Safety and effectiveness of omalizumab for the treatment of chronic urticaria in pediatric patients.

BACKGROUND: Evidence on safety and effectiveness of omalizumab for treatment of chronic urticaria in pediatric patients is scarce and limited to case reports. In particular, drug survival of omalizumab has not yet been investigated, which is a key element in the evaluation of its clinical performance. The aim of this study was to investigate safety, effectiveness, and drug survival rates of omalizumab in a daily practice cohort of pediatric patients with chronic urticaria (CU). METHODS: This is a multicenter study including all pediatric patients from an academic center (Wilhelmina Children's Hospital) and a general center (Diakonessenhuis Hospital) in the Netherlands, who started omalizumab treatment before the age of 18 years. Data on safety, effectiveness, time to discontinuation, and reasons for discontinuation of treatment were assessed. Drug survival of omalizumab was estimated using the Kaplan-Meier survival analysis. RESULTS: A total of 38 patients, who started treatment between January 2014 and January 2020, were included. Most patients (68.4%) used omalizumab without reporting any side effects and a complete or good response to treatment was achieved in 76.3% of patients. The 1- and 2-year drug survival rates were 62% and 50%, respectively, with well-controlled disease activity as the most frequent reason for discontinuation in 69.2% of patients, followed by ineffectiveness in 23.1% and side effects in 7.7% of patients. CONCLUSIONS: This study demonstrates high safety and effectiveness of omalizumab treatment in pediatric patients with CU, which will aid clinical decision making and management of expectations when choosing omalizumab treatment for pediatric patients with CU.

Response of FcεRI-bearing leucocytes to omalizumab in chronic spontaneous urticaria.

BACKGROUND: The pathogenesis of chronic spontaneous urticaria (CSU) and the mechanism of action of omalizumab in CSU remain unclear. OBJECTIVE: In this study, we assessed the responsiveness and FcεRI expression of various subsets of leucocytes in patients with CSU treated with omalizumab. METHODS: In this prospective cohort study, 30 patients were treated with 6 administrations of 300 mg omalizumab every 4 weeks, followed by a follow-up period of 12 weeks. FcεRI expression and the percentage of basophils, monocytes, and dendritic cell subsets were analysed before and during treatment, and after follow-up. In addition, anti-IgE- and C5a-induced basophil degranulation was measured. The results were correlated with disease activity and response to omalizumab. RESULTS: In addition to a rapid and significant reduction in FcεRI on basophils, we demonstrated a reduction in FcεRI on plasmacytoid dendritic cells during omalizumab treatment, which persisted until 3 months after discontinuation. FcεRI expression on basophils and its reduction did not correlate with the treatment response. Omalizumab led to an increased percentage of basophils in blood but not of the other FcεRI-bearing leucocytes. Basophil responsiveness was differentially affected; anti-IgE-, but not C5a-induced basophil degranulation increased during the treatment. Apart from clinical non-responders showing a stronger increase in anti-IgE-induced basophil degranulation over a period time, no differences were found in omalizumab responders vs non-responders. CONCLUSIONS/CLINICAL RELEVANCE: FcεRI expression on basophils decreased rapidly, while anti-IgE-induced degranulation significantly increased due to omalizumab treatment in patients with CSU, persisting at least for 3 months after stopping the treatment. None of the markers were able to predict the effectiveness of treatment. Whether basophils play a role in omalizumab responsiveness in CSU remains unclear.

Multinational Drug Survival Study of Omalizumab in Patients With Chronic Urticaria and Potential Predictors for Discontinuation.

