Update on Biologic Therapy of Chronic Spontaneous Urticaria

While urticaria is quite common in childhood, it is less frequent as chronic condition. In this narrative review we have highlighted the causes of chronic urticaria (CU), indicating the diagnostic work-up according to age and characteristics of the patients, giving importante to the symptom presentations. The therapeutic options of CU even in children are also represented by the biologic drugs, which are usually recommended from the twelve years of life. Biologic option represents in case of CU an effective and safe intervention. Further molecules are indicated for this condition in the next future. In the review these options are discussed and experimental and registratory studies are indicated.

INTRODUCTION

Urticaria is a common cutaneous disorder characterized by transient wheals that typically present as pruritic, edematous lesions with a central pale area surrounded by an erythematous halo. The shape and size of the wheals are highly variable, but each individual lesion is short-lived, usually resolving within minutes to several hours and almost invariably disappearing within 24 hours. In some patients, wheals are associated with angioedema, which involves deeper layers of the dermis and subcutaneous tissue. Angioedema most frequently affects the eyelids, lips, dorsal aspects of the hands and feet, and, in males, the scrotum. Unlike wheals, angioedema tends to resolve more slowly, usually within 1 to 3 days, and is often accompanied by pain, burning, or a sensation of tension rather than pruritus.

Clinically, urticaria is classified according to its duration: acute urticaria is defined by the presence of wheals, with or without angioedema, lasting less than 6 weeks; in contrast, chronic urticaria (CU) is diagnosed when symptoms occur on most days of the week for a period exceeding 6 weeks. In children, acute urticaria is frequently associated with infections, particularly viral illnesses, or with IgE-mediated allergic mechanisms. When IgE-mediated, onset typically occurs within minutes to 2 hours after allergen exposure. Moreover, allergic urticaria rarely presents as an isolated manifestation and is usually part of a broader IgE-mediated reaction that may also involve mucosal tissues, the gastrointestinal tract, the respiratory system, or the cardiovascular system ^1-3.

Chronic Urticaria: Classification and Epidemiology

CU in the pediatric population is generally classified in two categories: chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIU), depending on the presence of identifiable triggers, detected through clinical history and/or laboratory testing (Tab. I). CSU represents the most frequent form in children, accounting for approximately 85% of cases. In adults, the autoimmune subtype of CSU is reported in nearly 45% of patients, whereas in children it is less common, occurring in fewer than 10% of cases ^4,5. CIU accounts for 15% to 40% of pediatric CU patients. The most prevalent subtypes of CIU include symptomatic dermographism, cholinergic urticaria, and cold-induced urticaria. Unlike CSU, several forms of CIU (such as cold-induced, pressure-induced, or cholinergic urticaria) may also be associated with systemic symptoms, including bronchospasm, hypotension, syncope, gastrointestinal wall edema, and, in the most severe cases, anaphylaxis or even death. CIU can be triggered by infections, parasitic infestations, allergies, and physical stimuli. Viral and bacterial infections may exacerbate or induce CU in children, with a reported frequency ranging from 0% to 35%, whereas parasitic infestations account for 0% to 37.8% of cases. Establishing a causal relationship between urticaria and infection requires the resolution of skin symptoms following an effective treatment of the infection. Among the pathogens investigated, bacteria, in particular Helicobacter pylori, have been most extensively studied. Certain H. pylori proteins have been shown to activate mast cells in vitro, leading to the release of histamine, TNF-α, IL-3, IFN-γ, and leukotriene B4. Allergic triggers (aeroallergens, foods, and drugs) are considered a rare cause of CU in children ². From an epidemiological standpoint, an Italian population-based study in children aged 0 to 14 years reported an annual incidence of 0.6-2.1 cases per 1,000 children and an estimated prevalence between 0.38% and 0.84% ³.

Chronic Urticaria and Autoimmune Disease

Children with CU have an increased prevalence of autoimmune thyroid disease, especially Hashimoto thyroiditis and coeliac disease. Several studies report a higher prevalence of thyroid autoimmunity and celiac disease in children with CSU compared to the general pediatric population ⁴. There is no consistent evidence that the clinical course of CU differs in children with autoimmune thyroid disease, but there is evidence that treating the thyroid disorder reliably improves urticaria. Some case reports and small studies indicate that a gluten-free diet may lead to remission of urticarial symptoms in children with celiac disease and CU ^6,7.

