Advances in Pathophysiology and Therapeutic Paradigm Shifts in Chronic Spontaneous Urticaria: A Narrative Review

Abstract

Chronic spontaneous urticaria (CSU) is a debilitating inflammatory skin disorder characterized by recurrent wheals and/or angioedema lasting beyond 6 weeks without identifiable triggers. Recent advances have shifted the understanding of CSU from a historically idiopathic condition to one increasingly recognized as an immune-mediated disease with distinct endotypes, including type I (autoallergic) and type IIb (autoimmune). This narrative review synthesizes contemporary insights into CSU pathophysiology, endotype classification, and systemic manifestations, while highlighting the substantial impact on quality of life, sleep, and psychological health. Advances in biomarker research, including total serum immunoglobulin E (IgE) levels, basophil activation tests (BAT), and eosinophil counts, support progress toward personalized treatment approaches. Therapeutically, management of CSU has evolved from empirical symptom control with H1 antihistamines toward mechanism-based precision medicine. Omalizumab remains the established second-line therapy, and dupilumab received US Food and Drug Administration (FDA) approval in 2025 for antihistamine-refractory disease. In parallel, several targeted therapies are under investigation, including Bruton’s tyrosine kinase (BTK) inhibitors, anti-KIT antibodies, and Janus kinase (JAK) inhibitors. These therapeutic mechanisms may offer sustained benefit, though long-term outcomes require validation through controlled trials. Integration of psychological interventions, such as cognitive behavioral therapy combined with pharmacotherapy, underscores the need for holistic patient care. Despite these advances, challenges remain in biomarker validation, sequencing of new therapies, and bridging clinical trial evidence with real-world practice. Future directions include refining endotype-driven personalized care, conducting long-term real-world studies, and developing cost-effective, globally accessible treatment strategies to optimize patient outcomes.

Key Summary Points

Chronic spontaneous urticaria (CSU) is now recognized as a primarily autoimmune disease with distinct type I (autoallergic) and type IIb (autoimmune) endotypes.

CSU significantly impairs quality of life, with profound psychological, sleep-related, and socioeconomic burdens comparable to other chronic diseases.

Biomarkers such as total IgE, basophil activation, and eosinophil counts are emerging as predictors of treatment response, enabling personalized medicine.

The therapeutic paradigm is shifting from empirical therapy toward mechanism-based precision treatment, with biologics, BTK inhibitors, and anti-KIT showing preliminary evidence of sustained therapeutic benefit during treatment, though long-term durability and optimal treatment sequencing require further investigation.

Integrated care that addresses both dermatological and psychological comorbidities is essential for optimal CSU management, given the high prevalence of anxiety, depression, and stress-related exacerbations.

Introduction

Chronic spontaneous urticaria (CSU) is a complex dermatological disorder that has gained increasing recognition as a significant medical condition in recent years [1]. This inflammatory disease is characterized by spontaneous urticarial eruptions and/or angioedema persisting for more than 6 weeks without identifiable external triggers [1]. Wheals typically appear as pink to red, centrally pale, raised papules or plaques with highly variable morphology, sometimes coalescing into larger lesions. A defining clinical feature of CSU is the short duration of individual wheals. These usually resolve within 24 h without pigmentation or scarring. This characteristic helps differentiate CSU from urticarial vasculitis, where lesions may persist longer and leave postinflammatory changes [1].

Angioedema frequently accompanies CSU, affecting the deep dermis or mucous membranes [2]. It commonly involves the lips, periorbital area, face, tongue, pharynx, and extremities, with affected areas appearing skin-colored or erythematous and often accompanied by discomfort, pain, or pruritus [2]. This swelling can persist for up to 72 h [1]. Epidemiological data indicate that angioedema occurs in approximately 40–50% of CSU cases, with about 10% of patients presenting it as the predominant clinical manifestation, suggesting that CSU extends beyond superficial skin involvement to systemic participation [1].

Recent epidemiological studies report a global prevalence of 0.5–1%, with consistent patterns across diverse populations despite variation in diagnostic criteria and demographics [1]. The condition demonstrates a 2:1 female predominance, most commonly occurring between ages 20–40 years [1].

Accurate differentiation of CSU from other chronic urticaria subtypes is essential for appropriate management. Acute urticaria, typically lasting less than 6 weeks, is often attributable to identifiable factors such as allergens, infections, or medications [1]. In contrast, chronic inducible urticaria (CIndU) is defined as persistent urticaria triggered by consistent, reproducible physical stimuli such as temperature changes, pressure, ultraviolet exposure, or exercise [1]. CSU is distinguished by its spontaneous and unpredictable nature without consistent external triggers [1].

The evolution from “chronic idiopathic urticaria” (CIU) to “chronic spontaneous urticaria” (CSU) reflects deepened understanding of disease mechanisms [1]. Recent studies from January 2020 through 2025 have revolutionized the CSU concept, establishing autoimmune and autoallergic endotypes that form the foundation for precision therapeutic approaches [1]. These insights have facilitated targeted biologic development and biomarker-based treatment selection, signifying a paradigm shift from empirical to personalized management strategies.

Methods

Search Strategy and Study Selection

This narrative review was conducted to synthesize contemporary evidence on the pathophysiology, clinical burden, and therapeutic advances in chronic spontaneous urticaria (CSU). We have clarified our literature search strategy to more accurately reflect our comprehensive approach. We systematically searched literature from January 2020 through June 2025 (emphasizing 2023–2025 findings) to synthesize contemporary evidence on CSU pathophysiology, clinical burden, and therapeutics. We explicitly acknowledge the selective incorporation of foundational pre-2020 studies where they established key mechanistic principles, reported landmark trials, or developed validated outcome measures. This ensures both currency and essential foundational context.

Electronic databases, including PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library were searched using the following predefined search strategy:

(“chronic spontaneous urticaria” OR “chronic idiopathic urticaria” OR “CSU”) AND (“pathophysiology” OR “endotype*” OR “autoimmun*” OR “biomarker*” OR “treatment” OR “therap*” OR “omalizumab” OR “dupilumab” OR “BTK inhibitor*” OR “anti-KIT” OR “quality of life (QoL)” OR “patient impact”).

Additional searches were performed on ClinicalTrials.gov as well as regulatory agency websites such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to identify investigational therapies. The reference lists of key studies and recent international guidelines were manually screened to capture additional relevant publications.

Inclusion criteria were as follows:

1. Peer-reviewed original articles, clinical trials, systematic reviews, or meta-analyses published in English.

2. Studies involving adult and/or adolescent patients with CSU.

3. Studies reporting on CSU pathophysiology, endotypes, biomarkers, therapeutic efficacy, safety, or patient-reported outcomes.

Exclusion criteria were as follows:

1. Studies focusing exclusively on acute urticaria or chronic inducible urticaria without overlap with CSU.

2. Case reports with fewer than five patients unless they offered novel pathophysiologic or therapeutic insights.

3. Non-English publications.

While initial searches included non-English articles, final inclusion was limited to English-language publications, which may introduce language bias by underrepresenting CSU research published in other languages, particularly from non-English-speaking regions.

Title and abstract screening was independently performed by two authors (H.B.K. and J.Y.U.), and disagreements were resolved through discussion with a third author (H.O.K.). Given the narrative nature of this review, formal risk-of-bias assessment tools were not employed; however, priority was given to high-quality evidence from randomized controlled trials, large prospective cohorts, and systematic reviews.

