This cross-sectional study was conducted in Izmir City Hospital Dermatology Clinic and included patients diagnosed with chronic spontaneous urticaria (CSU) who were treated with omalizumab. A total of 50 patients receiving omalizumab therapy were retrospectively evaluated through electronic medical records. Patients who had received omalizumab treatment for at least three months and had available clinical follow-up data were included in the study. CSU diagnosis was established according to international guideline criteria and was defined as the spontaneous occurrence of wheals, angioedema, or both for longer than six weeks in the absence of an identifiable external trigger. Monotherapy response data were available for 48 patients, who constituted the primary analytical population.

Clinical, demographic, and laboratory data were extracted using a structured case report form. Recorded demographic and clinical variables included age, sex, height, weight, and body mass index (BMI). Disease-related characteristics comprised disease duration, the presence of angioedema, and the coexistence of inducible urticaria. At omalizumab initiation, all patients were antihistamine-refractory and had received up-dosed second-generation H1-antihistamines according to guideline recommendations. Although standardized disease activity scores (e.g., UAS7 or UCT) were not consistently available due to the retrospective design, all patients had clinically active disease requiring escalation to third-line therapy. Prior treatment intensity was comparable across patients, minimizing potential confounding effects on treatment response classification. Treatment-related parameters included duration of omalizumab therapy, monthly omalizumab dose (300 mg, 450 mg, or 600 mg), and the sufficiency of omalizumab monotherapy. Monotherapy sufficiency was defined as achieving adequate disease control without the need for additional systemic therapy. Omalizumab monotherapy sufficiency was defined as achieving adequate disease control without the need for additional systemic therapy during follow-up. Adequate disease control was operationally defined as the absence of persistent wheals and/or angioedema requiring treatment escalation, as determined by the treating physician. Patients requiring additional therapies (e.g., cyclosporine, systemic corticosteroids, or high-dose antihistamines beyond standard dosing) were classified as monotherapy-insufficient. Treatment response classification was based on clinical evaluation at the third month of omalizumab therapy, consistent with routine clinical practice. Patients requiring concomitant systemic treatment were classified as monotherapy-insufficient. Concomitant therapies were also recorded, including antihistamines, cyclosporine, and systemic corticosteroids.

Baseline laboratory parameters were retrieved from patient records. These included total serum immunoglobulin E (IgE), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), thyroid stimulating hormone (TSH), anti-thyroid peroxidase (Anti-TPO), anti-thyroglobulin (Anti-TG), and complete blood count parameters. Due to the retrospective nature of the study, not all laboratory parameters were available for every patient. Analyses were performed using a complete-case approach, with each variable analyzed based on the number of patients with available data. No imputation methods were applied. Baseline laboratory parameters were defined as values obtained within 4 weeks before or after initiation of omalizumab therapy. When multiple measurements were available, the value closest to treatment initiation was selected for analysis.

All statistical analyses were performed using IBM SPSS Statistics version 27.0 (IBM Corp., Armonk, NY, USA). The distribution of continuous variables was assessed using the Shapiro-Wilk test, as well as histogram and Q-Q plot visualization. Normally distributed variables were expressed as mean ± standard deviation, whereas non-normally distributed variables were reported as median and interquartile range (IQR). Categorical variables were summarized as frequencies and percentages. Patients were stratified into two groups according to omalizumab monotherapy response: monotherapy-sufficient and monotherapy-insufficient. Between-group comparisons were performed using the independent samples t-test for normally distributed variables and the Mann-Whitney U test for non-normally distributed variables. Categorical variables were compared using the chi-square test or Fisher’s exact test where appropriate. To identify independent predictors of omalizumab monotherapy insufficiency, binary logistic regression analysis was conducted. Variables entered into the regression model included body mass index, disease duration, angioedema presence, inducible urticaria, total IgE level, anti-TPO positivity, omalizumab treatment duration, and omalizumab dose. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A two-tailed p value < 0.05 was considered statistically significant.

A total of 50 patients with chronic spontaneous urticaria receiving omalizumab therapy were included in the study. Monotherapy response data were available for 48 patients, who constituted the primary analytical cohort. Omalizumab monotherapy achieved adequate disease control in 26 patients (54.2%), whereas 22 patients (45.8%) required additional systemic therapy and were classified as monotherapy-insufficient. Baseline demographic characteristics were comparable between groups. Median age did not differ significantly between monotherapy-insufficient and sufficient patients (46.5 vs 47.5 years, p = 0.41). Female predominance was observed in both groups without statistical significance (63.6% vs 69.2%, p = 0.76). Angioedema was present in the majority of patients overall and did not differ between response groups (77.3% vs 69.2%, p = 0.75). Similarly, the frequency of inducible urticaria was not associated with treatment sufficiency (22.7% vs 38.5%, p = 0.35). Detailed demographic and clinical characteristics are summarized in Table 1.

Table 1. Demographic and clinical characteristics.

Body mass index differed significantly between groups. Patients with monotherapy insufficiency had higher BMI values compared with sufficient responders (median 29.05 kg/m² [IQR 26.55 - 33.40] vs 25.40 kg/m² [IQR 23.40 - 27.40], p = 0.006). No significant association was observed between disease duration and monotherapy response (p = 0.63). Similarly, omalizumab treatment duration did not differ between groups.