Quality of Life and Natural History

CSU is by definition benign and self-limiting in many children, but its unpredictable and prolonged course may substantially impair quality of life. Recent work has shown that the burden of CSU, determined through the SF-36, can be comparable to that of chronic rheumatologic or endocrine diseases (e.g., insulin-treated diabetes). Itching frequently disrupts sleep and is often related to emotional stress compared to peers ⁸. The mean duration of the disease in pediatric series is about 2-3 years, with a full remission within 5 years from onset. There are currently no reliable biomarkers to predict the duration or course of disease. However, some factors, including severity at onset, low total IgE, early response to H1-antihistamines, basopenia, and positive basophil activation test (BAT) with CD63, have been associated with a shorter disease duration in some studies ⁹.

Pathogenesis

Chronic urticaria results from inappropriate activation of mast cells and basophils with subsequent release of proinflammatory mediators, principally histamine, which increases vascular permeability and produces wheals.

Two immunological mechanisms are prominent:

• Type IIb autoimmunity (autoimmune CSU): IgG and/or IgM autoantibodies bind the α-subunit of the high-affinity portion of IgE receptor (FcεRI) or the IgE already bound on mast cells/basophils, causing cell activation and degranulation, with release of histamine and cytokines. This subtype is often associated with other autoimmune conditions, notably celiac disease and Hashimoto thyroiditis. Diagnostic criteria for type IIb autoimmune CSU require positivity on all three assessments: (1) specific immunoassays (e.g., Western blot or ELISA — not widely commercially available), (2) functional autoantibody activity demonstrated by basophil assays (BAT and/or BHRA), and (3) cutaneous autoreactivity assessed by autologous serum skin test (ASST). Fulfilling all three criteria is uncommon (≈8% of CSU patients) ¹¹.
• IgE-mediated autoallergy (type I CSU): In this model, IgE directed against self-proteins (for example thyroid peroxidase [TPO], dsDNA, eosinophil peroxidase [EPO], tissue factor, thyroglobulin [TG], IL-24) bind and activate mast cells. This mechanism may explain the excellent responses to anti-IgE therapy (omalizumab) observed in many patients with CSU. Type I autoallergy is frequently accompanied by atopic comorbidities and normal or elevated total IgE serum levels.

Finally, non-immunologic mechanisms — direct mast cell activation through physical stimuli, stress, or infectious agents — also contribute as a trigger for symptoms. These mechanisms often coexist and help explain the heterogeneity of clinical phenotypes and treatment responses ^5,10.

Diagnosis

The diagnosis of CU is clinical and primarily relies on careful history and physical examination. The core of the diagnostic features is pruritic migrating wheals that blanch with pressure and appear daily or on most days for at least 6 weeks. Because individual wheals are transient and may be absent at the clinic visit, photographs documenting wheals or angioedema provided by families can be very helpful. Routine laboratory or imaging tests are not required for diagnosis.

The differential diagnosis should include conditions that cause wheal-like lesions but have distinct pathophysiology, such as papular urticaria, mastocytosis, certain vasculitis and genetic syndromes. History and exams are the first step in identifying potential underlying causes and deciding whether additional testing is warranted.

Key elements to explore the clinical history:

• Frequency and duration of individual lesions (wheals lasting > 24 hours — consider pressure-induced delayed urticaria or urticarial vasculitis; lesions lasting < 1 hour suggest physical urticaria, except delayed pressure urticaria).
• Size, morphology, and distribution of lesions.
• Presence of angioedema (isolated or concurrent).
• Family history of atopy, urticaria, or systemic disorders.
• Age at onset.
• Temporal relation with potential triggers or exacerbating factors (foods, drugs, exertion).
• Settings or locations where eruptions occur.
• Systemic signs or symptoms suggestive of underlying disease (e.g., celiac disease, vasculitis, autoinflammatory syndromes).
• Subjective symptoms (pruritus, burning, pain).
• Impact on quality of life impact.
• Treatment responses and prior therapies.

