between different second-generation H1-antihistamines,2 thereby discouraging this approach.
In line with international recommendations from the EAACI/GA²LEN/EuroGuiDerm/APAAACI guidelines, dose escalation up to fourfold is the preferred evidence-based approach for 2–4 weeks, after which alternative treatments, such as omalizumab, can be considered if symptoms persist.3
Real-world evidence reinforces that omalizumab is typically introduced only after prolonged high-dose antihistamine therapy rather than rotation of agents at standard doses.4 In clinical practice, omalizumab was introduced following high-dose antihistamine use in patients who remained symptomatic.4
In a retrospective analysis of 110 patients with CSU treated with omalizumab, 81.8% achieved a complete or significant response.4 Moreover, 60% of those patients remained asymptomatic on omalizumab alone, and no serious adverse events were reported.4
A recent practical review further highlights that many patients experience delays and inefficiencies when cycling through antihistamines and providers before accessing biologic therapy, reinforcing the importance of an early, structured dose escalation strategy.5
Gülseren Tuncay outlines treatment escalation guidance for CSU and discusses how forthcoming updates will expand options, including the addition of two new biologics and a stronger focus on patient-specific factors. View transcript.
What factors have impacted CSU care decisions over time? Gülseren Tuncay reflects on the evolution of CSU management, from antihistamine cycling strategies to financial pressures and disparities in healthcare access. View transcript.
Gülseren Tuncay outlines recent advances in CSU treatment, explaining how newly approved and emerging treatments may change disease management approaches and drug selection. View transcript.
“We are excited to see the real-world data of these new treatments over the next 1.5 years.” Gülseren Tuncay considers how new treatments and improved understanding of CSU will help clinicians to tailor care and improve outcomes for their patients. View transcript.
References
- Kolkhir, 2025. Update on the treatment of chronic spontaneous urticaria. https://www.doi.org/10.1007/s40265-025-02170-4
- AAAAI, 2021. Rotating the use of oral second generation H1 antihistamines. https://www.aaaai.org/allergist-resources/ask-the-expert/answers/2021/rotateuse
- Zuberbier, 2022. The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. https://www.doi.org/10.1111/all.15090
- Giménez Arnau, 2019. Therapeutic strategy according to differences in response to omalizumab in patients with chronic spontaneous urticaria. https://www.doi.org/10.18176/jiaci.0323
- Friedman, 2024. A practical approach to diagnosing and managing chronic spontaneous urticaria. https://www.doi.org/10.1007/s13555-024-01173-5
- Regeneron Pharmaceuticals. 2025. Dupixent® (dupilumab) approved in the U.S. as the first new targeted therapy in over a decade for chronic spontaneous urticaria (CSU). https://www.globenewswire.com/news-release/2025/04/18/3064133/0/en/Dupixent-dupilumab-Approved-in-the-U-S-as-the-First-New-Targeted-Therapy-in-Over-a-Decade-for-Chronic-Spontaneous-Urticaria-CSU.html
- EMA, 2024. Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 18-21 March 2024. https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-18-21-march-2024
- Zuberbier, 2024. Chronic urticaria: Unmet needs, emerging drugs, and new perspectives on personalised treatment. https://www.doi.org/10.1016/S0140-6736(24)00852-3
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This content has been developed independently by Medthority who previously received educational funding from Novartis in order to help provide its healthcare professional members with access to the highest quality medical and scientific information, education and associated relevant content.