Chronic urticaria (CU) is characterized by erythematous and pruritic plaques, accompanied or not by angioedema, lasting more than six weeks. It can be classified as chronic spontaneous urticaria (CSU) when it occurs without a specific trigger, or chronic inducible urticaria (CIndU) when it occurs after a specific stimulus, primarily physical. Its course and duration are unpredictable, ranging on average from six months to five years.1 It is estimated that CSU affects 0.5% to 1% of the global population, which is equivalent to two-thirds of CU cases, negatively impacting patients' quality of life.2

The pathophysiology of CU has not yet been fully elucidated, but the role of histamine, as well as some pro-inflammatory cytokines released by mast cells and basophils, is indisputable. The main mechanism associated with CSU is autoimmune, based on the presence of class G autoantibodies directed at high-affinity IgE receptors (FceRI) on mast cells and basophils or at circulating IgE molecules, in addition to IgE autoantibodies directed at various endogenous antigens.3 The pathogenesis of CIndU is not yet fully understood, but the mechanisms involved in CSU also seem to play an important role.4

Therapeutic management is escalated according to severity and refractoriness to treatment and includes the use of second-generation H1 antihistamines at standard doses as recommended in the package insert up to quadruple doses, anti-IgE monoclonal antibody (omalizumab), and cyclosporine.1

Despite advances in treatment, CU management is still based on a trial-and-error approach, with little ability to predict which patients will respond to a given treatment phase, which contributes to a longer time to achieve symptom control and increases the costs associated with therapy.5

In recent years, several studies have sought to identify clinical and laboratory markers capable of predicting therapeutic response in patients with chronic urticaria, particularly regarding the second-generation H1 antihistamines, omalizumab, and cyclosporine. According to a systematic review by Fok et al.,5 elevated Urticaria Activity Score (UAS7) values, as well as increased serum CRP and D-dimer levels, are associated with a lower response to second-generation H1 antihistamines. Regarding omalizumab, low IgE levels, a positive Autologous Serum Test (AST), and a positive Basophil Histamine Release Test (BHRA) were identified as possible predictors of poor or delayed response. In contrast, in the case of cyclosporine, there is evidence that a positive BHRA and reduced IgE levels may indicate a better response to treatment.

Complementarily, Giménez-Arnau et al.6 also observed that high disease activity, increased CRP, ESR, and D-dimer levels are the main predictors of an absent or unsatisfactory response to second-generation H1 antihistamines. Furthermore, low or very low baseline IgE, a positive AST, a positive basophil activation/histamine release test (BAT/BHRA+), basopenia, eosinopenia, and elevated D-dimer were associated with an absence of response to omalizumab but a good response to cyclosporine. Conversely, normal or slightly elevated baseline IgE levels, as well as increased expression of the FcεRI receptor on basophils, seem to indicate a more rapid response to omalizumab.

Despite these findings, there is still little solid evidence in the literature on clinical and laboratory markers that can practically guide therapeutic choices, especially in specific contexts such as in Brazil. Therefore, further studies to validate these findings in different populations are needed.

Therefore, the present study aims to analyze possible clinical and laboratory predictors of treatment response in patients with chronic urticaria treated at a referral center, aiming to contribute to more personalized and efficient disease management.

This study evaluated clinical and laboratory predictors of treatment response in 175 patients with CU followed at a referral center. The analysis showed that clinical variables such as high BMI, female gender, early symptom onset, prolonged disease duration, and the presence of mental disorders were associated with a worse therapeutic response, especially in the initial phases of treatment with second-generation H1 antihistamines.