If history points to a specific trigger or systemic disease, targeted laboratory tests should be performed. When inducible urticaria is suspected, the provocation test to the suspected subtype is indicated, but up to one-third of these tests may be negative. For accuracy in provocation testing, H1-antihistamines should be discontinued approximately 7 days beforehand and systemic corticosteroids about 3 days before testing; stimuli should be applied on skin areas free of urticaria in the previous 24 hours (see Table II of provocation tests below). Routine allergy tests are not recommended unless the clinical history suggests a cause-effect relationship between exposure and symptoms. When allergy tests are positive, confirmation requires symptom remission after allergen avoidance and a positive controlled challenge to the allergen implicated. Infection screening should be reserved for situations with a strong clinical suspicion based on history/exam.

The ASST is a screening test for autoreactivity, but is not recommended as a routine test in all patients with CU. Conversely, screening tests for celiac disease and autoimmune thyroid disease are recommended in all children with CU, even if they lack specific symptoms, and should be followed over time. Testing for other autoimmune conditions or malignancy is generally not advised because such associations are uncommon.

If history and physical examination do not suggest a cause, routine laboratory testing is usually of limited value. Clinicians may still consider basic inflammatory markers [complete blood count (CBC), erythrocyte sedimentation rate (ESR) and CRP (C-reactive protein)] to reassure families and to screen for systemic inflammation.

Practical diagnostic summary

• If a single wheal persists > 24 hours (and delayed pressure urticaria is excluded) perform skin biopsy to evaluate for urticarial vasculitis.
• If individual wheals last < 24 hours:
  1. Perform targeted testing if history suggests an underlying cause (physical triggers, drugs, foods, infections, autoimmune disease). Dermographism should be evaluated in all children with CU.
  2. In recurrent isolated angioedema without other symptoms, hereditary angioedema should be evaluated.
  3. If a genetic disorder is suspected (e.g., cryopyrin-associated), analysis of the NLRP3 (cryopyrin) gene should be considered.
  4. In other cases, basic laboratory tests (CBC, ESR, CRP) and screening for thyroid and celiac antibodies may be appropriate to exclude associated autoimmune conditions and to reassure families ^1,2,4.

Treatment

The therapeutic goal for all forms of urticaria is control of the symptoms, reducing wheal frequency, relieving pruritus, and resolving angioedema. Removing identifiable triggers where possible and symptomatic therapy when avoidance is insufficient are the priorities in management.

First-line therapy: second-generation H1-antihistamines at standard doses. A trial of 1-2 weeks is appropriate; if effective, it is possible to continue and reassess the need for ongoing therapy every 3-6 months. No specific second-generation H1-antihistamine is universally preferred as first-line because comparative efficacy is not clearly established. If standard doses fail to control symptoms, in patients aged > 12 years clinicians may increase the dose of second-generation H1-antihistamine up to 4 times the standard dose (off-label). For children < 12 years, although controlled studies are lacking, dose escalation up to twice the standard dose has been used and appears safe. Combining first- and second-generation antihistamines or adding H2-blockers to H1-antagonists is not recommended.

Second-line therapy: for patients > 12 years with inadequate control despite high-dose second-generation H1-antihistamines, it is suggested to add omalizumab (anti-IgE monoclonal antibody). Omalizumab binds circulating IgE and prevents the binding of IgE to FcεRI on mast cells and basophils, thereby reducing mediator release. The recommended initial regimen for CSU is 300 mg subcutaneously every 4 weeks. If symptoms remain uncontrolled despite maximal antihistamines and omalizumab, or if omalizumab is unavailable, cyclosporine-A may be considered, even if its use is limited by potential adverse effects and off-label status. Cyclosporine is usually considered after failure of approximately 6 injections of omalizumab. Cyclosporine acts as an immunomodulator, suppressing T-cell activation and NF-κB-mediated transcription (off label).

Corticosteroids: short courses (≤ 10 days) of systemic corticosteroids can be prescribed for severe exacerbations, but prolonged use is discouraged due to systemic toxicity.

