Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2025;15(3):5196 1 Factors Influencing Relapse After Omalizumab in Chronic Urticaria. Does the Method of Discontinuation Influence Relapse? Petek Üstün1, Esra Adışen2 1 Deparment of Dermatology, Aksaray Training and Research Hospital, Aksaray, Turkey 2 Deparment of Dermatology, Gazi University Faculty of Medicine, Ankara, Turkey Key words: Urticaria, Omalizumab, Relapse Citation: Üstün P, Adışen E. Factors Influencing Relapse After Omalizumab in Chronic Urticaria. Does the Method of Discontinuation Influence Relapse? Dermatol Pract Concept. 2025;15(3):5196. DOI: https://doi.org/10.5826/dpc.1503a5196 Accepted: February 4, 2025; Published: July 2025 Copyright: ©2025 Üstün et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Petek Üstün, MD, Department of Dermatology, Aksaray Training and Research Hospital, Tacin Street, 68200 Aksaray, Türkiye. Orcid ID: 0000-0001-9051-8580. E-mail: pustun8@gmail.com Introduction: Omalizumab is recommended for chronic urticaria (CU) until spontaneous remission occurs rather than for a specific period of time. The rate of relapse after treatment varies depending on the method of discontinuation. Objectives: Our study aimed to investigate how the method of omalizumab discontinuation and other factors affect the rate of post-treatment relapses. Methods: Patients with CU were divided into three groups based on their method of discontinuing omalizumab treatment: direct discontinuation, extending treatment intervals to eight weeks, and re- ducing the treatment dose to 150 mg/4 weeks. These groups were then compared for relapse rates. Results: A total of 200 patients were included in this study. Among the 109 patients who discontinued omalizumab directly, 65.1% experienced a relapse. The relapse rate was 40.7% in those who extended the treatment intervals to eight weeks and 15.6% in those who reduced the dose to 150 mg/4 weeks. There was a statistically significant difference in post-treatment relapse rates according to the method of discontinuation (P< 0.001). Conclusions: Gradual tapering of treatment rather than direct discontinuation has been shown to prolong remission. Achieving the lowest relapse rate with a reduction in the treatment dose to 150 mg/4 weeks is significant for the design of omalizumab discontinuation protocol and provides insights for future studies. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2025;15(3):5196 Introduction Chronic urticaria (CU) is characterized by wheals and an- gioedema that persist for more than six weeks and signifi- cantly impair the quality of life of patients due to its pruritic nature. The prevalence of CU is estimated to be between 0.5% and 1% of the population [1]. Omalizumab is a mono- clonal antibody that targets IgE and is the preferred third- line treatment for CU patients who have not responded to a fourfold dose of antihistamines (AHs). The efficacy and safety of omalizumab 300 mg in patients with CU refractory to AHs have been demonstrated in three pivotal Phase III randomized controlled trials in which 52.4% to 58.8% of patients achieved well-controlled urticaria [2]. In patients with a complete response to omalizumab, there is currently no consensus on the optimal method and timing for cessation of treatment. To determine whether the disease is in remission, periodic attempts to discontinue omalizumab in patients with completely controlled disease may be beneficial. This is frequently achieved by discontin- uing omalizumab treatment within six months to one year in a significant proportion of patients [3]. To date, three dis- tinct methods of discontinuation have been described in the literature: direct discontinuation, gradual extension of the dose intervals to eight weeks while maintaining a response for at least two doses within this period, and dose reduction to 150 mg every four weeks while maintaining a response for at least two doses at this level. Stepwise tapering has been linked to both improved disease control and a longer remis- sion period. Patients who discontinued omalizumab directly were compared with those who gradually extended the dose intervals before discontinuation [4,5]. Objective Given the limited literature available on this topic, the aim of our study was to investigate how the method of omalizumab discontinuation, as well as other factors, affects the rate of post-treatment relapses. Methods Ethics Approval This study was approved by the local ethics committee and conducted in accordance with the tenets of the Declaration of Helsinki (05.2023.499.). Informed consent was obtained from all participants. Study Population This study included patients aged 12 years or older who were diagnosed with CU and treated with omalizumab at a dose of 300 mg every four weeks for at least three months between January 2009 and May 2022. Each patient was followed for at least 15 months after discontinuing omalizumab. Patients who were resistant to standard omalizumab