Among patients who responded or did not respond to low doses of H1 antihistamines, high BMI was significantly more common in nonresponders, reinforcing previous data associating obesity with greater CU severity, poorer symptom control, and longer disease duration, possibly due to chronic low-grade inflammation with higher concentrations of cytokines such as IL-6.13,14

Longer disease duration and early symptom onset were also markers of refractoriness, especially in patients taking increased doses of H1 antihistamines, which is consistent with data from Engstrom et al.,15 which indicate worse clinical outcomes in these subgroups. Prolonged duration of chronic urticaria is associated with greater clinical severity, as demonstrated by Toubi et al.,16 who observed that moderate to severe forms of CU persisted for significantly longer periods than mild cases. This association may reflect a more intense and sustained inflammatory process, possibly related to autoimmune mechanisms, such as the presence of autoantibodies against the IgE receptor (positive TSA) or antithyroid autoantibodies, both associated with longer disease duration. Additionally, a study showed that young patients with CU (18–40 years) had higher mortality, and that each additional year of disease increases the risk of developing mental disorders by 64% compared to controls.17

Furthermore, the higher proportion of women in the group requiring omalizumab may reflect the greater severity of CU in this group, which is also consistent with studies that attribute the higher frequency of refractory forms of the disease to the female sex, possibly due to the higher prevalence of autoimmune diseases among women.18

The presence of mental disorders, in turn, was consistently associated with a worse response to both antihistamines and omalizumab. This finding reinforces the importance of neuroimmunoendocrine axes in the pathophysiology of CU and the impact of stress, anxiety, and substance P on mast cell activation.19,20 Substance P, in particular, can bind to the MRGPRX2 receptor, present on the surface of mast cells, promoting their exacerbated activation, which may contribute to the persistence of symptoms in these patients.21 It is worth noting that the study by Kolkhir et al.17 revealed an increased risk of mortality among patients with CSU, including higher rates of suicidal ideation and suicide attempts. This evidence reinforces the need for a multidisciplinary approach in the management of CSU.

Although previous studies5,6 have shown that elevated CRP and D-dimer levels, as well as eosinopenia, are associated with poor response to H1 antihistamines, and that low total IgE, elevated CRP/ESR, eosinopenia, and increased D-dimer could predict a lower response to omalizumab and a better response to cyclosporine, none of these associations were confirmed in the present study in the evaluated therapeutic phases. These tests were requested based on the hypothesis that systemic inflammatory processes, reflected by markers such as CRP and ESR,22,23 and coagulation activation, evidenced by D-dimer, play a role in the pathophysiology of chronic urticarial.23,24 Eosinopenia, in turn, has been associated with increased migration of eosinophils into tissues, which contributes to local inflammation and may indicate increased disease activity, autoimmunity, and poor therapeutic response,8,25 while total IgE is considered a possible marker of atopic phenotype and response to omalizumab.26,27 However, the present results suggest that, taken alone, these biomarkers have limited predictive value in clinical practice, especially in the present sample. It is important to highlight that the number of patients with D-dimer measurements was small, which may have compromised the analysis. Furthermore, in the present population, eosinophil and total IgE levels may have been higher due to confounding factors, such as the presence of concomitant atopic diseases and intestinal parasitic infections, common in endemic regions.

The analysis of omalizumab response subtypes and IgE levels revealed no statistically significant association, although all partial responders had IgE levels <40 IU/mL. This finding differs from the meta-analysis by Chuang et al.,28 but is consistent with studies that also failed to identify this correlation,9,29,30 reinforcing the complexity of this relationship. IgE plays a central role in the pathophysiology of CSU, being involved in both autoallergic mechanisms (type I) and type IIb autoimmune forms, where low IgE levels often coexist with IgG autoantibodies against IgE or its receptor (FcεRI).26 Therefore, the quantification of total IgE has been proposed as a predictive marker of response to omalizumab, with worse results observed in patients with lower IgE. However, in the present sample, the small number of non-responders and partial responders may have limited the detection of a statistically significant association.