Adjunctive agents: Montelukast may be added to second-generation H1-antihistamines when symptoms remain uncontrolled; however, pediatric data are limited ^1,2,4,12.

BIOLOGICS APPROVED FOR TREATMENT OF CSU

Omalizumab

Omalizumab, a monoclonal anti-IgE antibody, has been recommended since 2014 in Europe and the US as second-line treatment for antihistamine-refractory chronic spontaneous urticaria in adolescents older than 12 years ¹³. Omalizumab has also been approved in the US for the treatment of moderate-to-severe allergic asthma in children older than 12 years of age since 2003 and extended to 6 years of age in 2016. Similarly, this drug has been used in analogous clinical conditions and populations in Europe with off-label prescribing ^14,15. In 2024, the FDA also approved omalizumab for preventing accidental food exposure and idiopathic anaphylaxis in patients older than 1 year ^16,17.

In the treatment of CSU, the results with omalizumab are consolidated in adults and adolescents ^18-20. However, in the literature, substantial gaps related to the management of pediatric cases of chronic urticaria, especially CSU, are still present. High-quality trial data are lacking in the pediatric population, while case reports and small series supporting the use of omalizumab in severe or antihistamine-refractory CSU in children have been described in the last decade ²¹.

A recent systematic review and meta-analysis summarized 36 studies conducted on pediatric patients with CSU. The results described a pooled response in a rate of 88% of subjects (95% CI 80.7-95.2%). Of those, the complete response rate was reached in 51% (95% CI 32.7-69.2%), with a relapse rate of 24.3% (95% CI: 8.1-40.6%; I² = 66.6%; p = .006). Among pediatric patients under 12 years, 18 of 21 achieved complete response, with a median age of 8 years, that was maintained during follow-up at 4 and 18 months. In all, 3.4% of patients experienced adverse events, in particular urticaria, angioedema, headaches, fatigue, flu-like symptoms, and mild joint pain, as well as serum sickness in one pediatric patient ²².

Focusing on an analysis of the pivotal phase 3 studies ASTERIA II, ASTERIA I, and GLACIAL, these included adolescents, aged from 12 to 18 years, with CSU refractory to licensed-dose H1-antihistamines, for a 12-week follow-up in ASTERIA II and 24-weeks follow-up in the other studies. The results showed significant, dose-dependent improvements, with large reductions in ISS, high percentages of well-controlled disease (UAS7 ≤ 6), and complete response (UAS7 = 0) rates versus placebo. Moreover, consistent efficacy was suggested in adolescents, matching with the overall population, but are underpowered to detect small age-related differences. None of these studies provided separate powered efficacy outcomes; efficacy is purported to be comparable between adolescents and adults. In adolescents, there were no differential safety concerns compared to adults, and regulators confirmed that the labeling was appropriate for patients 12-17 years of age. However, the efficacy analyses in this population are limited by small numbers of patients, since adolescents comprised only a small fraction (3% to 6%) of participants ^18-20,23,24.

The recent literature offers real-world studies, retrospective and prospective studies, review, case series, individual case reports, with a total population of 523 subjects among children and adolescents, aged from 2 to 18 years, affected by CSU. Perspective and retrospective studies reported a reduction of UAS7 up to 60% in 70-85% of the subjects treated for 4 weeks, with significant improvement especially on itch and extension of cutaneous lesions, compared with placebo and conventional therapy with omalizumab; up to 40% of patients had a complete clinical remission ^25-28. Staubach’s group followed patients with CSU treated with omalizumab up to 12 months, with the maintenance of good clinical results for most patients, with progressive reduction of the dose needed, and good tolerance. The cost-benefit ratio seemed to favor the use of omalizumab in children and adolescents with severe refractory CSU ^28,29. The overall results describe a significant effect on the reduction of severe symptoms of CSU during the treatment with omalizumab, even if with a variable individual response. Additional research on clinical and laboratory biomarkers and prolonged follow-up seem necessary to ensure optimal therapy and refine better outcomes ^30,31.