Importance: Treating patients with chronic urticaria using omalizumab has been shown to be safe and effective in randomized clinical trials. Multinational studies on long-term omalizumab performance in chronic urticaria in clinical practice settings are lacking, especially on drug survival. Drug survival, which refers to the length of time that patients are treated with a specific drug, is a comprehensive outcome covering effectiveness, safety, and patient and physician preferences. Furthermore, little is known about the reasons and potential predictors for omalizumab discontinuation. Objective: To investigate omalizumab drug survival as well as reasons and potential predictors for discontinuation in a large, diverse population. Design, Setting, and Participants: This international multicenter cohort study was conducted at 14 Urticaria Centers of Reference and Excellence in 10 countries, including all patients with chronic urticaria from these centers who were ever treated with omalizumab. Main Outcomes and Measures: Drug survival analysis was performed to assess time to discontinuation. Patient characteristics and treatment protocols were investigated by Cox regression analysis to identify potential predictors for omalizumab discontinuation. Results: In 2325 patients with chronic urticaria who started omalizumab between June 2009 and July 2022, the mean (SD) age of the cohort was 42 (6) years, and 1650 participants (71%) were female. Overall omalizumab survival rates decreased from 76% to 39% after 1 to 7 years, respectively (median survival time, 3.3 [95 % CI, 2.9-4.0] years), primarily due to discontinuation from well-controlled disease in 576 patients (65%). Ineffectiveness and adverse effects were reasons for discontinuation in a far smaller proportion of patients, totaling 164 patients (18%) and 31 patients (4%), respectively. Fast treatment response was associated with higher rates of omalizumab discontinuation due to well-controlled disease (hazard ratio, 1.45 [95% CI, 1.20-1.75]), and disease duration of more than 2 years was associated with lower rates of discontinuation due to well-controlled disease (HR, 0.81 [95% CI, 0.67-0.98]). Immunosuppressive cotreatment at the start of omalizumab and autoimmune disease was associated with a higher risk for discontinuation due to ineffectiveness (HR, 1.65 [95% CI, 1.12-2.42]). The presence of spontaneous wheals (HR, 0.62 [95% CI, 0.41-0.93]) and access to higher dosages (HR, 0.40 [95% CI, 0.27-0.58) were both associated with a lower risk for discontinuation of omalizumab due to ineffectiveness. Conclusion and Relevance: This multinational omalizumab drug survival cohort study demonstrated that treatment of chronic urticaria with omalizumab in a clinical setting is effective and safe, and well-controlled disease is the main reason for treatment discontinuation. These findings on omalizumab drug survival rates and reasons and potential predictors for discontinuation may guide patients and physicians in clinical decision-making and expectation management. These results may call for the identification of biomarkers for chronic urticaria remission in complete responders to omalizumab treatment.

Systemic and local evidence for complement involvement in chronic spontaneous urticaria.

BACKGROUND: The pathogenesis of chronic spontaneous urticaria (CSU), including the mechanism of action of omalizumab, remain unclear. We hypothesized complement system involvement given the often fast clinical response induced by treatment, including omalizumab. Therefore, we assessed the role of various complement factors surrounding omalizumab treatment. METHODS: Thirty CSU patients (median age 42 [range 21-70]; 73 % female) with a median once daily Urticaria Activity Score over 7 days (UAS7) score at baseline of 31.5 points were enrolled. Treatment consisted of six administrations of 300 mg omalizumab every 4 weeks succeeded by a follow-up period of 12 weeks. Four punch skin biopsies were taken per patient; at baseline from lesional skin, at baseline from nonlesional skin, and after 1 and 7 days from formerly lesional skin. Complement activity, including C1q, C3, C3bc/C3, C4, C4bc/C4, C5a, and Membrane Attack Complex in peripheral blood were analyzed and complement activation in the skin was determined by the analysis of C4d deposition. Results were related to the clinical response to omalizumab. RESULTS: Fifteen patients showed a UAS7 score of 6 or lower (median 0) at Week 24, 15 patients did not (median 16). Lesional skin biopsies at baseline revealed complement deposition (C4d) in blood vessels in the papillary dermis of 53% (16/30) of the patients, which suggests involvement of immune complexes in the pathogenesis of urticaria. Moreover, indication of increased complement activation in CSU was substantiated by increased C5a levels in peripheral blood compared to healthy controls (p = 0.010). The clinical effect of omalizumab could not be linked to the variation of complement components. CONCLUSIONS: Both C4d deposition in lesional skin and elevated C5a levels in peripheral blood indicate the involvement of complement activation in the pathogenesis of CSU. No correlation was found between omalizumab and activation of complement indicative of independent processes in the immunopathogenesis of CSU.