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

Abstract

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

Introduction

Chronic Spontaneous Urticaria (CSU) is a debilitating inflammatory skin disorder affecting approximately 1% of the global population,¹ predominantly women aged 30–50 years.² Higher prevalence has been reported in Asian populations,¹ and variation in access to guideline-recommended therapies across regions and healthcare systems may contribute to treatment disparities, potentially influencing disease outcomes.³ The disease is defined by spontaneous, recurrent, pruritic wheals (hives), angioedema, or both, persisting for ≥ 6 weeks.⁴ Despite being considered a self-limiting disease there remains a substantial need for effective treatment, as the unpredictable and disruptive nature of symptoms can significantly impair patients’ quality of life and work performance. Furthermore, CSU is associated with an increased risk of mental health disorders, including depression and anxiety⁵ and even suicidal behavior.⁶

First-line treatment consists of standard dose second-generation antihistamines (sg-AH), up-dosed up to fourfold if symptoms persist. For patients who remain uncontrolled, omalizumab is added.⁴ Other options include newly approved therapies such as dupilumab or remibrutinib, off-label agents like leukotriene receptor antagonists, and, in select severe cases, cyclosporine.⁴ As no current therapy can cure the disease or shorten its course, the primary therapeutic goal is to achieve disease control until spontaneous remission occurs.⁴ Disease control is typically evaluated using patient-reported outcome measures (PROMs), including the Urticaria Control Test (UCT) and the weekly Urticaria Activity Score (UAS7). Complete symptom control, indicating a complete absence of symptoms, is defined as a UCT score of 16 or a UAS7 score of 0,^4,7 whereas well-controlled disease is defined as a UCT score ≥12 or UAS7 score ≤6.⁴

Advances in treatment have been driven by growing insights into the pathophysiology of CSU, though it remains complex and not fully understood. Mast cell and basophil activation, with subsequent release of mediators such as histamine, is however recognized as a central driver.^8,9 Two endotypes with distinct pathways of mast cell and basophil activation have been described. The most common, autoallergic or type I CSU, involves immunoglobulin E (IgE) autoantibodies that cross-link self-antigens on the high-affinity IgE receptor, Fc epsilon receptor I (FcεRI).⁸ The second, autoimmune or type IIb CSU, is driven by immunoglobulin G (IgG) autoantibodies targeting either FcεRI or IgE bound to the receptor on mast cells and basophils.⁸ It can be identified by triple positivity: a positive autologous serum skin test (ASST), IgG autoantibodies against FcεRI and/or IgE, detected by immunoassays, and a positive basophil test result, such as the basophil activation test (BAT) and/or basophil histamine release assay (BHRA).¹⁰ Although the two endotypes of CSU have traditionally been considered distinct, recent evidence suggests they may coexist.¹¹ Moreover, some patients exhibit neither type I nor type IIb features (non–type I/non–type IIb CSU),¹² in whom mast cell activation may be driven by mechanisms independent of FcεRI, such as the Mas-related G protein–coupled receptor X2 (MRGPRX2).^11,13 These insights not only enhance our understanding of CSU endotypes and the underlying pathophysiology but also provide novel targets for therapeutic development. Herein, we provide an overview of approved and emerging therapeutic options that may support the achievement of disease control in patients with CSU.

Current Treatments for CSU

The treatments discussed in the following section include those recommended by the international CSU treatment guidelines from 2025, as well as approved therapies that may be used off label. An overview of each agent’s mechanism of action is shown in Figure 1, while Figure 2 presents the treatment algorithm for CSU. Therapies and their current trial status are summarized in Table 1.

Figure 1.

Pathophysiology of chronic spontaneous urticaria, illustrating mechanisms of approved (black) and emerging (grey) therapies.

Figure 2.

Treatment algorithm for chronic spontaneous urticaria, modified based on current clinical guidelines. ^a The preferred first-line option, supported by the strongest evidence and licensed in most countries. ^b Option for severe, treatment-refractory CSU, particularly type IIb autoimmune CSU. ^c Other therapies with limited evidence (eg, leukotriene receptor antagonists, H2-antagonists, dapsone, phototherapy, sulfasalazine, methotrexate, interferon, plasmapheresis, IV immunoglobulins) may be considered at any stage in the algorithm.

Abbreviations: CSU, Chronic spontaneous urticaria; IV, Intravenous; sg-AH, Second-generation antihistamines.

Table 1.