In conclusion, most recent data highlight that second-generation antihistamines are effective for the treatment of CSU in children and describe the use of omalizumab for more severe cases. However, the response to omalizumab is insufficient up to 30% of patients with CSU, especially those with an IgG-mediated autoimmune underlying mechanism ³². Moreover, the effectiveness and safety of omalizumab in the entire range of the pediatric population needs to be clarified in future randomized case-control trials involving a wider and exclusive pediatric population for better management of more severe and refractory cases of CSU in children.

EMERGING THERAPEUTIC OPTIONS UNDER STUDY

In the last years, worldwide working groups have been analyzing new therapeutic options for CSU.

According to the most recent data, some studies have been presented and are still ongoing, regarding the treatment of adults affected by moderate-to-severe refractory CSU with promising biologic drugs, such as UB-221 ³³, YH35324 ³⁴, mepolizumab ³⁵, tezepelumab ³⁶, and briquilimab ^37,38.

None of these drugs have been approved in the pediatric population. However, the literature is being enriched with data derived from the testing of new biologicals in children affected by severe forms of CSU that do not respond to conventional approved treatments in trials or case control studies that are summarized in the sections below.

Ligelizumab

Ligelizumab, a high-affinity humanized monoclonal anti-IgE antibody that prevents free IgE binding to both high-affinity FcεRI and low-affinity CD23 receptors, was developed to inhibit IgE-driven mast-cell and basophil activation with more potency and stability than earlier anti-IgE agents ³⁹.

It has not been approved for the treatment of CSU.

In adolescents (12-18 years) with H1-antihistamine-refractory chronic spontaneous urticaria (CSU), a dedicated multicentre, double-blind phase-2b dose-finding trial (NCT03437278) randomized 49 patients 2:1:1 to subcutaneous ligelizumab 24 mg (n = 24), 120 mg (n = 13) or placebo (n = 12) every 4 weeks for 24 weeks. Baseline mean UAS7 scores were approximately 30-33 across groups; at week 12 the mean change from baseline in UAS7 was -15.7 ± 10.9 for 24 mg, -18.4 ± 12.3 for 120 mg and -13.0 ± 13.0 for placebo, and ligelizumab was generally well tolerated. Importantly, population pharmacokinetic-pharmacodynamic modeling combining adolescent and adult data demonstrated that body weight (but not age) influenced clearance, while model-estimated potency (EC50) and maximal effect (Emax) were similar between adolescents and adults. These findings support the adult-derived dosing regimens in adolescents ⁴⁰. This pediatric and adult phase-2 data were followed by two large, phase-3 “twin” trials (PEARL-1 and PEARL-2), with an identical design, enrolling patients aged ≥ 12 years. Across both studies 2,057 patients were randomized to ligelizumab 72 mg, ligelizumab 120 mg, omalizumab 300 mg, or placebo (3:3:3:1) every 4 weeks for 52 weeks. At the prespecified primary timepoint (week 12, change from baseline in weekly UAS7) both ligelizumab doses were significantly superior to placebo (estimated treatment differences versus placebo ranged approximately -8 to -11 UAS7 points across trials and doses; all p < 0.0001). However, neither ligelizumab dose demonstrated superiority over omalizumab, and no new safety signals were identified versus the established anti-IgE therapy. These results confirm robust anti-urticarial activity for ligelizumab versus placebo but temper the expectations of a clear efficacy advantage over omalizumab in a broadly enrolled population that included adolescents ³⁹.

Beyond controlled trials in CSU, real-world and single-patient reports suggest potential utility of ligelizumab in selected, treatment-refractory, chronic inducible urticaria; for example, Hershkovitz et al. reported successful treatment of a severe, refractory case of solar urticaria with ligelizumab, indicating that anti-IgE therapy with this higher-affinity antibody may be effective in some refractory inducible phenotypes. This observation remains a case report and provides a clinical signal warranting further systematic evaluation in non-CSU urticaria subtypes ⁴¹.

