Targeting immune dysregulation in chronic spontaneous urticaria: beyond antihistamines

Anti-IgE therapies

Omalizumab is a well-established second-line treatment for antihistamine-refractory CSU [1, 10, 53]. Large randomized controlled trials (ASTERIA I/II, GLACIAL) and multiple real-world studies have consistently demonstrated its efficacy, with significant reductions in UAS7 scores, improvements in CU-specific quality of life, and rapid symptom relief, often within the first 1–2 weeks of therapy [55, 57-61]. Its long-term safety profile remains favorable, with anaphylaxis being rare (< 0.2%) and > 95% of cases occurring within the first 3 months of treatment [59]. Its efficacy and safety have been validated in diverse populations, including children, pregnant women, and older adults [60]. Current guidelines recommend the subcutaneous administration of 150–300 mg every 4 weeks [10]. Approximately 60% of patients achieve well-controlled disease within 6 months, and 20–40% may attain complete remission, depending on the study population and response criteria [60-64].

Our retrospective longitudinal cohort of 386 patients treated with omalizumab for > 6 months demonstrated progressively increasing cumulative response rates of 55.2% at 3 months, 71.0% at 6 months, and 81.4% at 9 months [62]. To improve treatment accessibility, an omalizumab biosimilar was approved in 2025. In a phase III trial (NCT0442689), the omalizumab biosimilar CT-P39 exhibited therapeutic equivalence to the reference omalizumab 300 mg in terms of change in weekly itch severity score (difference, 0.77; 95% confidence interval, −0.37 to 1.90), with parallel reductions in UAS7 and sustained efficacy after switching [65]. Its introduction is expected to enhance cost-effectiveness and broaden patient access; however, confirmation from long-term real-world data is warranted. Nevertheless, approximately 22% of patients exhibit a persistently poor response from as early as 3 months onward, underscoring the need for biomarkers to identify non-responders [62]. A low baseline total IgE level (< 40 kU/L) has consistently been identified as a predictor of a poor response to omalizumab. The clinical and laboratory features associated with non-response often overlap with the characteristics of type IIb autoimmune CSU, including basopenia, autoreactivity (positive basophil activation or ASSTs), elevated systemic inflammatory markers, and concomitant autoimmune diseases [6, 62, 66-69]. These findings emphasize the importance of endotype-driven therapeutic strategies in guiding patient selection for omalizumab treatment.

Ligelizumab, a humanized anti-IgE monoclonal antibody with higher IgE-binding affinity than omalizumab, has been evaluated for CSU [54,55]. It more effectively suppresses free IgE levels and downregulates FcɛRI expression in preclinical models and early-phase clinical studies [54]. In phase III clinical trials, ligelizumab demonstrated numerically greater reductions in urticaria activity scores than omalizumab; however, it did not consistently achieve superiority across the primary clinical endpoints [55]. Consequently, its clinical development for CSU was discontinued, and a next-generation approach to IgE neutralization involves the development of IgE traps and engineered fusion proteins designed to bind IgE with a markedly higher affinity [70,71]. YH35324, the first-in-class IgE trap, is a long-acting IgE Trap-Tc fusion protein comprising the extracellular domain of human FcɛRIα fused to a human IgD/IgG4-modified Fc region. In a phase 1 clinical trial, YH35324 was well tolerated, with no dose-limiting toxicities, and demonstrated a favorable pharmacokinetic and safety profile. Treatment led to rapid and sustained suppression of free IgE levels and FcɛRI expression [71,72]. Although the efficacy data for CSU are not yet available, the IgE trap strategy offers potential advantages over conventional anti-IgE therapy by enabling more complete IgE depletion and broader downregulation of IgE-mediated pathways.

BTK inhibitors

Beyond targeting IgE directly, inhibition of downstream FcɛRI signaling has emerged as a promising therapeutic strategy. This approach is particularly relevant in type IIb autoimmune CSU, where anti-FcɛRI or anti-IgE autoantibodies drive mast cell activation independent of free IgE. In such cases, blocking FcɛRI-mediated signaling through BTK inhibition may help overcome resistance to anti-IgE therapies [56].

Fenebrutinib, a first-generation oral BTK inhibitor, has demonstrated efficacy in a phase II trial for H1AH-refractory CSU [73]. Preclinical studies further indicated that BTK blockade may reduce the production of anti-FcɛRIα autoantibodies, implicating BTK in autoreactive B-cell function in type IIb autoimmune CSU [74]. However, clinical development of fenebrutinib was discontinued because of its hepatotoxicity.