Overview of Approved and Emerging Therapies for Chronic Spontaneous Urticaria, Including the Primary Targets, Routes of Administration, Recommended Doses, Endotype Relevance, Common Adverse Effects, and Current Approval Status

Treatment	Primary Target	Route	Recommended Dose	Most Common Side Effects	Response Across Endotypes	Status
H1-Antihistamines	H1 receptor blockade	Oral	Up to 4 x standard dose daily*	Drowsiness, somnolence, dry mouth	Effective in both endotypes; responses generally stronger in type I	Approved
Omalizumab	Anti-IgE	Subcutaneous	300 mg Q4W Off label dose modification**	Injection site reactions, headache, fatigue	Effective in both; more rapid and robust responses in type I	Approved in 2014
Remibrutinib	BTK-inhibition	Oral	25 mg BID	Nasopharyngitis, petechiae, headache, nausea, abdominal pain	Effective in both; may be particularly effective in type IIb	Approved in 2025
Dupilumab	IL-4Rα blockade	Subcutaneous	≥18 yrs or 12–17 yrs ≥60 kg: 600 mg loading dose, then 300 mg Q2W; 12–17 yrs 30–<60 kg: 400 mg loading dose, then 200 mg Q2W	Injection site reactions, increased risk of infections	Effective across endotypes; evidence indicates efficacy smaller in omalizumab non-responders	Approved in 2025
Cyclosporine	Calcineurin inhibition	Oral	3.5–5 mg/kg/day	Hyperlipidemia, headache, renal impairment, immunosuppression	Primarily effective in type IIb	Not approved Off label use
c-KIT-inhibitors	c-KIT-inhibition	Subcutaneous	Investigational 150 mg Q4W or 300 mg Q8W	Hair color change, neutropenia, skin hypopigmentation, nasopharyngitis	Likely beneficial across endotypes	Not yet approved Phase 3 ongoing
JAK-inhibitors	JAK-inhibition	Oral	Investigational 75 mg QD	Investigational	Potential across both endotypes	Not yet approved Phase 2 completed
MRGPRX2-antagonists	MRGPRX2-antagonism	Oral	Investigational	Investigational	Potential in non-type I/ Type IIb CSU	Not yet approved Phase 2 ongoing
IL-2	Regulatory T cells	Intramuscular	Investigational 1.0 MIU daily for 7 days	Investigational	Potentially most effective in type IIb CSU	Not yet approved Currently recruiting for phase 2
Rilzabrutinib	BTK-inhibition	Oral	Investigational 1200 mg daily	Diarrhea, nausea, headache	Effective in both; may be particularly effective in type IIb	Not yet approved Phase 2 completed
Tezepelumab	Anti-TSLP	Subcutaneous	Investigational 210 mg Q2W or 420 mg Q4W	Headache, urticaria, pyrexia	Possible benefit in type IIb / Iow-IgE subgroup	Not yet approved Phase 2 completed

Notes: *Exact dosing varies by the specific antihistamine **Dose escalation or interval shortening up to 600 mg Q2W (guided by patient symptoms and physician experience).

Abbreviations: BID, Twice daily; BTK, Bruton’s tyrosine kinase; c-KIT, KIT receptor; IgE, Immunoglobulin E; IL-2, Interleukin-2; IL-4Rα, Interleukin-4 receptor α chain; JAK, Janus kinase; kg, Kilogram; mg, Milligram; MIU, Million International Units; MRGPRX2, Mas-related G-protein coupled receptor X2; TSLP, thymic stromal lymphopoietin; QD, Daily dose; Q2W, Every two weeks; Q4W, Every four weeks; Q8W, Every eight weeks; yrs, Years.

Antihistamines

Histamine is the primary mediator released by activated mast cells and basophils. Antihistamines therefore represent the cornerstone of treatment in CSU. These agents primarily exert their effect by inhibiting histamine signaling at peripheral H₁ receptors, thereby limiting histamine-driven vasodilation, increased vascular permeability, and sensory nerve activation responsible for wheal formation, angioedema, and pruritus.¹⁴ Second-generation H₁-antihistamines are preferred in clinical practice due to their minimal penetration of the blood-brain barrier, which reduces central nervous system adverse effects, particularly sedation.¹⁴

International guidelines therefore recommend initiating therapy with standard-dose sg-AH,⁴ such as cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, and bilastine, which are generally well tolerated, with mild sedation being the most common adverse effect.^4,14

However, according to a 2016 systematic review and meta-analysis, standard dose sg-AH only provides adequate disease control in less than half of patients, with a pooled response rate of 38.6% (95% CI: 34.7–42.7).^15,16 For patients with insufficient control on standard doses, guidelines recommend increasing the dose up to fourfold as second-line therapy.⁴ This approach yields symptom control in 63.2% (95% CI: 57–69.6) of patients who are refractory to the standard dose¹⁶ and is generally considered safe, although the risk of side effects increases.¹⁷

Combination therapy with different sg-AH is not advised, as evidence does not show superiority over up-dosing a single agent.¹⁸ Furthermore, no specific sg-AH has been shown to be more effective than others, and selection therefore relies on the physician’s experience.^4,14

First-generation H₁-antihistamines are no longer recommended in clinical practice because of central nervous system effects related blood-brain barrier penetration, including sedation, drowsiness, psychomotor impairment, and even coma.^4,14

In case of inadequate disease control on fourfold sg-AH, add-on therapy is recommended after 2–4 weeks, or earlier if symptoms are intolerable, to reduce the impact of persistent symptoms.^4,14