To minimize selection and publication bias, multiple databases were searched broadly during the initial screening, and both positive and negative or neutral trial outcomes were considered where available. Real-world evidence was also evaluated alongside randomized controlled trials to enhance clinical relevance. Conflicting data, particularly regarding autoimmune endotypes and heterogeneous treatment responses, were critically appraised. Peer-reviewed studies were prioritized, and all conference abstracts and press releases were clearly distinguished to avoid overinterpretation of preliminary data.

Ethical Approval

This article is based on previously conducted studies, and published literature and does not contain any new studies with human participants or animals performed by any of the authors. Therefore, ethical approval and informed consent were not required.

Pathophysiology and Underlying Mechanisms

Cellular and Molecular Mechanisms in CSU Pathogenesis

Recent advances have refined our understanding of CSU as a fundamentally mast-cell-driven disease [1, 3]. Beyond the traditional immunoglobulin E (IgE)/high-affinity IgE receptor (FcεRI) activation pathway, studies from 2020 to 2025 have revealed complex cellular networks involving coordinated responses of mast cells, basophils, and eosinophils [4]. Advanced transcriptomic analyses have identified previously unknown cytokine–chemokine cascade reactions, providing direct insights for developing targeted therapeutics such as Bruton’s tyrosine kinase (BTK) inhibitors and anti-KIT antibodies that extend beyond traditional histamine blockade approaches [4, 5]. The cellular and molecular mechanisms underlying CSU are illustrated schematically in Fig. 1.

Fig. 1.

Pathogenesis of CSU. Chronic spontaneous urticaria (CSU) arises from the interplay between genetic predisposition (e.g., human leukocyte antigen (HLA) and immune-related genes) and environmental triggers such as infection, stress, and drugs, which together promote mast cell activation. Two major immunologic endotypes contribute to mast cell activation in CSU. In the type I (autoallergic) endotype, immunoglobulin E (IgE) autoantibodies (e.g., IgE–anti-thyroid peroxidase (TPO), IgE–anti-interleukin-24 (IL-24)) recognize autoantigens and crosslink FcεRI on mast cells. In contrast, the type IIb (autoimmune) endotype is driven by IgG autoantibodies (e.g., IgG–anti-FcεRI, IgG–anti-IgE) that directly bind to and activate mast cells. Complement C5a further amplifies mast cell activation, particularly in the type IIb endotype through the IgG-mediated complement cascade. Bruton’s tyrosine kinase (BTK) is a key intracellular signaling molecule shared by both IgE- and IgG-mediated pathways. In addition, Mas-related G protein-coupled receptor X2 (MRGPRX2) represents an IgE-independent activation pathway that may contribute to both endotypes. These mechanisms collectively lead to mast cell degranulation and release of inflammatory mediators, including histamine, cytokines (IL-4, IL-5, IL-6, IL-13, IL-31, tumor necrosis factor alpha (TNF-α)), and chemokines (C–C motif chemokine ligand 2 (CCL2), CCL5, CXCL8), resulting in the characteristic clinical manifestations of wheals, angioedema, and pruritus. BTK Bruton’s tyrosine kinase, CCL2 C–C motif chemokine ligand 2, CCL5 C–C motif chemokine ligand 5, CSU chronic spontaneous urticaria, CXCL8 C–X–C motif chemokine ligand 8, FcεRI high-affinity IgE receptor, HLA human leukocyte antigen, IgE immunoglobulin E, IgG immunoglobulin G, IL interleukin, MCP-1 monocyte chemoattractant protein-1, MRGPRX2 Mas-related G protein-coupled receptor X2, TNF-α tumor necrosis factor alpha, TPO thyroid peroxidase

Autoimmune and Autoallergic Endotypes

CSU encompasses a spectrum of diverse phenotypes and immunological endotypes [6]. Research advances over recent decades have illuminated the autoimmune foundation of this disease, revealing overlapping yet distinct pathogenic mechanisms [7]. Current evidence increasingly supports autoimmunity as a major contributor to CSU pathogenesis, though the disease demonstrates considerable heterogeneity with multiple pathogenic mechanisms potentially operating simultaneously [7–9]. While autoimmune mechanisms have been identified in a substantial proportion of patients (estimated 40–60%), not all CSU cases demonstrate clear autoimmune markers, suggesting involvement of additional pathways, including nonimmunological mast cell activation and coagulation abnormalities [9]. The current model proposes two major autoimmune endotypes: type I (IgE-mediated “autoallergy”) and type IIb (IgG-mediated classical autoimmunity) [8].

Type I (autoallergic) endotype: This endotype is characterized by IgE autoantibodies directed against self-antigens such as thyroid peroxidase (TPO) or interleukin-24 (IL-24), which activate mast cells via the high-affinity IgE receptor (FcεRI) [10, 11].

Type IIb (autoimmune) endotype: This endotype is mediated by functional IgG autoantibodies that directly target FcεRI or IgE itself, causing mast cell degranulation through complement activation [12, 13].

Genomic data increasingly suggest that CSU is immunologically closer to autoimmune diseases than atopic disorders [9, 14]. Autoantigens such as FcεRI and tissue transglutaminase have been identified, supporting autoimmune theory. Evidence suggests that type I and type IIb endotypes can coexist within individuals, emphasizing the complexity and overlap of underlying immune dysregulation [9].

Heterogeneity and Overlapping Mechanisms beyond Binary Classification

Recent evidence challenges the traditional binary endotype classification, revealing greater complexity in CSU pathogenesis. Studies indicate that a substantial proportion of patients exhibit features of both type I (IgE-mediated) and type IIb (IgG-mediated) endotypes simultaneously [14, 15]. Xiang et al. (2023) demonstrated that most patients with type IIb autoimmune CSU also have autoallergic features, though the reverse is not true, suggesting autoallergy may be a more common underlying mechanism, with autoimmunity representing an additional layer in some patients [14].

Furthermore, emerging data identify a third subgroup of patients with CSU who do not clearly fit either type I or type IIb classifications [15]. These patients may lack detectable IgE or IgG autoantibodies yet still experience significant mast cell activation, suggesting alternative pathogenic mechanisms, including:

• Nonimmunological mast cell activation pathways [15]

• Coagulation cascade abnormalities [12]

• Mas-related G protein-coupled receptor X2 (MRGPRX2)-mediated IgE-independent activation [16, 17]

• Yet-unidentified autoantibody targets or mechanisms

This heterogeneity has important therapeutic implications. Patients with mixed or unclassified endotypes may require combination therapies or novel agents targeting multiple pathways [15]. The limitations of current binary classification systems underscore the need for refined endotyping approaches incorporating multiple biomarkers and the development of mechanism-agnostic therapies that can benefit patients regardless of endotype [9, 14, 15].

Systemic Symptoms and Non-Skin-Related Symptoms (NSRS)

CSU frequently accompanies non-skin related symptoms (NSRS), including fatigue, arthralgia, and gastrointestinal symptoms, supporting recognition as a systemic rather than merely cutaneous disease [1]. Some patients also report recurrent fever and systemic malaise [10]. These patients often exhibit longer wheal duration, poorer sleep quality, and higher levels of psychological distress [10]. In addition, CSU shows significant comorbidity with autoimmune diseases such as autoimmune thyroiditis and systemic lupus erythematosus, as well as other endocrine abnormalities [11]. The presence of systemic symptoms and frequent angioedema suggests widespread immune dysregulation beyond skin-limited disease, supporting multidisciplinary management approaches and systemic biologic interventions [1].