Similarly, no association was observed between anti-TPO levels and response to omalizumab, a result similar to that described by Asero et al.,31 but different from that by Kolkhir et al.32 The association between thyroid autoimmunity and CU has been described, with several studies demonstrating a high prevalence of IgE and IgG autoantibodies against thyroid antigens (such as TPO and thyroglobulin) in patients with CSU. These autoantibodies can promote mast cell and basophil activation, contributing to the disease pathophysiology.33 Although thyroid autoimmunity is associated with greater severity and poorer therapeutic response,34 it is unclear whether isolated autoantibodies predict refractoriness. Biomarkers such as BAT, positive TSA, and elevated ANA have been associated with poor response in other studies but were not included in this analysis.

ROC curve analysis for total IgE demonstrated limited performance, with an area under the curve of 0.634 (p = 0.327), confirming its low specificity as an isolated marker of response to omalizumab. Although higher IgE levels are associated with a more favorable response in some studies,5,35 these data were not significantly replicated in the present sample, limiting its usefulness as an isolated predictor of response to treatment with this drug.

Therefore, the results reinforce the hypothesis that clinical and psychosocial characteristics are, to date, the main predictors of therapeutic response in chronic urticaria. The cross-sectional design, the small number of non-responders to omalizumab, and the lack of data on the duration of drug exposure are limitations that should be considered. In addition to these limitations, it is important to recognize that the study was conducted with a convenience sample recruited at a specialized tertiary center, which may have generated selection bias, limiting the representativeness of the general population with chronic urticaria. To minimize this bias, well-defined inclusion and exclusion criteria were used, with data collection performed in a standardized manner by a trained team using validated instruments (UCT and AECT). The potential information bias is also recognized, inherent to the use of medical record data, which was mitigated by systematically reviewing records and supplementing information during medical consultations, always with the patients’ prior consent.

Regarding external validity, because this is a single-center study, extrapolation of the results to other populations should be done with caution, taking into account the specific clinical and epidemiological profile of the study sample. On the other hand, internal validity was ensured by adopting diagnostic criteria based on international guidelines (EAACI/GA²LEN/EDF/WAO), using standardized therapeutic protocols, and by applying validated instruments to assess treatment response.

Prospective studies with standardized biomarker assessment are required to validate the findings and guide precision medicine in CU management.

The study aimed to analyze predictive markers of treatment response in patients with chronic urticaria. The research reinforces the complexity of CU and its management challenges, highlighting its predominance in women, adult onset, and long disease duration. The main predictors of poorer response to treatment were longer disease duration, female sex, high BMI, early symptom onset, and the presence of mental disorders. Eosinophils, total IgE, and the other evaluated laboratory markers (ESR, CRP, D-dimer, and anti-TPO) showed no significant association with therapeutic response.

Joanemile Pacheco de Figueiredo: 0000-0002-1899-8935

Leila Vieira Borges Trancoso Neves: 0000-0003-2364-2391

José Carlisson Santos de Oliveira: 0000-0003-4040-8257

Janinne Souza de Oliveira: 0009-0002-0108-945X

Vitória Rani Figueiredo: 0009-0002-9518-2806

Régis de Albuquerque Campos: 0000-0001-9524-761X

Joice Trigo da Fonseca: Design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript; statistical analysis; approval of the final version of the manuscript.

Joanemile Pacheco de Figueiredo: Collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript; approval of the final version of the manuscript.

Leila Vieira Borges Trancoso Neves: Collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript; approval of the final version of the manuscript.

José Carlisson Santos de Oliveira: Collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript; approval of the final version of the manuscript.

Janinne de Souza Oliveira: Collection, analysis, and interpretation of data; critical review of the literature. Critical review of the manuscript; approval of the final version of the manuscript.

Vitória Rani Figueiredo: collection, analysis, and interpretation of data; critical review of the literature; critical review of the manuscript; approval of the final version of the manuscript.

Régis de Albuquerque Campos: Design and planning of the study; effective participation in research orientation; collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript; approval of the final version of the manuscript.

None declared.

The entire dataset supporting the results of this study was published in this article.