In special patient populations, such as children and pregnant or lactating women, sg-AH are considered first-line therapy.⁴ In pediatric populations, bilastine,¹⁹ cetirizine,²⁰ desloratadine,^21,22 fexofenadine,²³ levocetirizine,²⁴ loratadine,²⁰ and rupatadine²⁵ have demonstrated efficacy and safety, although licensed ages vary between countries. Up-dosing regimens in children are not well studied and should be considered on an individual basis.⁴

In pregnant women, systemic treatment should generally be limited, particularly during the first trimester. However, adequate disease control remains important, as emergency referrals for chronic urticaria have been associated with an increased risk of preterm birth.²⁶ Second-generation antihistamines are the preferred first-line therapy, as they have not been linked to an increased risk of birth defects or preterm births, although data are limited,^27,28 and up-dosing should be approached with caution.⁴ In lactating woman, sg-AH are also preferred due to their favorable safety profile.⁴

Omalizumab

Omalizumab, a monoclonal anti-IgE antibody, binds to circulating IgE and downregulates the expression of FcεRI on mast cells and basophils, thereby reducing their activation and degranulation.² Following the approval of omalizumab for CSU by the Food and Drug Administration (FDA) in 2014, it has become the most extensively studied and established therapeutic option for patients with antihistamine-refractory CSU. It is therefore recommended as add-on treatment to fourfold-dose sg-AH for patients aged ≥12 years.^2,4 The FDA-approved standard dose is 300 milligram (mg) every four weeks (Q4w) administered subcutaneously.⁴

Several studies have demonstrated the clinical efficacy of omalizumab. A 2021 systematic review and meta-analysis by Nochaiwong et al included nine randomized controlled trials comprising 1,126 patients treated with omalizumab 300 mg Q4W versus placebo. The pooled analysis showed a standardized mean difference (SMD) of –0.77 (95% CI: –0.91 to –0.63), indicating a moderate effect of omalizumab on urticaria symptoms.²⁹ In addition, a separate systematic review and meta-analysis reported significant improvements in health-related quality of life (HRQoL), with an SMD of –0.53 (95% CI: –0.67 to –0.39) within 12 weeks of therapy and sustained thereafter.³⁰ Evidence from real-world studies further supports these findings with a meta-analysis including 97 studies reporting substantial symptom improvement, with 72.2% of patients achieving a complete response and 17.8% a partial response across various dosing regimens.³¹ Omalizumab is generally well-tolerated and considered safe for long term use,² with adverse events reported in approximately 4% of patients, the most common being headache, fatigue, and injection-site reactions.^31,32

In patients who achieve disease control with omalizumab, gradual treatment reduction is often implemented, either by dose reduction or by prolonging treatment intervals, with the aim of eventual discontinuation.³³ In case of relapse, treatment may be reintroduced following the same treatment regimen.²

Notably, in around one fourth to one third of patients with CSU the standard dosing regimen with omalizumab is insufficient to achieve disease control.³⁴ Type IIb CSU has been associated with a poorer and slower treatment response compared with type I CSU,^10,34 likely reflecting mechanistic differences, with direct IgE neutralization in type I CSU and slower FcεRI downregulation in type IIb CSU.³⁵ In cases of insufficient disease control, up-dosing may be considered by increasing the dose or shortening the treatment interval, based on symptoms, up to 600 mg every two weeks (Q2W), although these regimens remain off label.⁴ If disease control remains suboptimal, other therapies, including newer targeted therapeutic options, are recommended.⁴

One of the major limitations of omalizumab therapy is its high cost, which restricts accessibility. Consequently, biosimilar formulations have recently been introduced into clinical practice. As biosimilars contain the same active substance as the reference product, they are expected to demonstrate comparable efficacy and safety. This has been supported by a double-blind, randomized, active-controlled Phase 3 trial comparing the biosimilar CT-P39 with omalizumab, which demonstrated equivalent efficacy and a comparable safety profile.³⁶ The introduction of biosimilar omalizumab may therefore provide economic benefits and improve access to anti-IgE therapy.

Next-generation high-affinity anti-IgE therapies have also been investigated for the management of CSU. Among these, ligelizumab demonstrated superior inhibition of IgE binding to the high-affinity FcεRI receptor and reduced adverse effects in preclinical mouse models.³⁷ However, despite demonstrating superiority over placebo in phase 3 clinical trials, ligelizumab did not show superiority compared with omalizumab and was therefore not approved for clinical use.³⁸

Although omalizumab is approved for CSU from 12 years of age, evidence in younger children remains limited. While the drug is licensed for allergic asthma in children aged ≥ 6 years, data supporting its use in pediatric CSU are sparse, and treatment in this population should be reserved for specialist settings.⁴ Available observational data suggest that omalizumab treatment during pregnancy is not associated with teratogenicity or adverse pregnancy outcomes.^39–41 However, controlled data are lacking, and treatment decisions during pregnancy should be individualized based on a risk-benefit assessment.⁴

Remibrutinib

Remibrutinib is an oral, highly selective Bruton’s tyrosine kinase (BTK) inhibitor, recently approved by the FDA in September 2025 as an add-on therapy for adults with CSU who remain symptomatic despite sg-AH treatment.⁴² The recommended dosage is 25 mg twice daily (BID).⁴² Data in children, pregnant, or lactating women are lacking.