Considered together, the evidence to date indicates that ligelizumab produces clinically meaningful symptom reduction and quality of life benefits in adolescents and adults with antihistamine-refractory CSU, with pharmacometric data supporting similar pharmacodynamic potency across age groups, and a weight-dependent pharmacokinetic profile that clinicians should consider related to the exposure. While the phase-3 PEARL trials confirm superiority versus placebo, they do not show superiority of ligelizumab versus omalizumab; consequently, in pediatric allergology practice, ligelizumab should be regarded as an important emerging option, rather than a clearly superior replacement for established anti-IgE therapy. Its use in adolescents may be justified, considering prior treatment response, body weight, comorbidities, and access considerations, and where possible within the context of registries or trials; larger, dedicated pediatric phase-3 studies and longer-term safety data (particularly in younger children and in non-CSU inducible urticarias) are still needed to define its role in routine management of pediatric CSU.

Dupilumab

Dupilumab is a fully human monoclonal antibody that binds the IL-4 receptor α subunit (IL-4Rα) and thereby blocks signaling of both interleukin-4 and interleukin-13, upstream mediators of type-2 immunity that contribute to IgE class switching, mast-cell activation and pruritus; because of this mechanism dupilumab is approved for multiple type-2 conditions (notably atopic dermatitis and certain forms of asthma) and has been actively investigated for CSU.

In the randomized, placebo-controlled LIBERTY-CSU CUPID program the phase-3 LIBERTY-CSU CUPID Study A (omalizumab-naïve patients, n = 138, aged ≥ 6 years) demonstrated significant and clinically meaningful reductions in urticaria activity at week 24: the difference versus placebo in weekly UAS7 was -8.5 (95% CI -13.2 to -3.9; P = 0.0003) and the difference in itch (ISS7) was -4.2 (95% CI -6.6 to -1.8; P = 0.0005). Study B (omalizumab-intolerant or incomplete responders, n = 108, aged ≥ 12 years) showed an improvement in UAS7 versus placebo (difference -5.8; 95% CI -11.4 to -0.3; P = 0.039), with a numerical (but not statistically significant after multiplicity adjustment) signal for itch reduction, and pooled safety data were consistent with the known dupilumab profile ⁴². Regarding specific pediatric evidence, in addition to the age subgroups included in the CUPID trials, there are ongoing and/or completed pharmacokinetic/safety studies dedicated to children (e.g. the registered CUPIDS KIDS studies/pediatric studies with the following codes: NCT05526521 and NCT04180488). These studies aim to better define dosages, pharmacokinetics and the safety profile in younger children, and form the basis for optimizing clinical use in pediatric patients. Complementary real-world and off-label pediatric experience – while clearly lower in evidence than randomized trials – provides additional, clinically useful signals. A retrospective series and review by Staubach et al. described 18 children with severe or refractory CSU and reported that 3 children treated with alternative agents including dupilumab (approved by local ethics committees) markedly improved (mean UAS7 decreased from ~29 to ~6 in those treated with dupilumab/cyclosporine). Earlier pediatric case series and case reports have documented marked and sustained improvements in severe, treatment-refractory atopic and urticarial phenotypes following dupilumab initiation (examples include a 6-patient pediatric case series with sustained IGA improvements and individual case reports of dramatic responses in children with severe atopic dermatitis or complex immune-mediated dermatitis) ⁴³. Taken together, these data indicate that dupilumab – by interrupting IL-4/IL-13 signaling – can reduce hives and itch and improve the quality of life in patients with H1-antihistamine-refractory CSU, with randomized evidence strongest in omalizumab-naïve patients and an overall safety profile consistent with prior dupilumab trials; however, the pediatric evidence base still rests largely on weight-tiered subgroup data, ongoing pediatric PK/safety trials (CUPIDS KIDS), and small series/case reports. Accordingly, clinicians should integrate clinical trial results, individual patient characteristics (including prior omalizumab response), body weight, and careful safety monitoring when considering dupilumab for children with refractory CSU.