Biomarkers for Disease Activity, Endotype Classification, and Treatment Response Prediction

CSU diagnostic testing is generally limited to routine laboratory evaluations including complete blood counts and inflammatory markers to exclude other causes, with allergy-specific testing rarely proving useful [1]. Nevertheless, there is growing interest in biomarkers that may help predict disease severity, classify endotypes, and guide treatment selection [6].

Current evidence supports several biomarkers for distinguishing type I autoallergic CSU from type IIb autoimmune CSU. These biomarkers include peripheral eosinophil counts, basophil histamine release assays, serum total IgE levels, and anti-TPO IgG antibodies [6, 9, 14]. These assays particularly examine anti-IgE or anti-FcεRI autoantibodies [6, 14]. While these biomarkers have frequently been included as exploratory endpoints in clinical trials of novel therapeutics, robust validation through randomized controlled studies and real-world cohort analyses is still needed to confirm routine clinical applicability [6, 11, 12].

For example, markers suggestive of IgG-mediated autoimmunity (such as positive autologous serum skin test and low total IgE) identify patients who are unlikely to respond to omalizumab but may respond to cyclosporine A [9, 12]. Conversely, markers consistent with IgE-centered autoallergy, such as high IgE and presence of specific IgE autoantibodies, predict better omalizumab response rates [12]. This biomarker-based approach could lead to preferential consideration of cyclosporine A or BTK inhibitors over omalizumab for patients with IgG-centered autoimmunity [9, 12]. Table 1 presents a comprehensive overview of biomarkers for CSU endotype classification and treatment response prediction, including strength of association ratings, clinical utility, and practical interpretation guidance.

Table 1.

Biomarkers for CSU endotype classification and treatment response prediction

Biomarker	Associated endotype	Clinical utility	Strength of association	Interpretation
Total serum IgE
Elevated (> 100 IU/mL)	Type I (autoallergic)	Predicts omalizumab response	Moderate	Higher IgE correlates with better omalizumab response; low IgE (< 50 IU/mL) suggests type IIb
Low (< 50 IU/mL)	Type IIb (autoimmune)	Predicts omalizumab nonresponse	Moderate	Consider cyclosporine or BTK inhibitors
Peripheral eosinophils
Elevated (≥ 300 cells/μL)	Type I/type II—high	Predicts dupilumab response	Moderate	May indicate better response to IL-4/IL-13 blockade (dupilumab); also associated with anti-IL-5 therapies
Normal/low (< 300 cells/μL)	Type IIb or mixed	Less predictive value	Limited	Does not exclude treatment response
Autologous serum skin test (ASST)
Positive	Type IIb (autoimmune)	Suggests IgG autoantibodies	Moderate	Positive test indicates functional autoantibodies; correlates with omalizumab nonresponse and cyclosporine A response
Negative	Type I or uncertain	Less definitive	Limited	Does not exclude autoimmunity; low specificity
Basophil activation test (BAT)
Positive (CD63+)	Type IIb (autoimmune)	Detects functional autoantibodies	Moderate	More specific than ASST; not widely available
IgE autoantibodies
Anti-TPO IgE	Type I (autoallergic)	Confirms autoallergy	Limited	Specific for type I; research assay, not routine
Anti-IL-24 IgE	Type I (autoallergic)	Confirms autoallergy	Limited	Emerging target; requires validation
IgG autoantibodies
Anti-FcεRI IgG	Type IIb (autoimmune)	Confirms autoimmunity	Moderate	Research assay; not standardized
Anti-IgE IgG	Type IIb (autoimmune)	Confirms autoimmunity	Moderate	Functional significance established
Anti-TPO IgG	Type IIb (autoimmune)	Associated with thyroid autoimmunity	Moderate	May indicate autoimmune comorbidity
Other markers
D-dimer (elevated)	Coagulation activation	Marker of disease severity	Limited	Associated with severe/refractory CSU; not endotype-specific
C-reactive protein (CRP) (elevated)	Systemic inflammation	Nonspecific severity marker	Limited	Elevation suggests active inflammation; not predictive of treatment response
Complement (C3, C4) (low levels)	Complement activation	Research marker	Very limited	Role unclear; not routinely useful

ASST autologous serum skin test, BAT basophil activation test, BTK Bruton’s tyrosine kinase, CSU chronic spontaneous urticaria, TPO thyroid peroxidase

Patient Impact

Disease Activity, Control, and Patient-Reported Outcome Measures

Assessment of CSU encompasses three interrelated concepts: disease activity (objective symptom severity), disease control (achievement of treatment goals), and quality-of-life (QoL) impact (patient-perceived burden) [18].

Disease activity is most commonly measured using the Urticaria Activity Score over 7 days (UAS7), which combines daily wheal count (0–3) and pruritus intensity (0–3) for a total score of 0–42 [19]. Scores are categorized as: well-controlled (0), mild (1–6), moderate (7–15), severe (16–27), and very severe (28–42) [19]. The Angioedema Activity Score (AAS) provides parallel assessment for patients with angioedema [19].

Disease control reflects treatment response and symptom management, assessed through the Urticaria Control Test (UCT), a 4-item patient-reported questionnaire (score 0–16, with ≥ 12 indicating well-controlled disease) [19, 20]. Recent data emphasize that disease control, rather than complete symptom absence, represents a realistic treatment goal for many patients [20].

QoL captures the broader impact on daily functioning, emotional well-being, and social participation, extending beyond symptom severity alone [19, 21]. The comprehensive assessment framework using validated patient-reported outcome measures (PROMs) is essential for holistic CSU management and increasingly recognized as critical for treatment decision-making [19, 20].

Table 2 summarizes the commonly used patient-reported outcome measures (PROMs) for CSU assessment.

Table 2.