BTK is expressed in various immune cells including mast cells, basophils and B-cells, and mediates intracellular signaling that drives mast cell and basophil degranulation, leading to CSU symptoms.³⁴ By irreversibly binding and inhibiting BTK, remibrutinib blocks downstream FcεRI-mediated degranulation and suppresses the expansion of autoreactive B-cells, thereby reducing autoantibody levels that can activate mast cells.³⁴ Given its downstream mechanism of action, remibrutinib is expected to be effective in both Type I and Type IIb CSU.^10,43

Two identical phase 3 trials (REMIX-1 and REMIX-2) were conducted as multicenter, double-blind, randomized, placebo-controlled studies evaluating oral remibrutinib 25 mg (BID) as add-on therapy for symptomatic CSU.⁴⁴ The primary endpoint was the change in UAS7 at week 12. In both studies, remibrutinib resulted in significantly greater improvement compared with placebo, with least-squares (LS) mean differences of −6.2 (95% CI: −8.5 to −4.0; P<0.001) in REMIX-1 and −7.7 (95% CI: −9.9 to −5.5; P<0.001) in REMIX-2. Furthermore, the proportion of patients with well-controlled CSU (UAS7 ≤6) was significantly higher with remibrutinib compared to placebo at week 12 (REMIX-1: 49.8% vs 24.8%, OR: 3.1; 95% CI: 2.0 to 4.8; P<0.001; REMIX-2: 46.8% vs 19.6%, OR: 3.8; 95% CI: 2.4 to 6.2; P<0.001).⁴⁴ Remibrutinib also led to higher proportion of patients with complete resolution of itch and hives (UAS7 score = 0) (REMIX-1: 31.1% vs 10.5%, OR: 3.8; 95% CI: 2.2 to 6.8; P<0.001, REMIX-2: 27.9% vs 6.5%, OR: 5.8; 95% CI: 2.8 to 11.8; P<0.001).⁴⁴ Importantly, these clinical benefits were maintained through week 24⁴⁴ and up to one year.⁴⁵

Regarding safety, adverse event rates were comparable between remibrutinib and placebo (64.9% vs 64.7%), with most events classified as mild to moderate without impairing daily activities. The most common adverse events included infections, nasopharyngitis, headache, and petechiae, the latter occurring more frequently in the remibrutinib group (3.8% vs 0.3%).⁴⁴

While these findings establish robust efficacy and safety in placebo-controlled settings, direct comparative evidence against established biologic therapy and real-world evidence are still lacking. A phase 3b trial (NCT06042478) directly evaluating remibrutinib versus omalizumab is currently ongoing, but results have not yet been published.⁴⁶ Indirect evidence from a recent network meta-analysis suggests that omalizumab remains the most effective option across key CSU outcomes, with remibrutinib showing strong efficacy, particularly in quality-of-life measures.⁴⁷ However, these indirect comparisons should be interpreted with caution due to heterogeneity and the dominance of larger omalizumab trials.⁴⁷

A concern with BTK inhibitors is the potential for rare but serious off-target adverse effects, such as bleeding or cytopenia. More selective BTK inhibitors with reversible binding⁴⁸ are therefore being developed with the aim of improving safety profiles.^49,50 Next-generation BTK inhibitors under investigation for CSU include rilzabrutinib, which has completed a Phase 2 randomized controlled trial. The trial included 160 patients with CSU refractory to sg-AH, including 143 omalizumab-naive individuals and 17 omalizumab incomplete-responders.⁵⁰ Participants were randomly assigned to receive daily rilzabrutinib at doses of 400 mg, 800 mg, 1200 mg, or placebo. The 1200 mg daily was the only group that demonstrated significant improvements in both itch and hives compared with placebo, with a change in UAS7 from baseline at week 12 of LS mean difference: −6.75 (95% CI: −12.23 to −1.26). Additionally, a higher proportion of patients in the 1200 mg group achieved well-controlled disease (UAS7 ≤ 6) at week 12 compared with placebo (34.3% versus 11.1%, response difference: 20.3%, 95% CI: 1.9% to 38.8%) and complete disease control (UAS7=0) was observed in 20.0% versus 11.1% of patients, respectively.⁵⁰ Importantly, efficacy was observed in patients with severe disease, low IgE levels, and positive BHRA, reflecting type IIb CSU.

Furthermore, rilzabrutinib exhibited a favorable safety profile, with nausea, headache and diarrhea being the most common adverse events, generally mild in severity.⁵⁰

These findings support further evaluation of next-generation BTK inhibitors in phase 3 trials, including head-to-head comparisons with remibrutinib for both efficacy and safety.