Since then, more selective BTK inhibitors have been developed, and remibrutinib has emerged as the most advanced candidate [75]. The phase III REMIX-1 and REMIX-2 trials demonstrated rapid and significant reductions in urticaria activity compared to placebo. At week 12, approximately 48% of remibrutinib-treated patients achieved well-controlled disease (UAS7 ≤ 6), and 29% attained complete control (UAS7 = 0) [13]. Patients who switched from placebo to remibrutinib after week 12 experienced rapid improvements that were sustained through week 24. Notably, the efficacy was consistent regardless of prior omalizumab exposure [59].

Remibrutinib was generally well-tolerated, with an overall adverse event profile comparable to placebo. A characteristic treatment-related event was petechiae, reflecting BTK’s role in platelet signaling, which is typically mild, transient, and occurs slightly more frequently (approximately 3%) than in the placebo group [13]. Although BTK is essential in B-cell receptor signaling and could theoretically impair immunoglobulin synthesis or increase infection risk, recent studies have demonstrated no clinically meaningful effects on IgG, IgA, or IgM levels, and the infection rates were comparable to placebo [76]. Despite its promising efficacy and safety profile, remibrutinib has not yet received FDA approval, and long-term safety data remain limited. Real-world studies across diverse geographic and ethnic populations are crucial to confirm its sustained efficacy, safety, and overall risk–benefit profile.

Rilzabrutinib, another next-generation oral BTK inhibitor with enhanced selectivity and prolonged BTK occupancy, has demonstrated dose-dependent suppression of FcɛRI-mediated basophil and mast cell activation in phase I/II studies, accompanied by reductions in serum biomarkers, such as IL-31, soluble MRGPRX2, and autoantibodies (anti-TPO IgG and anti-FcɛRIα IgG) [77,78]. In a phase II trial, rilzabrutinib at a dose of 1200 mg/day significantly improved UAS7 scores compared with placebo at week 12 [78]. Ongoing phase III trials are expected to elucidate the clinical efficacy and long-term safety of H1AH-refractory CSU. Rilzabrutinib has thus far exhibited a favorable safety profile, with most adverse events being mild and transient, including headache and gastrointestinal symptoms.

Cytokine blockade

Cytokines such as IL-4, IL-5, IL-13, IL-17, and IL-33 are important mediators of CSU pathogenesis [32,33, 85]. Dupilumab, an IL-4Rα antagonist that blocks both IL-4 and IL-13 signaling, has demonstrated clinically meaningful efficacy in H1AH-refractory CSU. In the phase III LIBERTY-CSU CUPID trials, dupilumab significantly improved UAS7 scores and quality of life compared with placebo [86]. In omalizumab-naïve patients, up to 30% achieved a complete response at week 24 and approximately 60% achieved well-controlled disease [86]. Conversely, in omalizumab non-responders, the efficacy was less pronounced, emphasizing the importance of appropriate patient selection. Based on these results, dupilumab has been approved for CSU in Japan, the UAE, and the USA in patients aged ≥ 12 years with a disease uncontrolled by H1AHs. Dupilumab exhibits a favorable safety profile, with the most common adverse events being injection-site reactions, conjunctivitis, and transient eosinophilia. Notably, no increase in serious adverse events or anaphylaxis was observed compared to the placebo, and long-term data from other indications, such as atopic dermatitis and asthma, support its continued safety.

Other cytokine-targeted strategies remain investigational. IL-5 blockade and IL-17 inhibition have shown anecdotal or preliminary benefits in small case series, but the evidence remains inconsistent [87,88]. Notably, a recent phase IIb trial of benralizumab failed to demonstrate its clinical efficacy despite complete eosinophil depletion, implying a limited role for eosinophils in CSU [89]. Anti-TSLP therapy with tezepelumab was recently evaluated in the phase IIb INCEPTION trial in H1AH–refractory CSU; however, our findings did not show a clinically meaningful benefit over placebo, limiting enthusiasm for further development in CSU [90].

Mast cell depletion

An alternative therapeutic approach for CSU is direct depletion of mast cells, which are the central effector cells in disease pathogenesis. Unlike strategies that inhibit downstream mediators or upstream IgE pathways, mast cell depletion eliminates primary sources of histamine, lipid mediators, and cytokines by modulating mast cell survival and proliferation.