Summary of patient-reported outcome measures (PROMs) for CSU assessment

PROM category	Instrument	Domains assessed	Scoring	Interpretation	Use case
Disease activity
Urticaria Activity Score over 7 days (UAS7)	Disease-specific	Wheal count, itch severity	0–42 (7 days)	0 = none; 1–6 = mild; 7–5 = moderate; 16–27 = severe; 28–42 = very severe	Primary endpoint in clinical trials; daily monitoring
Angioedema Activity Score (AAS)	Disease-specific	Angioedema episodes, severity, location	Variable	Higher = worse	Patients with recurrent angioedema
Disease control
Urticaria Control Test (UCT)	Disease-specific	Symptoms, life impact, treatment satisfaction	0–16	≥ 12 = well-controlled; < 12 = poorly controlled	Routine clinical monitoring; simple, quick
Angioedema Control Test (AECT)	Disease-specific	Angioedema control, symptom burden	0–16	≥ 10 = well-controlled	Angioedema-predominant patients
Quality of life (disease-specific)
Dermatology Life Quality Index (DLQI)	Dermatology-specific	Symptoms, daily activities, work, relationships	0–30	0–1 = no effect; 2–5 = small; 6–10 = moderate; 11–20 = very large; 21–30 = extremely large	Most widely used dermatology QoL tool; regulatory trials
Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL)	CSU-specific	Pruritus, swelling, life impact, sleep	0–100	Higher = worse QoL; ≥ 30 = significant impairment	Most specific to CSU; comprehensive
Angioedema Quality of Life Questionnaire (AE-QoL)	Angioedema-specific	Functioning, fatigue/mood, fears/shame, food	0–100	Higher = worse	Angioedema-predominant patients
Quality of life (generic)
Short Form-36 (SF-36)	Generic health	Physical/mental health, functioning, pain	0–100 (8 domains)	Higher = better QoL	Comparison across diseases; health economics
EQ-5D	Generic health	Mobility, self-care, activities, pain, mood	Index + VAS	Index: utility score; VAS: 0–100	Health economics; QALY calculations
Sleep quality
Pittsburgh Sleep Quality Index (PSQI)	Generic sleep	Sleep quality, duration, efficiency	0–21	> 5 = poor sleep quality	Research; comprehensive sleep assessment
Medical Outcomes Study Sleep Scale (MOS-SS)	Generic sleep	Sleep initiation, maintenance, adequacy	Multiple subscales	Higher = worse (except adequacy)	Clinical trials
Psychological burden
Hospital Anxiety and Depression Scale (HADS)	Generic mental health	Anxiety and depression (7 items each)	Each 0–21	0–7 = normal; 8–10 = borderline; 11–21 = abnormal	Screening for anxiety/depression in medical patients
Patient Health Questionnaire-9 (PHQ-9)	Depression-specific	Depressive symptoms	0–27	0–4 = minimal; 5–9 = mild; 10–14 = moderate; 15–19 = moderately severe; 20–27 = severe	Depression screening
Generalized Anxiety Disorder-7 (GAD-7)	Anxiety-specific	Anxiety symptoms	0–21	0–4 = minimal; 5–9 = mild; 10–14 = moderate; 15–21 = severe	Anxiety screening
Work productivity
Work Productivity and Activity Impairment Questionnaire (WPAI)	Generic work impact	Absenteeism, presenteeism, impairment	Percentages (0–100%)	Higher = greater impairment	Economic impact assessment

AAS Angioedema Activity Score, AECT Angioedema Control Test, AE-QoL Angioedema Quality of Life Questionnaire, CSU chronic spontaneous urticaria, CU-Q2oL Chronic Urticaria Quality of Life Questionnaire, DLQI Dermatology Life Quality Index, EQ-5D EuroQol 5-Dimension, GAD generalized anxiety disorder, HADS Hospital Anxiety and Depression Scale, MOS-SS Medical Outcomes Study Sleep Scale, PHQ Patient Health Questionnaire, PSQI Pittsburgh Sleep Quality Index, QALY quality-adjusted life year, QoL quality of life, SF-36 Short Form-36, UAS7 Urticaria Activity Score over 7 days, UCT Urticaria Control Test, VAS visual analog scale, WPAI Work Productivity and Activity Impairment Questionnaire

Quality of Life (QoL) and Daily Functional Impairment

CSU imposes significant burden across multiple domains of daily life beyond skin symptoms [1]. The overall health-related QoL of patients with chronic urticaria has been reported to be similar to levels observed in patients with serious chronic conditions such as coronary artery disease or uncontrolled asthma [21]. The unpredictability of CSU symptoms interferes with basic activities, including walking, sitting, dressing, and bathing [1]. Occupational performance is also impaired, with studies showing that nearly one in five patients with CSU miss at least 1 h of work weekly owing to disease activity [22, 23]. The visibility of skin lesions profoundly affects psychosocial interactions, often leading to embarrassment and reduced social participation [1, 24].

A comprehensive cross-sectional study of Vietnamese patients with CSU from June 2023 to March 2024 demonstrated measurable correlations between disease severity and functional impairment, revealing significant QoL deterioration [25]. Patients with severe disease activity (Urticaria Activity Score over 7 days (UAS7) ≥ 28) showed much greater functional impairment compared with those with mild disease (UAS7 < 16). Facial angioedema was associated with significant reductions in social functioning scores, while prolonged wheals correlated with worsened sleep quality assessment scores [25]. The progressive nature of CSU’s psychosocial burden was particularly evident in long-term cases, with disease duration exceeding 2 years independently associated with higher depression and anxiety scores [25]. While this Vietnamese cohort provides valuable data, cultural, socioeconomic, and healthcare system factors may influence QoL impacts differently across regions. Multiregional studies are needed to confirm these associations across diverse populations. Older studies from Western populations (e.g., O’Donnell et al. 1997) established foundational QoL burden, but contemporary data reflecting current treatment landscapes and varying healthcare access patterns remain limited globally [26].

Economic Burden and Work Productivity Impact

Beyond personal suffering, CSU imposes substantial economic burden on both patients and healthcare systems. Work productivity data from the ASSURE-CSU real-world study indicate that patients with CSU miss an average of 3.2 workdays per month owing to disease activity, with an additional 1.8 days of significantly reduced productivity [27]. These workplace impacts represent a substantial increase over previous estimates of weekly hourly absenteeism [21, 22]. Economic analyses show that patients with uncontrolled CSU (UAS7 ≥ 12) incur healthcare costs 2.7 times higher than those achieving disease control, primarily owing to emergency room visits and additional specialist consultations [28]. Current economic data predominantly derive from high-income countries with established healthcare systems. The economic burden likely varies substantially across regions owing to differences in healthcare access, medication costs, insurance coverage, and work policies. Studies from low- and middle-income countries are critically needed to capture the global economic impact of CSU.

Psychological Burden: Anxiety, Depression, and Stress Interactions

CSU frequently accompanies psychological comorbidities [29]. A substantial number of patients report symptoms of anxiety, depression, or elevated emotional stress, with prevalence estimates indicating that up to one-third of patients with CSU are affected [1, 29]. More than half of these experience moderate-to-severe QoL impairment [1].

A meta-analysis demonstrated significant mental health burden in patients with CSU [25]. Patients with CSU have a sixfold higher probability of developing anxiety or depression compared with the general population [25]. The unpredictability of symptom manifestation significantly compounds psychological distress [1]. Importantly, stress acts as both a trigger and consequence of disease exacerbation, supporting a bidirectional relationship involving neuropeptides and hypothalamic–pituitary–adrenal (HPA) axis dysregulation [30].

Integrated Mental Health Treatment: Clinical Evidence and Case Studies

This bidirectional stress–CSU relationship has important therapeutic implications. While large-scale controlled trials are lacking, emerging case reports and small series indicate that integrating cognitive behavioral therapy (CBT) with selective serotonin reuptake inhibitors (SSRIs) may achieve significant symptom improvement in selected patients, though these findings should be considered hypothesis-generating rather than definitive evidence [31].

A groundbreaking case report published in 2025 provides compelling evidence for the transformative potential of integrated mental health interventions in CSU management [31]. A patient with refractory CSU and generalized anxiety disorder had failed multiple conventional treatments, including high-dose antihistamines, omalizumab, and immunosuppressants, consistently showing severe disease activity despite extensive pharmacological therapy. The breakthrough came when the treatment paradigm shifted to simultaneously address both dermatological and psychological components. This approach included chronic disease-specific cognitive behavioral therapy (CBT) and daily escitalopram 10 mg for anxiety management. Within weeks, remarkable improvement occurred, with complete symptom resolution, allowing discontinuation of biologic therapy [31].