Comparative laboratory analyses revealed no statistically significant differences in total serum IgE levels between groups (p = 0.36). Inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein, were comparable between monotherapy-insufficient and sufficient patients (p = 0.75 and p = 0.59, respectively). Thyroid function tests (TSH) and anti-thyroglobulin antibody levels did not differ significantly. Anti-thyroid peroxidase antibody levels were higher in the monotherapy-insufficient group and reached statistical significance (p = 0.022). However, laboratory availability was limited to a subset of patients. Anti-TPO levels were available in 10 patients, whereas Anti-TG levels were available in 10 patients, and IgE levels were available in 34 patients. These varying sample sizes should be considered when interpreting laboratory comparisons. Laboratory findings are presented in Table 2.

Table 2. Laboratory parameters.

The majority of patients received standard omalizumab dosing of 300 mg/month. Among these, 18 patients were classified as monotherapy-insufficient, whereas 26 achieved adequate disease control. Dose escalation to 450 mg or 600 mg was observed in two patients. Both patients underwent dose escalation due to persistent disease activity despite standard dosing. The duration of treatment at higher doses ranged between 3 and 6 months, and both patients were receiving concomitant antihistamine therapy. Despite dose escalation, adequate disease control was not achieved in these cases. Given the small number of patients undergoing updosing, these findings should be considered descriptive rather than inferential.Dose distribution according to treatment response is shown in Table 3.

Table 3. Omalizumab dose distribution.

Binary logistic regression analysis was performed to identify independent predictors of monotherapy insufficiency. Variables entered into the model included BMI, disease duration, angioedema presence, inducible urticaria, total IgE level, anti-TPO positivity, omalizumab treatment duration, and omalizumab dose. Higher BMI emerged as the only independent predictor of monotherapy insufficiency, whereas other variables did not demonstrate statistical significance.

Overall, these findings indicate that while omalizumab monotherapy provides adequate disease control in approximately half of CSU patients, metabolic factors—particularly increased BMI—may influence treatment sufficiency.

The most notable finding of our study was the significant association between higher body mass index (BMI) and omalizumab monotherapy insufficiency. Importantly, BMI remained the only independent predictor of insufficient response in multivariate analysis.

Obesity is increasingly recognized as a state of chronic low-grade inflammation characterized by adipokine imbalance, altered cytokine profiles, and immune dysregulation [12]. Adipose tissue secretes pro-inflammatory mediators such as leptin, TNF-α, and IL-6, which may enhance mast cell activation and perpetuate inflammatory signaling pathways relevant to CSU pathogenesis [13].

From a pharmacologic perspective, omalizumab dosing in CSU is fixed rather than weight-adjusted. Consequently, patients with higher BMI may receive relatively lower drug exposure per kilogram of body weight. This pharmacokinetic discrepancy has been proposed as a contributing factor to reduced treatment responsiveness [14].

Although limited CSU-specific data exist, similar obesity-related reductions in biologic efficacy have been reported in psoriasis and other inflammatory diseases, supporting the plausibility of this association.

We observed higher Anti-TPO levels in monotherapy-insufficient patients. While the number of tested individuals was limited, this finding aligns with the established association between CSU and autoimmune thyroid disease [11].

Autoimmune CSU endotypes, characterized by autoantibodies against FcεRI or IgE, may exhibit different therapeutic responsiveness compared with IgE-driven disease [10]. It is plausible that autoimmune-mediated mast cell activation may be less responsive to anti-IgE blockade alone, necessitating broader immunomodulatory strategies.

Future studies incorporating basophil activation testing and functional autoantibody assays may further clarify this relationship.

In our cohort, angioedema and inducible urticaria were not associated with monotherapy sufficiency. The prognostic relevance of these features remains controversial in the literature. Some studies suggest angioedema predicts more severe disease, whereas others, similar to our findings, do not demonstrate a significant impact on biologic response [9].

Another clinically relevant observation was the limited efficacy of dose escalation. Only two patients underwent dose escalation to 450 - 600 mg, and both remained insufficient responders. Real-world studies evaluating omalizumab updosing have produced heterogeneous results. While some cohorts report improved response rates, others demonstrate limited benefit [14]-[18]. Our findings support the notion that treatment insufficiency may reflect disease endotype rather than inadequate drug dosing alone. In resistant cases, autoimmune mechanisms, IgE-independent mast cell activation, or alternative inflammatory pathways may predominate, explaining the lack of response to higher anti-IgE dosing.

Taken together, our findings carry several practical implications:

Elevated BMI may serve as a readily accessible clinical predictor of omalizumab monotherapy insufficiency.

Dose escalation alone may not reliably overcome treatment resistance.

Patients with metabolic or autoimmune comorbidities may require earlier consideration of combination or alternative therapies.

These observations underscore the importance of phenotype-driven and potentially endotype-guided treatment strategies in CSU. The limited number of patients undergoing dose escalation precludes definitive conclusions regarding the efficacy of higher dosing strategies. Therefore, our findings should be interpreted as descriptive observations rather than evidence against dose escalation.

In conclusion, our study highlights the multifactorial nature of omalizumab treatment response in CSU. Metabolic status, particularly increased adiposity, appears to play a clinically meaningful role in therapeutic sufficiency. Integrating clinical, immunologic, and metabolic profiling into treatment algorithms may enhance personalized care and optimize outcomes in chronic spontaneous urticaria.