Dupilumab

Dupilumab, a monoclonal antibody, was approved in April 2025 by the FDA as an add-on therapy for patients with CSU aged 12 years or older who remain symptomatic despite sg-AH treatment.⁵¹ Treatment is recommended at a loading dose of 400 mg or 600 mg and subsequent dosage of 200 or 300 mg Q2W.⁵²

Dupilumab inhibits interleukin (IL)-4 and IL-13 signaling by targeting the alpha subunit of the IL-4 receptor (IL-4Rα), expressed on multiple immune cell types including mast cells. By acting upstream at the receptor level, it prevents IL-4-driven immunoglobulin class switching to IgE, thereby reducing IgE production in B-cells.⁵³ It also suppresses Th2-mediated inflammation and may limit pruritus by reducing cytokine activation of sensory neurons.⁴⁷ These mechanisms reduce mast cell activation and downregulate FcεRI expression over time, benefiting both type I and type IIb CSU endotypes.

In clinical trials dupilumab has demonstrated significant improvements in urticaria symptoms in both omalizumab-naive patients and non-responders.⁵³ Two phase 3, 24-week, double-blind, randomized, placebo-controlled, multicenter trials highlighted these effects.⁵³

One trial included 138 omalizumab-naive patients, while the other enrolled 108 patients who were incomplete responders to or intolerant of omalizumab, defined as insufficient symptom relief after at least three months of standard treatment or treatment discontinuation due to intolerance. In both trials, dupilumab was superior to placebo in reducing urticaria symptoms, assessed by improvements in the Itch Severity Score over 7 days (ISS7) and UAS7 at week 24.

Among omalizumab-naive patients, the LS mean change in UAS7 was −20.5 versus −12.0 for dupilumab and placebo, respectively (difference −8.5 points; 95% CI: −13.2 to −3.9; P = 0.003), while the change in ISS7 was −10.2 versus −6.0 (difference −4.2 points; 95% CI: −6.6 to −1.8; P = 0.005). Furthermore, the proportion of patients achieving well-controlled (UAS7 ≤6) or completely controlled (UAS7 = 0) CSU symptoms was significantly higher with dupilumab than placebo (45.7% vs 23.5% and 31.4% vs 13.2%, respectively).

Although improvements in UAS7 and ISS7 were also observed in omalizumab non-responders or intolerant patients, the effect was attenuated and did not reach statistical significance for ISS7 at week 24. The LS mean change in UAS7 was −14.4 versus −8.5 for dupilumab and placebo, respectively (difference −5.8 points; 95% CI: −11.4 to −0.3; P = 0.039), and the change in ISS7 was −7.7 versus −4.8 (difference −2.9 points; 95% CI: −5.7 to −0.1; P = 0.0449). Furthermore, 24.1% of dupilumab-treated patients versus 18.5% of placebo-treated patients achieved well-controlled CSU symptoms, while complete control was achieved in 59.3% versus 38.9%, respectively. Notably, the treatment effect appeared to persist from week 24 to 36, even after discontinuation of dupilumab.⁵³

Adverse event rates were comparable to placebo (57.3% vs 56.6%), with nasopharyngitis and injection-site erythema being the most common.⁵³

As with remibrutinib head-to-head studies are lacking. However, a network-analysis reported that dupilumab was less effective than remibrutinib and omalizumab in wheal resolution and overall disease control.⁴⁷ Improvements in UAS7 were also delayed with greater reduction at week 24 compared to week 12, suggesting that longer treatment periods may be warranted before declaring lack of response.⁴⁷ Nevertheless It remains an important treatment option for patients refractory to antihistamines or intolerant to other therapies,^47,53 or with atopic comorbidities such as asthma, chronic rhinosinusitis, and eosinophilic esophagitis.

Data in children under 12 years, pregnant, or lactating women are lacking. While dupilumab is approved for atopic dermatitis in children as young as 6 months, its safety and efficacy in younger children with CSU have not been established.⁴

Cyclosporine

Cyclosporine, a calcineurin inhibitor, indirectly limits mast cell activation through its immunomodulatory effects, including suppression of T- and B-cell proliferation and reduced cytokine-driven autoantibody production.^10,54 It has been used off-label as add-on therapy in patients with CSU and is recommended in current international guidelines for those with severe disease refractory to antihistamines, omalizumab, dupilumab and remibrutinib, at doses of up to 5 mg/kg body weight per day.⁴

Evidence on its efficacy is supported by a meta-analysis of 18 studies including 909 patients, two of which were randomized controlled trials. The pooled mean reduction in UAS7 after 4 weeks of treatment with cyclosporine was −17.89 (95% CI: −21.95 to −13.83), compared with −2.3 (95% CI: −3.72 to −0.88) in a placebo-controlled group. The pooled response rates after 4, 8 and 12 weeks were 54.2% (95% CI: 32.9% to 74.1%), 65.9% (95% CI: 30.0 to 89.7%), and 73.1% (95% CI: 65.4% to 79.5%), respectively.⁵⁵ However, when compared with omalizumab, cyclosporine is generally associated with smaller improvements in both quality of life and disease control.⁵⁶