This case demonstrated dynamic stress–CSU relationships, with symptom recurrence during stressful events but rapid recovery of control through psychological interventions, directly illustrating underlying HPA axis mechanisms [30, 31]. While this case provides compelling preliminary evidence, it represents a single patient experience and cannot be generalized. The success of this integrated approach suggests that comprehensive CSU management may benefit from addressing both dermatological and psychological components, though this hypothesis requires validation through controlled trials. Prospective studies with larger patient cohorts, standardized psychological interventions, and objective outcome measures are critically needed before mental health integration can be recommended as standard care [1, 31].

Current evidence supports: (1) screening for anxiety and depression in patients with CSU; (2) considering referral to mental health specialists for patients with significant psychological comorbidity; (3) recognizing that stress management may complement but not replace pharmacological CSU treatment; and (4) future research priority for controlled trials of integrated psychological–dermatological interventions.

Sleep Disturbances and Bidirectional Relationships with CSU

Sleep disturbance is a prominent yet underrecognized symptom of CSU [1]. Pruritus often interferes with sleep initiation and maintenance, with over 50% of patients with CSU experiencing frequent sleep disruptions related to itching [1]. Recent comprehensive studies have quantified the extent and clinical significance of sleep disturbances in patients with CSU. A patient-control study conducted from June 2023 to January 2024 found that 79.1% of patients with CSU had clinically significant sleep quality deterioration [32]. This study provided detailed correlation data demonstrating the interconnected nature of sleep, disease activity, and psychological burden. Patients with poor sleep quality had significantly higher mean UAS7 scores, depression scores, and perceived stress levels compared with those with adequate sleep [32]. These findings confirm that sleep disturbance is not merely a consequence of itching but is intrinsically connected to overall disease severity and psychological impact. These findings from Turkish and Asian cohorts require validation in more diverse populations, as sleep patterns, cultural attitudes toward sleep disorders, and access to sleep medicine specialists vary significantly across regions, potentially influencing the observed relationships.

Population-based cohort studies have established sleep disorders as independent risk factors for subsequent CSU development. Large-scale analyses show that pre-existing sleep disorders significantly increase CSU risk, with the strongest associations observed in sleep apnea and chronic insomnia [33]. This bidirectional relationship suggests that sleep disorders can trigger and perpetuate CSU through inflammatory pathway activation and immune dysregulation [33].

Therapeutic interventions targeting CSU have shown promising effects on sleep quality. Pilot studies indicate that omalizumab treatment can significantly improve sleep efficiency, with sleep improvement often preceding clinical response in most patients [24]. This temporal relationship suggests that sleep quality improvement may serve as an early predictive indicator of therapeutic success in CSU management [24].

Current and Emerging Therapeutic Strategies: Mechanism-Based Reconceptualization

The therapeutic paradigm for CSU is rapidly evolving as understanding of pathophysiological mechanisms deepens. While past approaches were primarily empirical and focused on symptom relief, recent advances are moving toward precision medicine targeting specific molecular pathways related to mast cell activation. This section systematically integrates the latest clinical research findings to present emerging treatment strategies organized by mechanism of action (Table 3). The stepwise treatment approach with evidence levels is shown in Fig. 2.

Table 3.

Treatment options for CSU

Category	Examples	Mechanism of action	Place in therapy
Standard therapies
Second-generation H1 antihistamines	Cetirizine, loratadine, fexofenadine, levocetirizine	Block histamine H1 receptors	First-line; up to fourfold dose increase
Biologics (anti-IgE)	Omalizumab	Binds free IgE; downregulates FcεRI	Second-line for H1-antihistamine-refractory CSU
	Ligelizumab	High-affinity anti-IgE monoclonal antibody	Under development
Biologics (type II inflammation)	Dupilumab	IL-4Rα blocker; inhibits IL-4 and IL-13 signaling	FDA approved (2025) for moderate-to-severe CSU
Immunosuppressants	Cyclosporine A	Calcineurin inhibitor	Third-line option; especially in type IIb endotype
	Tacrolimus	Calcineurin inhibitor	Rarely used; topical/off-label in refractory cases
Emerging therapies
BTK inhibitors	Remibrutinib, rilzabrutinib	BTK inhibitors; suppress mast cell and basophil activation	In clinical trials; may serve as oral alternatives
Anti-KIT antibodies	Barzolvolimab, briquilimab	Anti-KIT monoclonal antibodies; inhibit mast cell activation	Investigational; promising results in early studies
JAK inhibitors	Tofacitinib, ruxolitinib	JAK inhibitors (JAK1/2/3 selective)	Investigational/off-label use; demonstrated efficacy in patients with antihistamine and omalizumab-refractory CSU as oral therapeutic alternatives
Biologics (other cytokine)	Mepolizumab, secukinumab, tildrakizumab	Anti-IL-5, anti-IL-17, anti-IL-23	Investigational; some efficacy in omalizumab-refractory patients
	Tezepelumab	Anti-TSLP monoclonal antibody	Investigational; phase 2 results anticipated
Novel pathway inhibitors	EP262	MRGPRX2 antagonist (IgE-independent)	Phase 2 clinical trials; targets IgE-independent mast cell activation
	Eculizumab, avdoralimab	Complement C5 and C5aR inhibitors	Investigational; aimed at autoimmune pathways
Supportive care
Nonpharmacological	Cold compress, oatmeal baths, vitamin D	Supportive measures; vitamin D may help with symptom control	Adjunctive measures
Mental health interventions	CBT, SSRIs (e.g., escitalopram)	Address bidirectional stress–CSU relationship; modulate HPA axis dysregulation	Essential for refractory cases with psychological comorbidity

BCR B cell receptor, BTK Bruton’s tyrosine kinase, CBT cognitive behavioral therapy, CSU chronic spontaneous urticaria, FcεRI high-affinity IgE receptor, FDA US Food and Drug Administration, IL interleukin, JAK Janus kinase, MRGPRX2 Mas-related G protein-coupled receptor X2, SSRI selective serotonin reuptake inhibitor, TSLP thymic stromal lymphopoietin

Fig. 2.

CSU treatment algorithm with evidence levels. Clinical evaluation includes biomarker assessment (total immunoglobulin E (IgE), peripheral eosinophil counts, autologous serum skin test (ASST), basophil activation test (BAT), anti-thyroid peroxidase (TPO) antibodies), symptom scoring tools (Urticaria Activity Score over 7 days (UAS7), Urticaria Control Test (UCT), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Angioedema Activity Score (AAS), Dermatology Life Quality Index (DLQI)), and recognition of quality-of-life impairment due to anxiety, depression, or sleep disturbance. Management begins with second-generation H1 antihistamines (step 1–2), followed by add-on omalizumab in antihistamine-refractory patients (step 3). Dupilumab is US Food and Drug Administration (FDA) approved as an alternative biologic option (step 4), particularly in patients with type II inflammatory features. Emerging therapies such as Bruton’s tyrosine kinase (BTK) inhibitors and anti-KIT antibodies are investigational, while cyclosporine A and Janus kinase (JAK) inhibitors may be considered as add-on options in selected cases. Evidence strength: ★★★★★ = FDA/European Medicines Agency (EMA) approved with extensive real-world data; ★★★★ = strong guideline recommendation; ★★★ = guideline-mentioned with randomized controlled trial (RCT) evidence; ★★ = limited data or investigational. Treatment selection should consider clinical endotypes, disease severity, comorbidities, and shared decision-making. AAS angioedema activity score, ASST autologous serum skin test, BAT basophil activation test, BTK Bruton’s tyrosine kinase, CSU chronic spontaneous urticaria, CU-Q2oL Chronic Urticaria Quality of Life Questionnaire, DLQI Dermatology Life Quality Index, EMA European Medicines Agency, FDA US Food and Drug Administration, FcεRI high-affinity IgE receptor, IgE immunoglobulin E, IgG immunoglobulin G, IL interleukin, JAK Janus kinase, MRGPRX2 Mas-related G protein-coupled receptor X2, RCT randomized controlled trial, TPO thyroid peroxidase, UAS7 Urticaria Activity Score over 7 days, UCT Urticaria Control Test