Tezepelumab

Tezepelumab is a fully human monoclonal antibody that targets thymic stromal lymphopoietin (TSLP), an epithelial cytokine implicated in initiating type 2 inflammation through both innate and adaptive immune pathways. By inhibiting TSLP, tezepelumab aims to modulate the early stages of allergic inflammation, offering a potential therapeutic strategy for conditions such as asthma, chronic rhinosinusitis with nasal polyps, and CSU. The phase 2b INCEPTION study evaluated the efficacy and safety of tezepelumab in patients with CSU who were inadequately controlled with second-generation H1 antihistamines. In this multicenter, randomized, double-blind trial, 183 patients were assigned to receive either placebo, tezepelumab (210 mg every 4 weeks or 420 mg every 2 weeks), or omalizumab (300 mg every 4 weeks) for 16 weeks, followed by a 16-week off-treatment period. The primary endpoint, change from baseline in weekly Urticaria Activity Score (UAS7) at week 16, was not met in the overall population. However, in the anti-IgE-naïve subgroup, both tezepelumab doses demonstrated greater improvements in UAS7 compared to placebo, with a trend toward significance observed with omalizumab. Notably, after treatment cessation, a sustained reduction in UAS7 was observed through week 32 in the tezepelumab groups, suggesting a delayed, sustained effect of TSLP blockade. This prolonged benefit was more pronounced in patients with lower baseline IgE levels and longer CSU duration, accompanied by sustained reductions in IL-5 and IL-13 levels. The safety profiles for tezepelumab and placebo were comparable, with no new safety concerns ³⁶.

These findings indicate that while the primary endpoint was not achieved, tezepelumab may offer a novel, upstream-targeted treatment option for CSU, particularly in patients with specific immunologic profiles. Further studies are warranted to confirm these results and to explore the potential role of tezepelumab in the pediatric population.

Rituximab

Rituximab shows potential benefit in severe, refractory chronic autoimmune urticaria, including pediatric cases as described in literature. However, the evidence is limited to a handful of case reports, with variable outcomes and unresolved safety concerns.

An article published by Arkwright et al. in 2009 consisted in a short letter, rather than a real detailed case report, highlighting the possibility that rituximab, an anti-CD20 drug, could be a therapeutic option, alongside anti-IgE approaches, for severe chronic autoimmune urticaria. A 12-year-old boy with immunodeficiency and chronic urticaria associated with angioedema, partially responsive to antihistamines, had a complete remission of symptoms within one week for about one year before a milder relapse after four infusions of rituximab. This contribution seems more a theoretical suggestion then an original clinical case report ^44,45. However, there is a previous published case describing poor results of rituximab in chronic urticaria given to a 33-year-old patient. In this case, the clinical history suggested a physical rather than autoimmune etiology, because of previous lack of response to pulse methylprednisolone, azathioprine or cyclosporine ⁴⁶.

Rituximab use remains off-label and experimental in CSU in children.

Benralizumab and Mepolizumab

The effect of benralizumab has been described in adults affected by CSU. Blocking IL-5 receptor seems improve CSU in some patients. The literature presented a positive single-patient case report describing rapid and clear benefit in symptoms and quality of life after benralizumab treatment in an adult with chronic symptomatic dermographism ⁴⁷. However, benralizumab may worsen CSU in other patients Another case report documented exacerbation of CSU after benralizumab treatment in an adult, suggesting unknown potential bidirectional effects of this drug on CSU ⁴⁸. A multinational, randomized, double-blind phase IIb/III trial was suspended following neutral or negative results of the use of benralizumab in adults with CSU ⁴⁹.

Benralizumab has been used in pediatric eosinophilic asthma (6-11 years) with efficacy and safety that support its use in this indication. Notwithstanding, its use in pediatric CSU is not supported by any trial or case series ⁵⁰.

The evidence for benralizumab in CSU are inconsistent for adults and children and its use for this indication remains experimental or off-label ⁴⁹.

Similar to benralizumab, mepolizumab has not been indicated for the treatment of CSU given the lack of consistent results.

A case report documented clinical benefits of mepolizumab in an adult patient with severe, antihistamine-refractory CSU, showing reduction in urticarial symptoms and improved control ⁵¹. An early phase I clinical trial (NCT03494881) is being conducted to explore the effects of this IL-5 targeting biologic on adults with CSU, with evidence still limited ⁵².

However, an open-label study reported inconsistent results, showing modest and variable efficacy of this drug in adults with CSU ⁵³.