treatment and required higher doses or intervals shorter than four weeks were excluded. Additionally, patients lost to follow-up after completing omalizumab treatment were also excluded. Data Collection and Analysis Patients with CU are followed at intervals of 4-8 weeks. At each visit, symptom severity and disease control are assessed using the 7-day Urticaria Activity Score (UAS7) and the Ur- ticaria Control Test (UCT). Moreover, serum IgE and blood basophil levels are measured and documented at weeks 0 and 4 of treatment. The demographic and clinical characteristics of the patients, including age, sex, comorbidities, disease duration, presence of angioedema, concomitant treatments, method of omalizumab discontinuation, and time to re- lapse after treatment, were obtained from electronic medical records. A UAS7 score of less than 6 is defined as a good response to omalizumab treatment [6]. In our study, we attempted to discontinue treatment in patients with a UAS7 score of less than 6 following omalizumab therapy. Patients were divided into three groups based on the method of discontinuing omalizumab treatment: direct discontinuation, extending the treatment intervals to eight weeks, and reducing the treat- ment dose to 150 mg every four weeks. Relapse in patients with CU was defined as the recurrence of symptoms after discontinuation of omalizumab treatment, determined by a UCT <12 or a UAS7 score >16 [7,8]. These groups were then compared for relapse rates. Statistical Analysis Statistical analysis of the data was performed using IBM SPSS 24.0. Descriptive statistics were calculated as mean (± standard deviation), median and range for continuous variables, and percentages for categorical variables. For cat- egorical variables, the chi-squared test was used to compare independent groups. Continuous variables with a normal distribution were analyzed using an independent samples t-test for independent groups and a paired samples t-test for dependent groups. For non-normally distributed variables, the Mann-Whitney U test was used to analyze data between independent groups. A p-value of less than 0.05 was consid- ered statistically significant. Results Demographic and Clinical Characteristics The study included 200 patients with CU. The mean age of the patients was 45.86 years, and 66% (n = 132) of the Original Article | Dermatol Pract Concept. 2025;15(3):5196 3 patients were female. The demographic, clinical, and labo- ratory characteristics of the patients are shown in Table 1. The duration of CU prior to omalizumab treatment ranged from 1 to 39 months, with a median of 6.09 months. A history of angioedema was present in 49.5% (n=99) of the patients. At baseline and week 4 UAS7 scores of the patients were available for 154 and 151 patients, respectively. The mean baseline UAS7 score was 37.45, and the mean week 4 UAS7 score was 7.79. There was a statistically significant decrease in UAS7 scores at week 4 compared to baseline (P<0.001). Laboratory Characteristics Serum IgE levels at baseline and week 4 were available for 106 and 65 patients, respectively. The median IgE level was 101.50 IU/ml at baseline and 275 IU/ml at week 4. Forty-seven patients (90.4%) demonstrated an increase in IgE levels at week 4, while five (9.6%) showed a decrease. A statistically significant increase in serum IgE levels was observed from baseline to week 4 (P<0.001). Blood baso- phil levels were measured in 143 patients at baseline and in 52 patients at week 4. The mean basophil level remained at 0.03 (1000/µL) from baseline to week 4. Basopenia was present in 20 patients (13.9%) at baseline. Omalizumab Treatment All patients had used AHs prior to starting omalizumab. While 27 patients (13.5%) had not received any additional treatment, 173 patients (86.5%) continued to use AHs along- side omalizumab treatment. Of these, 125 (62.5%) adhered to the treatment regularly, with a mean duration of 4.90 months, while 48 patients (24%) used AHs only as needed (Table 2). The total duration of omalizumab use ranged from 3 to 39 months, with a mean duration of 19.47 months. Post-Treatment Relapse Status After at least three months of standard omalizumab treat- ment, 109 patients (54.5%) discontinued omalizumab treatment directly, 59 patients (29.5%) extended the dose intervals to eight weeks, and 32 patients (16%) reduced the dose to 150 mg/4 weeks before discontinuation. Among pa- tients who completed treatment, relapse was observed in 100 patients (50%), with a median time to relapse of four months (range: 1–40). The most common relapse occurred in the third month, affecting 27% (n= 7) of the patients, and 49% (n=49) of patients experienced a relapse within the first three months of treatment (Table 2). Among those who discontinued omalizumab directly, relapse was observed in 65.1% (n=71) of cases, while among those who extended the dose intervals, relapse was observed in 40.7% (n=24) of cases. Among those who reduced the dose prior to