Standard Therapies: Mechanism-Based Reclassification and Enhancement

Standard treatment follows international guideline-recommended stepwise approaches, with each step based on clear mechanisms of action [1].

Mast Cell Mediator Blockade: Second-Generation H1 Antihistamines

Second-generation H1 antihistamines (cetirizine, loratadine, fexofenadine, levocetirizine) are recommended as first-line pharmacological treatment for CSU [1]. These medications selectively block histamine binding to H1 receptors on blood vessels and nerves, suppressing wheals and pruritus [34]. Their mechanism extends beyond simple receptor blockade to include “inverse regulation” that stabilizes receptors in inactive states [35]. Compared with first-generation antihistamines, they have lower central nervous system penetration, resulting in fewer side effects such as sedation [36].

For patients not responding to standard doses, guidelines recommend dose escalation up to fourfold to enhance therapeutic efficacy [1]. Multiple studies have demonstrated the safety and effectiveness of high-dose therapy, though drowsiness risk may increase in some patients [37–41]. Nevertheless, approximately 50% of patients fail to achieve complete symptom control despite antihistamine escalation therapy, necessitating next-step treatment [1, 27].

Mast Cell Activation Inhibition (IgE Pathway): Anti-IgE Biologics

For patients refractory to high-dose antihistamines, approaches that inhibit mast cell activation itself are required. The most critical treatment in this category is biologics targeting the IgE pathway.

• Omalizumab: This drug serves as the cornerstone of second-line therapy for patients with insufficient response to antihistamines [1]. Omalizumab binds to circulating free IgE, preventing IgE binding to high-affinity IgE receptors (FcεRI) on mast cells and basophils. This induces FcεRI downregulation and consequently inhibits mast cell degranulation and inflammatory mediator release [1, 42]. Clinical trials and real-world data show that omalizumab is effective in 70–85% of patients with antihistamine-resistant CSU, significantly improving UAS7 scores, pruritus, and QoL [1, 22, 23]. The 2025 EXOTIC trial is evaluating the effectiveness of dose interval extension strategies in patients with good initial response, representing ongoing efforts to optimize long-term treatment [35].

• Ligelizumab: A next-generation anti-IgE antibody with 50-fold higher IgE binding affinity than omalizumab, showing promising initial clinical results [1, 43, 44]. Despite being superior to placebo, the November 2023 phase 3 PEARL study results failed to demonstrate superiority over omalizumab as the key comparator, leading to development challenges [36, 37, 43, 45].

Broad Immune Modulation: Traditional Immunosuppressants

For patients with severe and refractory CSU who have failed both high-dose antihistamines and biologics, systemic immunosuppressants may be considered. These medications exert effects by suppressing the overall immune system rather than specific pathways.

• Cyclosporine A: A potent immunosuppressant that inhibits calcineurin to prevent T cell activation [46]. Before omalizumab introduction, it was a major treatment option for antihistamine-refractory patients and is currently considered after biologic failure [1, 47, 48]. On the basis of biomarker studies, it demonstrates particular efficacy in patients with type IIb endotype CSU with positive autologous serum skin test (ASST) and low total IgE levels (< 50 IU/mL), reflecting its mechanism of suppressing T cell-dependent B cell activation and autoantibody production [9, 12]. However, careful use is required owing to potential side effects, including hypertension and nephrotoxicity [1, 49].

Novel Targeted Therapies: Systematic Integration of Latest Research

The future of CSU treatment depends on developing new drugs that precisely target various signaling pathways related to mast cells. The following systematically organizes the latest research trends by mechanism of action.

Mast Cell Depletion and Functional Silencing

This approach represents one of the most innovative strategies that goes beyond blocking mast cell signals to reducing mast cell numbers or paralyzing their function. However, current evidence is limited to early phase studies, and long-term clinical relevance has yet to be established [21]. Evidence to date remains preliminary and is primarily derived from phase 2 trials and conference presentations, with peer-reviewed long-term data still pending. Sustained treatment responses and validated biomarkers require further investigation.

Anti-KIT antibodies: These target the KIT receptor (CD117) essential for mast cell survival and differentiation [50]. Blocking this receptor leads to mast cell depletion through apoptosis [51, 52].

• Barzolvolimab (CDX-0159): The 52-week extension of a phase 2 study, reported only as a meeting abstract at EAACI 2025 (not yet peer reviewed), demonstrated sustained improvement in angioedema activity. However, these findings remain preliminary and require confirmation through peer-reviewed publication and adequately powered phase 3 trials [53].

• Briquilimab (JSP191): An anti-KIT antibody with similar mechanisms to barzolvolimab, currently in phase 1b/2a clinical trials. Evidence remains insufficient to draw conclusions regarding long-term clinical impact [54].

• Evidence limitations: It is important to note that current evidence for anti-KIT antibodies comes primarily from phase 2 studies and conference presentations, with peer-reviewed phase 3 data still pending. Long-term efficacy, durability of response after treatment discontinuation, and real-world effectiveness require confirmation in well-controlled trials.

Table 4 provides a detailed comparison of evidence levels for emerging CSU therapies, clearly distinguishing peer-reviewed phase 3 randomized controlled trials from phase 2 studies and preliminary conference reports to guide appropriate interpretation of efficacy and safety claims.

Table 4.

Evidence levels and assessment of emerging agents in CSU

Agent	Evidence type	Study phase	Long-term outcomes	Status
BTK inhibitors
Remibrutinib	Peer reviewed	Phase 3 RCT	Requires validation	In development
Rilzabrutinib	Peer reviewed	Phase 2 RCT	Requires validation	In development
Anti-KIT antibodies
Barzolvolimab	Meeting abstract	Phase 2 extension	Preliminary data only	Early stage
Briquilimab	ClinicalTrials.gov	Phase 1b/2a	Too early to assess	Early stage
JAK–STAT inhibitors
Tofacitinib	Case series	Off-label use	Not established	Off-label
Ruxolitinib	Case series	Off-label use	Not established	Off-label
Type II biologic
Dupilumab	Peer reviewed	Phase 3 RCT	Not established	FDA approved
Ani-IgE biologic
Ligelizumab	Peer reviewed	Phase 3 RCT	Not established	Discontinued (development suspended for CSU indication following phase 3 results)
Cytokine-targeted
Mepolizumab	Case series	Off-label use	Not established	Off-label
Secukinumab	Case reports	Off-label use	Not established	Off-label
Tezepelumab	Clinical registry	Phase 2 ongoing	Under investigation	In development
Novel mechanisms
EP262 (MRGPRX2)	Clinical registry	Phase 2 ongoing	Under investigation	In development
Eculizumab	Preclinical	Research stage	Too early to assess	Early stage

BTK Bruton’s tyrosine kinase, CSU chronic spontaneous urticaria, FDA US Food and Drug Administration, MRGPRX2 Mas-related G protein-coupled receptor X2, RCT randomized controlled trial, JAK–STAT Janus kinase–signal transducer and activator of transcription

Mast Cell Activation Signaling Pathway Blockade

Oral small-molecule drugs that inhibit key signaling molecules within mast cells to fundamentally block activation are being actively developed.