In the pediatric population, mepolizumab has been approved for children older than 6 years with severe eosinophilic asthma, in consideration of confirmed data on efficacy, safety, and tolerability ⁵⁴.

Evident gaps still have to be analyzed regarding the use of mepolizumab in children with CSU, since no randomized trials, open-label studies, or case reports have been published in pediatric CSU treated with this biologic agent.

Etanercept, Anakinra, Canakinumab

Etanercept (anti-TNFα), anakinra (IL-1 receptor antagonist), and canakinumab (anti-IL-1β) have been used as off-label in some case reports, involving both adults and children with chronic urticaria occurring in the context of autoinflammatory syndromes or associated comorbidities. These biologics were administered in highly selected, treatment-refractory cases, and not in classic CSU ^55-57.

CONCLUSIONS, FUTURE PERSPECTIVES

At present, despite encouraging reports, no large head-to-head comparative studies have been conducted among the different biologics in heterogeneous patient populations, either between these agents or omalizumab. Looking ahead, biologics may hold promise for younger children, but no biologic has yet been approved for patients under 12 years of age. Only isolated off-label cases have been reported, in highly selected contexts, with weakness of consistence in terms of safety and efficacy. Moreover, evidence on long-term outcomes and specific subgroups such as adolescents, patients with comorbidities, or during pregnancy remains limited.

A critical unmet need should be the identification of predictive biomarkers of treatment response, which would allow a more personalized therapeutic approach.

Beyond biologics, non-biological targeted therapies, such as small-molecule inhibitors (e.g., remibrutinib, a Bruton tyrosine kinase inhibitor, and tofacitinib, a Janus kinase inhibitor), are currently under investigation. These oral agents may offer a lower-cost alternative. However, pediatric studies are still lacking in the literature.

Ethical consideration

None.

Funding

None.

Conflicts of interest statement

Authors declare no conflict of interest in relation to the present publication..

Author’s contributions

GG and EVB performed the literature analyses and wrote the paper. DP and CC discussed the manuscript and participated to the paper final draft.

History

Received: October 21, 2025

Published: January 23, 2026

Figures and tables

TABLE I. Classification of chronic urticaria (CU).

Clinical Type	Triggers / Comorbidities
Chronic spontaneous urticaria (CSU) with/without angioedema	IdiopathicAutoimmuneOther?
Chronic inducible urticaria (CIU) with/without angioedema	Physical triggersSymptomatic dermographismCold-induced*Heat-induced*Delayed pressureSolar-induced*VibratoryNon-physical triggersCholinergic*Drug-induced (NSAIDs) or allergen-induced*AquagenicAdrenergic*Infectious
* Some forms may be associated with anaphylaxis.

TABLE II. Diagnostic tests for chronic inducible urticaria (CIU).

Type of Urticaria	Site	Test Procedure	Time to Read Result
Symptomatic dermographism	Volar forearm or upper back	Stroke the skin with a blunt, smooth object	10 min
Cold urticaria	Volar forearm	Ice cube wrapped in thin plastic for 5 minutes	10 min
Heat urticaria	Volar forearm	Apply heat source at 45°C for 5 minutes	10 min
Delayed pressure urticaria	Back, thigh, or volar forearm	Apply weight (e.g., 7-kg backpack) for 15 minutes	~6 h (range 0.5-12 h)
Solar urticaria	Covered skin (e.g., buttock)	Expose to UVA, UVB, or direct light	10 min
Vibratory angioedema/urticaria	Volar forearm	Vibration (e.g., vortex at 1000 rpm) for 5 minutes	10 min
Cholinergic urticaria	Whole body or limb	(1) Exercise for 15-30 min or (2) immerse in 42°C water ≥ 15 min after ↑ core temp ≥ 1°C	During and 10 min after test
Aquagenic urticaria	Trunk	Apply compress with water at 35-37°C for 20-30 minutes	End of test
Contact urticaria	Back or forearm	Skin prick tests / Patch tests	15 min (prick);15 min-72 h (patch)
Adrenergic urticaria	Volar forearm	Intradermal injection with 5-15 ng epinephrine or 3-10 ng norepinephrine in 0.02 mL saline	20 min