Adverse effects are common and increase with higher doses and longer treatment duration, with an estimated 57.9% (95% CI: 32.3 to 79.8%) of patients experiencing at least 1 adverse event in doses up to 5 mg/kg/day.⁵⁵ Importantly cyclosporine is associated with significant adverse effects including hypertension, renal dysfunction, and broad immunosuppression, making it unsuitable as standard therapy.³⁴ Approximately one fifth of patients discontinue treatment due to adverse events.⁵⁵ Consequently, the use should be limited to patients with severe, uncontrolled disease in where the potential benefits outweigh these risks.⁴

Nevertheless, cyclosporine is considered a safer long-term option compared with systemic corticosteroids,⁴ and particularly effective in type IIb CSU, which typically has more severe disease and poorer response to omalizumab.^10,54

Use in children is supported only by studies with low levels of evidence and is generally not recommended in guidelines,^4,57,58 while use in pregnant women should be considered on an individual case-by-case basis, given evidence of embryotoxicity in animal models and potential risks to fetal growth in humans.⁴

Other Available Therapies for CSU

Several other off-label treatments have been proposed for CSU. Due to limited or low-quality evidence of their efficacy, they are not recommended for routine use in clinical guidelines and should be used with caution in children and in pregnant or lactating women.⁴ Nevertheless, they may still be appropriate for some patients, particularly when licensed therapies are unavailable or unsuitable.

Systemic corticosteroids, such as prednisolone, may be used for acute flares, but because of their risk for serious adverse effects, treatment is recommended in doses 20–50 mg/day for a maximum of 10 days.⁴

Leukotriene receptor antagonists, including montelukast, have been assessed as add-on therapy in CSU refractory to antihistamines in several studies, though study quality has been highly variable. A systematic review and meta-analysis of 34 randomized controlled trials including 3,324 children and adults found that, compared with sg-AH alone, add-on leukotriene receptor antagonists modestly reduced disease activity, with a pooled mean difference in UAS7 of −5.04 (95% CI: −6.36 to −3.71).⁵⁹ No significant difference in adverse events was observed between sg-AH alone and add-on treatment (RR: 0.8; 95% CI: 0.56–1.15). Montelukast was previously included in international guidelines but is now used off label, although, it remains widely prescribed in patients inadequately controlled on antihistamines prior to add-on biologics.⁴ Nonetheless, caution is recommended considering the FDA’s 2020 boxed warning for montelukast on serious neuropsychiatric events, although more evidence is needed to clarify this risk.⁶⁰

Other available therapies, including H₂-antagonists, dapsone, phototherapy, sulfasalazine, methotrexate, interferon, plasmapheresis, and intravenous immunoglobulins, are not recommended for routine use due to low-quality or limited evidence, and their application is therefore often guided by clinical experience.⁴

Emerging and Future Therapies for CSU

While several effective therapies exist for CSU, certain patient subgroups, such as those with type IIb or non-type I/non-type IIb CSU, continue to have unmet therapeutic needs that warrant further advancement. The following section reviews emerging therapies being investigated in ongoing and planned clinical trials with their mechanism of action illustrated in Figure 1. An overview of therapies and current trial status is also provided in Table 1. Data on the use of these emerging therapies during pregnancy, lactation, and in pediatric populations are limited or unavailable, as such populations are generally excluded from clinical trials.

Tyrosine Kinase (KIT) -Inhibitors

Barzolvolimab, a potent anti-KIT monoclonal antibody, reduces mast-cell numbers and downstream effector activity.^34,61 Mast cells depend on the binding of stem cell factor (SCF) to the KIT receptor for their development, survival, differentiation, and regulation of mediator release.^61–63 The KIT receptor is expressed not only on mast cells but also on other cell types, including hematopoietic stem cells, germ cells, and melanocytes.^34,63,64 Given its IgE-independent mechanism and mast-cell depleting effects, barzolvolimab may have therapeutic potential across CSU endotypes.

In a Phase 1b double-blind, placebo-controlled trial involving 42 adults with moderate to severe CSU who completed treatment, barzolvolimab was well tolerated across multiple dosing regimens, ranging from 0.5 mg/kg Q4W to 4.5 mg/kg every eight weeks (Q8W).⁶¹ The most common adverse events were mild to moderate and included hair color changes, neutropenia, headache, and COVID-19 infection. Clinically, symptom relief was rapid, occurring within one week and sustained through 12 weeks. At week 12, 71.4% of patients treated with barzolvolimab achieved well-controlled symptoms (UAS7 ≤6) compared with 30.0% of those receiving placebo.⁶¹ The efficacy was further supported by a phase 2 trial of 208 patients randomized to receive subcutaneous barzolvolimab 75 mg Q4W, 150 mg Q4W, 300 mg Q8W or placebo.^65,66 At week 12, significant improvements in UAS7 were observed for 150 mg Q4W compared with placebo (–23.02 vs –10.47, difference: −12.55, P<0.0001), as well as for 300 mg Q8W (–23.87 vs –10.47, difference: −13.41, P<0.0001).⁶⁶ Complete disease control (UAS7 = 0) was achieved in 37.5–51.1% in treatment groups, compared with 6.4% in the placebo group. Notably, efficacy was independent of prior omalizumab treatment.³⁴