BTK inhibitors: BTK is a key enzyme involved in both FcεRI (IgE-mediated) signaling and B cell receptor (BCR, autoantibody production) signaling [27]. Therefore, BTK inhibitors have a powerful dual mechanism of action that simultaneously blocks both major pathogenic pathways of CSU. However, current clinical studies evaluate symptomatic improvement during treatment, and long-term outcomes after treatment discontinuation have not been established.

• Remibrutinib: Phase 3 trials have demonstrated rapid and sustained symptom control with favorable safety profiles [23, 35], with network meta-analysis showing the highest complete response probability among BTK inhibitors [22, 35]. Nonetheless, available studies assess only on-treatment responses, and long-term durability of response has not yet been demonstrated.

• Rilzabrutinib: Phase 2 RILECSU trial results completed in April 2024 demonstrated rapid and sustained improvement in pruritus, urticaria activity, and angioedema in antihistamine-refractory patients [55]. However, data on long-term outcomes and durability of response after treatment discontinuation are not yet available.

Janus kinase (JAK) inhibitors: The Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway is essential for intracellular signal transduction of various inflammatory cytokines [56, 57]. JAK inhibitors block this pathway to exert broad anti-inflammatory effects.

• Tofacitinib (JAK1/3 inhibitor) and ruxolitinib (JAK1/2 inhibitor) have shown efficacy in patients with refractory CSU [36, 56, 58].

Safety Considerations for JAK Inhibitors:

While JAK inhibitors show promise in refractory CSU, their use remains off-label and requires careful patient selection and monitoring. Based on experience in approved indications (rheumatoid arthritis, atopic dermatitis (AD)), potential risks include increased infection risk, herpes zoster reactivation, cytopenias, lipid abnormalities, and cardiovascular/thromboembolic events [59, 60].

Recommended monitoring for off-label JAK inhibitor use in CSU includes: (1) baseline and periodic complete blood counts, liver function tests, and lipid panels; (2) screening for latent tuberculosis and hepatitis B/C; (3) assessment of cardiovascular risk factors; and (4) patient education regarding infection signs and vaccination status (including herpes zoster vaccination if eligible) [60, 61].

Given these safety considerations, JAK inhibitors should be reserved for patients with severe, refractory CSU after failure of approved therapies, with shared decision-making regarding risks and benefits [59–61].

Cytokine and Novel Pathway-Targeted Therapies: Dupilumab (Anti-IL-4/IL-13)

Treatments targeting various cytokines and novel receptors involved in CSU pathogenesis beyond IgE are being developed.

Dupilumab is a fully human monoclonal antibody targeting the IL-4 receptor alpha subunit, thereby blocking both IL-4 and IL-13 signaling—key cytokines driving type 2 inflammation. Originally approved for moderate-to-severe atopic dermatitis and asthma, dupilumab received FDA approval on 18 April 2025 for moderate-to-severe CSU in adult and adolescent patients (12 years and older) who remain inadequately controlled with H1 antihistamines, with or without prior omalizumab treatment. This represents the first new targeted therapy approved for CSU in over a decade [1].

Clinical evidence: The pivotal phase 3 LIBERTY-CSU CUPID trials (CUPID-1 and CUPID-2) demonstrated significant improvements in weekly Urticaria Activity Score over 7 days (UAS7), itch severity, angioedema, sleep quality, and dermatology-specific quality of life compared with placebo [62]. Response was observed across diverse patient populations, including those with prior omalizumab failure.

Endotype considerations: Dupilumab’s mechanism suggests potential preferential efficacy in patients with type 2 inflammation signatures (elevated eosinophils, IgE, or type 2 cytokines) [62]. However, phase 3 data showed benefit across biomarker subgroups, suggesting broader applicability than initially hypothesized [62]. Patients with higher baseline eosinophil counts (≥ 300 cells/μL) demonstrated numerically greater responses, though benefit was seen across the spectrum [62].

Treatment sequencing: In real-world practice, treatment escalation typically follows current guideline-based stepwise management, beginning with second-generation H1 antihistamines (up to fourfold dosing when required) and progressing to omalizumab as the preferred second-line biologic owing to its extensive real-world evidence and favorable safety profile [1]. For patients who remain refractory, dupilumab has emerged as an alternative biologic option, particularly in individuals with clinical or biomarker features of type 2 inflammation—such as elevated eosinophils or comorbid atopic dermatitis or asthma—while maintaining efficacy even after omalizumab failure [62]. BTK inhibitors may be prioritized when available, especially in patients with suspected type IIb autoimmune CSU [27, 36]. Cyclosporine A remains an option in selected refractory cases, although its use is limited by safety considerations and the need for laboratory monitoring [9, 12]. Real-world treatment selection often incorporates endotype-based reasoning when available, while also considering comorbidities, patient preference (biologic versus oral therapy), safety profile, and access or insurance constraints [13, 63].

Other Cytokine-Targeted Agents:

• Anti-IL-17 (secukinumab), anti-IL-23 (tildrakizumab): Some studies have shown efficacy in omalizumab-refractory patients [64, 65].

• Anti-IL-5 (mepolizumab, reslizumab): Effects have been reported in patients with high eosinophil counts [25, 66].

• Anti-TSLP (tezepelumab): Blocks TSLP, a key epithelial-derived alarmin, with phase 2 results anticipated [54, 67].

MRGPRX2 antagonists: MRGPRX2 is an important receptor that activates mast cells independently of IgE [35, 68]. Known to be involved in urticarial reactions from certain drugs or neuropeptides, it is emerging as a novel therapeutic target for CSU [16, 68]. Oral small-molecule antagonists such as EP262 are currently in phase 2 clinical trials [35, 66].

Complement pathway inhibitors: The complement system plays a crucial role in type IIb endotype CSU pathogenesis through C5a-mediated mast cell and basophil activation [39].

• Eculizumab: A humanized monoclonal antibody that binds complement protein C5, preventing the generation of C5a and formation of the membrane attack complex. Originally approved for paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, eculizumab is being investigated for complement-mediated inflammatory conditions, including CSU [39].

• Avdoralimab: A C5aR antagonist that specifically blocks C5a receptor signaling, preventing C5a-induced mast cell and basophil degranulation. This targeted approach may be particularly beneficial in patients with type IIb endotype CSU with evidence of complement activation [39].

