Assessing Risk Factors for Relapse Following Omalizumab Discontinuation in Chronic Urticaria

Chronic urticaria (CU) is a condition marked by recurring pruritic wheals and/or angioedema persisting for over 6 weeks, with a significant impact on quality of life [1]. Omalizumab provides effective disease control in a high percentage of patients, but little is known about relapse predictors in patients who discontinue the drug after achieving remission. Our study aimed to identify clinical and laboratory factors associated with relapse risk following omalizumab cessation, providing insights into CU management [2]. This observational, multicenter study included 61 CU patients diagnosed per EAACI/GA2LEN/EuroGuiDerm/APAAACI guidelines [1], treated at Hacettepe University and Coimbra University Hospital between 2010 and 2024. All individuals received omalizumab continuously for at least 6 months with good response to treatment, and one group discontinued omalizumab after CU control but had to restart treatment due to CU relapse at least 3 months thereafter and the other group did not experience any relapse, at least during the 6 months of follow-up after discontinuation of omalizumab. Collected data included demographic information, CU duration, weekly urticaria activity scores (Figure S1), and laboratory measures, such as CRP and IgE levels. Results indicated that 37.7% of patients relapsed following omalizumab discontinuation, with a median time to relapse of 8 months (Table S1). Key relapse predictors included male gender (p = 0.014), prolonged CU duration (p < 0.001), elevated baseline CRP (p < 0.001), and shorter omalizumab treatment duration (p = 0.003) (Table 1). In a logistic regression model, each additional month of CU duration was associated with a 1.03% increased relapse risk (OR = 1.033, p = 0.024), while longer omalizumab treatment duration appeared protective (OR = 0.933, p = 0.031). Notably, patients with higher baseline CRP levels experienced a threefold increased relapse risk (Table S2). This is consistent with findings from Baysak et al. who suggested CRP as an indicator of CU activity with CRP values over 3 mg/mL being associated with omalizumab resistance [3]. Our findings expand on previous research by demonstrating that elevated baseline CRP levels not only reflect disease activity but also serve as a predictive biomarker for relapse risk after omalizumab withdrawal, underscoring its clinical significance in CU management. ROC analysis identified optimal cut-off values: patients receiving omalizumab for less than 21 months showed significantly higher relapse risk, and those with CU duration exceeding 121 months had increased likelihood of relapse (Figure 1A,B). These findings suggest that omalizumab therapy should ideally be continued for at least 21 months to minimize the likelihood of relapse. This threshold aligns with previous research indicating that prolonged therapy, particularly exceeding 1 year, can sustain remission and reduce relapse risk [4], eventually explained by the greater chance of resolution of urticaria within a more extended time period. While previous studies have reported conflicting results regarding the impact of gender [5] on relapse risk, our study identified male gender as a significant risk factor despite the predominance of female patients in our population. The potential role of estrogen to enhance immune response and gender differences in histamine receptors and mast cells may support this hypothesis [6]. This finding highlights the need for further research to clarify the role of gender in CU relapse. In conclusion, our study identified male gender, prolonged CU duration, elevated CRP levels, and shorter omalizumab treatment duration as significant predictors of relapse in CU patients following cessation of treatment after complete response. These findings underscore the importance of personalized treatment strategies, suggesting that extending omalizumab therapy may offer protective benefits, especially in patients with prolonged CU history. The limited sample size constitutes a significant limitation of our study; however, the application of rigorous inclusion criteria ensured the reliability and accuracy of the data. Future research involving larger cohorts is warranted to validate these findings and further elucidate predictors of relapse in chronic urticaria after treatment withdrawal. M.C. analyzed the data, wrote, and edited the manuscript. G.K., M.G. conceptualized the study, analyzed the data, and edited the manuscript, H.K., Ç.T., J.T. assisted with data collection and analysis, and edited the manuscript, E.D., A.F.K. edited the manuscript. M.G. has performed lectures or acted as an advisor for AbbVie, AstraZeneca, Almirall, Eli Lilly, Leo Pharma, Novartis, Pfizer, Sanofi-Genzyme, and Takeda. G.K. has performed lectures or acted as an advisor for Novartis, GSK, AstraZeneca, Takeda, Acino. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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