Barzolvolimab, a humanized monoclonal antibody targeting the receptor tyrosine kinase c-kit (CD117), induces apoptosis and sustained depletion of dermal mast cells, accompanied by a marked reduction in serum tryptase [91]. In a phase II trial, barzolvolimab 150 mg every 4 weeks and 300 mg every 8 weeks significantly improved the UAS7 and UCT scores at week 12 compared to the placebo, with up to 71% of patients achieving a complete response in the 52-week analysis [92,93]. Barzolvolimab was generally well tolerated. However, unique on-target adverse effects, including hair color changes, skin hypopigmentation, taste disturbances, and transient neutropenia, have been reported, warranting careful monitoring in ongoing phase III trials [93]. Because mast cells contribute to host defense, tissue repair, and immune regulation, the long-term consequences of sustained mast cell depletion require further evaluation in larger and longer studies.

MRGPRX2 antagonists

MRGPRX2 has emerged as a potential therapeutic target for CSU. Skin biopsies from affected patients, particularly those with severe or H1AH–refractory disease, show increased MRGPRX2 expression in lesional mast cells compared to healthy controls, and elevated serum levels have been correlated with disease activity [94,95]. Moreover, recent studies indicate that IgE can upregulate MRGPRX2 expression in mast cells, enhancing their responsiveness to neuropeptides, antimicrobial peptides, and certain drugs [96–98]. This cross-talk between the IgE-FcɛRI and MRGPRX2 pathways may explain why patients with high total or autoreactive IgE levels exhibit exaggerated mast cell activation even in the absence of allergen exposure.

Based on these findings, the pharmacological inhibition of MRGPRX2 has been proposed as a novel therapeutic approach. EVO756, a first-in-class oral small-molecule antagonist, has shown potent dose-dependent inhibition of MRGPRX2-mediated mast cell degranulation in preclinical studies while sparing IgE-dependent signaling [99,100]. Early phase clinical trials are ongoing, although the efficacy data for CSU are not yet available.

Although experimental, MRGPRX2 antagonists may be particularly relevant for CSU subgroups characterized by neurogenic inflammation, drug hypersensitivity, or non-IgE-mediated mast cell activation. Future studies should focus on identifying biomarkers of MRGPRX2-driven disease and establishing the efficacy and long-term safety of these agents in large-scale CSU populations.

Emerging targets and experimental approaches

Complement-derived anaphylatoxins, particularly C5a, can directly activate mast cells and basophils, implicating the role of the complement system in autoimmune CSU [101]. Although agents such as C1s and C5a inhibitors are being evaluated in other autoimmune diseases, including avacopan for ANCA-associated vasculitis, their clinical efficacy in CSU has yet to be established [102,103].

Sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8), which is selectively expressed on mast cells and eosinophils, represents a promising target for mast cell silencing and eosinophil depletion [104,105]. Lirentelimab, a humanized Siglec-8 monoclonal antibody, demonstrated clinical activity in early phase trials [106]; however, subsequent phase III studies on eosinophilic gastrointestinal diseases failed to meet their primary endpoints, and further development in CSU has not been pursued.

Alarmins such as IL-25, IL-33, and TSLP are released upon tissue injury or stress and normally promote tissue repair and restoration of homeostasis [29, 85]. In CSU, sustained elevation of alarmins may perpetuate mast cell activation and type 2 inflammation rather than resolve it. Moreover, damage-associated molecules, including HSPs and haptoglobin, have been implicated in CSU pathogenesis; autoantibodies against these alarmins, such as anti-HSP10 IgG, may disrupt their regulatory functions, impair inflammation resolution, and sustain chronic diseases [20].

Epigenetic dysregulation is another layer of complexity. Altered miRNA profiles in CSU have been associated with disease activity, treatment refractoriness, and the presence of anti-HSP10 autoantibodies, indicating that miRNAs may modulate alarmin pathways, mast cell activation thresholds, and autoimmune responses [20, 107,108]. From a translational perspective, miRNA signatures hold promise as endotype-defining biomarkers; however, therapeutic modulation using miRNA inhibitors or mimics, already explored in other immune-mediated disorders, may offer a future strategy for disease modification in CSU [109].