Access, Cost, and Implementation Challenges for Novel Therapies

Although biologics and emerging targeted therapies have expanded treatment options for CSU, access and affordability remain major barriers to global implementation. These agents are substantially more expensive than traditional therapies, with annual costs for omalizumab reported between US $15,000 and $30,000, and dupilumab at similar or higher levels owing to more frequent dosing requirements [28]. BTK inhibitors and other oral targeted agents currently in development are also expected to be costly, and generic alternatives for most advanced therapies are not yet available [34, 36].

Real-world data demonstrate significant geographic and socioeconomic disparities in access to these treatments [34]. Delays in regulatory approval across low- and middle-income countries, restrictive insurance policies, and prior authorization requirements limit timely treatment initiation. Furthermore, limited availability of specialists trained to prescribe and monitor biologics, along with high out-of-pocket costs, continues to restrict equitable access—even in countries where these therapies are approved [28, 34]. These barriers underscore the need for cost-effectiveness strategies, health policy reform, and improved access models to ensure that innovations in CSU management translate into real-world benefit.

Supportive Therapies and Lifestyle Modifications

Alongside pharmacological treatment, nonpharmacological strategies play supportive roles in CSU management [1]. Patients are advised to avoid known exacerbating factors, including nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, emotional stress, high temperatures, and physical pressure on the skin [1]. Simple home remedies such as cool compress application (not ice directly on skin) [19], topical antipruritic use, lukewarm colloidal oatmeal baths [69], and wearing loose, breathable cotton clothing can help alleviate symptoms [1]. In addition, observational evidence suggests potential benefits of vitamin D supplementation in some patients with CSU with vitamin D deficiency, though randomized controlled trials are limited, and routine supplementation cannot be universally recommended [70]. These strategies should be viewed as adjunctive measures that may help reduce symptom burden but cannot replace pharmacological treatment for disease control. Patient education about these interventions is an essential component of holistic CSU treatment [1].

Patient Education and Healthcare System Improvement

Common Misconceptions and Educational Needs

One widespread misconception about CSU is its association with allergic reactions [1]. Many patients incorrectly attribute their symptoms to foods, environmental exposures, or contact allergens [1]. However, allergy testing such as skin prick tests or serum-specific IgE assays provides little diagnostically useful information in CSU, and elimination diets are rarely effective [1, 71]. It is also important to correct the misconception that CSU is contagious. Although visible symptoms may cause concern in social settings, it is not transmissible [1]. While factors such as stress, infections, or medications may exacerbate symptoms, they act as aggravating factors rather than root causes [1]. Understanding this difference can help reduce unnecessary worry and redirect efforts from searching for “triggers” to appropriate management [1]. Moreover, underlying causes are unknown in 80–90% of CSU cases, supporting why this condition is called “spontaneous” rather than having identifiable triggers [1]. This diagnostic uncertainty can frustrate patients and lead to prolonged searches for specific causative substances, but such efforts are usually unproductive [1].

Healthcare System Challenges and Implementation Gaps

Real-world data reveal significant CSU management challenges extending beyond individual patient care. Recent healthcare system studies show considerable diagnostic delays and treatment optimization gaps compared with clinical trial environments [34, 71]. These implementation problems include diagnostic delays, suboptimal antihistamine use, and regional disparities in advanced treatment access [34]. Treatment utilization patterns show substantial regional differences in biologic accessibility that cannot be explained by disease severity alone, suggesting healthcare system and insurance coverage factors as major barriers [34]. Real-world effectiveness data demonstrate efficacy gaps between clinical trials and routine practice, attributable to diagnostic delays, insufficient first-line treatment dosing, and delayed initiation of appropriate second-line therapy [34].

Systematic Educational Interventions and Outcomes

Educational interventions addressing these misconceptions and system gaps play pivotal roles in promoting accurate disease understanding and improving patient outcomes [1]. New evidence indicates that integrated education programs targeting both patients and healthcare providers can significantly shorten diagnostic timelines and greatly enhance treatment success rates [13]. Systematic approaches combining patient education campaigns, clinician training programs, and structured treatment pathways show promise in reducing diagnostic delays, improving treatment adherence, and optimizing healthcare resource utilization [13]. These findings emphasize the essential roles of patient-centered care, clinician awareness, and shared decision-making in effective CSU management [13, 63]. The success of these integrated approaches supports implementing comprehensive educational strategies as standard components of CSU care to address broader challenges of disease recognition, appropriate treatment selection, and patient empowerment beyond traditional symptom management [13].

Discussion

Encouragingly, therapeutic advances have transformed CSU management. Second-generation H1 antihistamines remain the recommended first-line treatment, while biologics such as omalizumab and the recently FDA-approved dupilumab have demonstrated meaningful symptom improvement in antihistamine-refractory patients [1]. In addition, development of novel agents—including anti-KIT antibodies, BTK inhibitors, JAK inhibitors, and MRGPRX2 antagonists—is accelerating the transition to precision medicine by introducing strategies such as mast cell depletion or IgE-independent pathway blockade [19, 27, 41, 46, 49, 51]. The emergence of targeted therapies such as BTK inhibitors and anti-KIT antibodies represents an important conceptual advance; however, long-term studies are needed to determine their sustained efficacy and long-term clinical impact beyond symptomatic improvement during active treatment.

Clarifying common misconceptions about CSU, particularly that it is neither allergic nor contagious, is crucial [1]. Through accurate patient education and targeted therapeutic interventions, individuals can experience significant symptom relief and improved QoL. The integration of psychological interventions, as demonstrated by successful case reports combining cognitive behavioral therapy with standard dermatological treatment, further underscores the importance of holistic care approaches addressing both physical and mental health.

Limitations

This narrative review has several important limitations. Our literature synthesis focused primarily on English-language publications from 2020 to 2025 (emphasizing 2023–2025), with selective inclusion of foundational earlier studies, which may have introduced language bias and underrepresented research from non-English-speaking regions. The heterogeneity of study designs and outcome measures across included literature limits direct comparisons. Furthermore, the lack of long-term real-world data for several emerging therapies constrains the generalizability of some conclusions.

Conclusions

Understanding of chronic spontaneous urticaria (CSU) has significantly evolved from a poorly characterized “idiopathic” condition to a mechanism-based autoimmune disease with clear therapeutic targets. This shift from empirical symptom management toward precision medicine reflects meaningful progress, driven by advances in endotype characterization and targeted therapies.

Future research should prioritize validation of predictive biomarkers across diverse populations, optimization of treatment sequencing strategies, and long-term real-world safety evaluation of emerging agents. Equitable access to advanced therapies and integration of psychological and quality-of-life (QoL) considerations into routine care will be essential to achieve sustained disease control and improve global outcomes for patients living with CSU.

Author Contributions

Han B. Kim: conceptualization, literature search, and writing—original draft preparation; Ji Y. Um: investigation and writing—review and editing; Bo Y. Chung: writing—review and editing; Chun W. Park: conceptualization; Hye O. Kim: supervision, conceptualization, and writing—review and editing.

Funding

This study was funded by the National Research Foundation of Korea (NRF) (grant no. RS-2022-NR070251), a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no. RS-2023-KH141546), and by Hallym University Research Fund. The journal’s Rapid Service Fee was funded by the authors.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. This review is based on previously published literature, all of which is cited in the reference list.

Declarations

Conflict of Interest

Han B. Kim has nothing to disclose. Ji Y. Um has nothing to disclose. Bo Y. Chung has nothing to disclose. Chun W. Park has nothing to disclose. Hye O. Kim has nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.