Adverse events were reported as being mild with the most common being hair color change (26%), neutropenia (17%), skin hypopigmentation (13%), and nasopharyngitis (10%).^34,65 In addition, barzolvolimab has been associated with a transient reduced taste in some patients.⁶⁷

Further evaluation of KIT-targeting therapies is ongoing, including the phase 3 EMBARQ-CSU1 and EMBARQ-CSU2^68,69 trials enrolling adults with antihistamine-refractory CSU, as well as the BEACON phase 1b/2a trial assessing briquilimab, another anti-KIT antibody.⁷⁰

Tezepelumab

Tezepelumab is a monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), an epithelial cell–derived cytokine that promotes mast cell and basophil activation and drives type 2 inflammation through downstream cytokines, including IL-4, IL-5, and IL-13.⁷¹ By inhibiting TSLP, tezepelumab may targets key inflammatory pathways implicated in CSU. This is supported by findings of upregulated TSLP and type 2–associated cytokines in lesional skin of patients with CSU compared with controls.⁷²

A phase 2b randomized, placebo-controlled study of 183 patients with CSU inadequately controlled by sg-AH did not meet its primary endpoint at week 16.⁷³ The reduction in UAS7 from baseline with tezepelumab was not significantly different from placebo at this time point.⁷³ However, following treatment discontinuation, a sustained improvement was observed through week 32, particularly among anti-IgE naive patients, individuals with low IgE, and those with longer disease duration (> 3 years).⁷³ These features overlap with the characteristics of type IIb CSU, suggesting therapeutic potential in more severe, sg-AH- and anti-IgE refractory disease.

Janus Kinase (JAK)-Inhibitors

Another emerging therapeutic strategy is inhibition of the Janus kinase (JAK) pathway. JAK inhibitors block intracellular tyrosine kinases that mediate signaling from receptors involved in type 1 and type 2 inflammation. By interfering with JAK-dependent pathways, these agents reduce cytokine-driven activation of immune cells, including mast cells and basophils, thereby reducing downstream inflammatory responses relevant to urticaria.⁷¹ Although JAK inhibitors have shown promising results in other inflammatory skin diseases, such as atopic dermatitis,⁷⁴ studies in CSU remain limited and consist mostly of case series and case reports. Among these, JAK inhibitors such as upadacitinib (JAK1), ruxolitinib (JAK1/JAK2), tofacitinib (JAK1/JAK3), abrocitinib (JAK1), ritlecitinib (JAK3/TEC), and povorcitinib (JAK1) have been reported as potential novel therapeutic agents.^75–79

A phase 1b randomized, double-blind, placebo-controlled study of TLL-018 in 41 patients with moderate-to-severe CSU refractory to sg-AH has been completed.⁸⁰ The study demonstrated that TLL-018 was well tolerated, and improvement in UAS7 was significantly greater in the active treatment groups compared with placebo, with LS mean changes from baseline at week 4 of −7.5 in the placebo group, −19.1 in the 10 mg BID group, and −23.6 in the 30 mg BID group.⁸⁰

A phase 2, randomized, double-blind study evaluating povorcitinib in 136 adults with moderate-to-severe CSU compared daily doses (QD) of 15 mg, 45 mg, and 75 mg with placebo over 36 weeks.⁸¹ The 75 mg QD group achieved the greatest LS mean reduction in UAS7 compared with placebo (−23.91 vs −17.90, P = 0.047). Clinical improvement was rapid, and after 12 weeks of treatment, 62.9% of patients receiving 75 mg QD achieved disease control (UAS7 ≤ 6) compared with 29.4% in the placebo group, while 42.9% became symptom-free (UAS7 = 0) versus 23.5% with placebo.

Other JAK inhibitors are currently under evaluation, including ritlecitinib, which is currently being investigated in an ongoing phase 2 trial (NCT07219615).⁸²

Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2)-Antagonists

It is increasingly acknowledged that a subset of patients does not fit either the type I or type IIb endotypes, and these patients are currently classified as having non–type I/non–type IIb CSU.^12,34 In this subgroup, mast cell activation is believed to be mediated through alternative receptors, such as the MRGPRX2.^11,13

MRGPRX2 is expressed on mast cells of the skin,⁸³ and in dorsal root ganglion neurons, where it may contribute to itch and pain signaling.⁸⁴ A broad range of endogenous and exogenous ligands, including neuropeptides such as substance P (SP), can bind to and activate this receptor, leading to subsequent mast cell degranulation.⁸⁵

In patients with CSU, expression of MRGPRX2 on mast cells has been found to be elevated, along with increased levels of its ligands, including SP.^85,86 These findings therefore suggest that targeting MRGPRX2 may represent a promising novel therapeutic strategy, particularly for patients who respond inadequately to anti-IgE therapies.^85,87,88

Following this, a phase 1 proof-of-concept study⁸⁹ demonstrated that EVO756 was well tolerated in healthy adults, and a phase 2b trial (NCT06873516)⁹⁰ in adults with moderate-to-severe CSU is currently ongoing.

Interleukin 2 (IL-2)

Considering the autoimmune features of CSU, immunomodulation of regulatory T cells has been proposed as a potential therapeutic strategy using interleukin-2 (IL-2), a cytokine with immunomodulatory effects on both regulatory T cells and effector T cells.⁹¹ A retrospective study of 15 patients with CSU refractory to antihistamines assessed symptom improvement following low-dose IL-2 treatment and found that 73.3% of patients achieved a complete response (UCT score ≥ 12) after 12 weeks, with 46.7% achieving this within the first 2 weeks.⁹¹ These findings have prompted further investigation, and IL-2 is currently being evaluated in a phase 2, randomized, placebo-controlled, multicenter clinical trial in adults with CSU refractory to antihistamine treatment.⁹²

Conclusion

Although the complex pathophysiology and heterogeneous endotypes of CSU can complicate treatment, current therapies provide effective disease control when applied in a stepwise approach. Treatment starts with up-dosed second-generation antihistamines, followed by add-on therapy with omalizumab. For patients with an inadequate response to this combination, newly approved therapies such as dupilumab or remibrutinib are recommended as add-ons to ongoing antihistamine treatment. Leukotriene receptor antagonists, including montelukast, are widely used off label in patients who remain uncontrolled, even though they are no longer recommended in guidelines. Cyclosporine may be considered in severe, omalizumab-refractory cases, particularly in patients with the type IIb autoimmune endotype, although it is not recommended as standard therapy.

Emerging therapies, including KIT inhibitors, other BTK inhibitors such as rilzabrutinib, TSLP inhibitors such as tezepelumab, JAK inhibitors, MRGPRX2 antagonists, and IL-2 based therapies, offer additional potential by targeting distinct mechanisms in CSU pathophysiology. However, CSU is not a one-size-fits-all disease, and treatment decisions can be challenging due to its heterogeneous nature and the current lack of validated biomarkers. A deeper understanding of CSU endotypes will be essential for developing personalized treatment strategies that optimize disease control.

Funding Statement

There is no funding to report.

Abbreviations

ASST, Autologous serum skin test; BAT, Basophil activation test; BHRA, Basophil histamine release assay; BID, Twice daily; BTK, Bruton’s tyrosine kinase; BTKi, Bruton’s tyrosine kinase inhibitor; CI, Confidence interval; CRP, C-reactive protein; CSU, Chronic spontaneous urticaria; FDA, US Food and Drug Administration; FcεRI, Fc epsilon receptor I; HSS7, Hives Severity Score over 7 days; HRQoL, Health-related quality of life; IgE, Immunoglobulin E; IgG, Immunoglobulin G; IL, Interleukin; IL-4Rα, IL-4 receptor, alpha subunit; ISS7, Itch Severity Score over 7 days; JAK, Janus kinase; Kg, Kilogram; LS, Least-squares; Mg, Milligram; MRGPRX2, Mas-related G protein–coupled receptor X2; OR, Odds ratio; PROMS, Patient-reported outcome measures; QoL, Quality of life; QD, Daily doses; QW2, Every two weeks; QW4, Every four weeks; QW8, Every eight weeks; RR, Relative risk; SCF, Stem cell factor; Sg-AH, Second-generation H₁-antihistamines; SP, Substance P; SMD, Standardized mean difference; Th2, Type 2 helper T cell; TSLP, Thymic Stromal Lymphopoietin; UCT, Urticaria Control Test; UAS7, Weekly Urticaria Activity Score.

Data Sharing Statement

No new data were generated or analyzed in this study. Data sharing is not applicable to this article.

Author Contributions

C.E.S.Ø: Conceptualization, Investigation, Writing – Original draft, Writing – Review and editing, S.F.T: Conceptualization, Writing – Review and editing, Supervision, D.G.Z: Conceptualization, Writing – Review and editing, Supervision.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Clara Emilie Syrene Østergaard, Ditte Georgina Zhang have no conflicts of interest for this paper. Simon Francis Thomsen has received research support from Almirall, AbbVie, Janssen, LEO Pharma, Novartis, Novo Nordisk, Sanofi, and UCB, and has been a speaker/consultant for Abbvie, Almirall, Boehringer, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Novartis, Novo Nordisk, Pfizer, Sanofi, Symphogen, UCB, and Union Therapeutics.