discontinuation, relapse was observed in 15.6% (n=5) of cases. There was a statistically significant difference in post-treatment relapse rates according to the method of treatment discontinuation (P<0.001) (Table 3, Figure 1). In patients who discontinued omalizumab directly, re- lapse occurred after an average of 6.77 months. For those who discontinued treatment by extending the dose inter- vals, the mean time to relapse was 6.71 months, while in patients who reduced the dose before discontinuation, it was 4.8 months. No statistically significant difference was ob- served between the groups in the time to relapse based on the method of discontinuation (P=0.841). In addition to the method of discontinuation of omal- izumab treatment, the impact of other demographic and clinical characteristics of patients with CU on relapse rates was evaluated (Table 4). The total disease duration before omalizumab treatment was 7.67 months in patients with re- lapses, while it was 4.51 months in patients without relapses. The pre-treatment disease duration was significantly longer in the relapse group (P<0.001). Patients who discontinued AHs within the first three months of omalizumab treatment had a significantly lower relapse rate than did those who continued AHs for a longer duration (P=0.005). The mean baseline UAS7 score was 39.21 for patients who experienced a relapse (n=78) compared to 35.64 for those who did not (n=76). A significantly higher relapse rate was observed in patients with higher baseline UAS7 scores (p=0.004). Sub- group analysis based on age, sex, coexisting angioedema, hypothyroidism, basopenia, previous treatments, treatment response time, baseline serum IgE level, reduction in UAS7 score, and increase in serum IgE level at week 4 of therapy did not reveal a statistically significant difference in terms of post-treatment relapse rates. After experiencing a post- treatment relapse, 10 patients (10%) achieved adequate symptom control with AH treatment, while 90 patients (90%) reinitiated omalizumab therapy. Discussion This study showed that the method of discontinuation of omalizumab significantly impacts the rate of post-treatment relapses. To our knowledge, this is the first study to com- pare three different methods of treatment discontinuation in terms of relapse rates. Our results suggest that reducing the dose or gradually increasing the intervals between doses, as opposed to direct discontinuation, leads to reduced relapse rates after omalizumab treatment. The female-to-male ratio for CSU reported in the liter- ature is consistent with our study findings [9]. A previous study reported that the prevalence of CSU was lowest in patients aged 18-24 years, while the disease was most com- monly observed in the 45-54 age group [10]. The mean age 4 Original Article | Dermatol Pract Concept. 2025;15(3):5196 Table 1. The demographic, clinical, and laboratory characteristics of the patients. Characteristics N = 200 Sex, n (%) Female Male 132 (66) 68 (34) Age, years Mean ± SD (range) 45.86 ± 14.97 (12-79) Duration of disease †, months Median (range) 6.09 (1-39) Angioedema, n (%) Present Absent 99 (49.5) 101 (50.5) Comorbidities, n (%) Hypertension Allergic diseases Diabetes mellitus Hypothyroidism Hyperlipidemia Psychiatric diseases 109 (54.5) 30 (15) 21 (10.5) 18 (9) 14 (7) 8 (4) 6 (3) Trigger factors, n (%) Stress Physical factors Pressure Heat Cold Dermographism Drug Food İnfection 150 (75) 90 (45) 37 (18.5) 10 (5) 9 (4.5) 5 (2.5) 5 (2.5) 25 (12.5) 24 (12) 10 (5) CU subtypes, n (%) CSU CIU CSU + CIU 163 (81.5) 14 (7) 23 (11.5) Previous treatments, n (%) AH Monotherapy In combination‡ Systemic CS Cyclosporine Doxepin 200 (100) 110 (55) 90 (45) 78 (39) 5 (2.5) 3 (1.5) UAS7 score, mean ± SD Baseline 4th week of the treatment 37.45 ± 7.67 7.79 ± 10.75 Serum IgE level, (IU/mL), median Baseline 4th weeks of the treatment 4th weeks of the treatment 101.5 275 2.7 Blood basophil level§, (1000/µl), mean ± SD (range) Baseline 4th week 0.03 ± 0.02 0.03 ± 0.03 Note: †The duration of disease encompasses the period before starting omalizumab treatment. ‡The group of patients utilizing antihistamines in combination, also received systemic corticosteroids, doxepin, and dapsone concurrently. §The laboratory’s reference range for the mea- surements was 0.01–0.07 (1000/µl). SD, standard deviation; CU, chronic urticaria; CSU, chronic spontaneous urticaria; CIU, chronic inducible urticaria; CS, corticosteroid; AH, antihistamine; UAS7, urticaria activity score over 7 days; IgE, Immunoglobulin E; IU, International unit. Original Article | Dermatol Pract Concept. 2025;15(3):5196 5 Table 2. Characteristics of Omalizumab Treatment and Post-Treatment Relapse. Characteristics Duration of treatment, months Mean ± SD (range) 19.47 ± 15.53 (3-39) Concomitant AH use, n (%) Present Regular Occasional Absent 173 (86.5) 125 (62.5) 48 (24) 27 (13.5) Treatment response time, months, median (range) Fast (1st month), n (%) Slow (>1 month), n (%) 1 (1-12) 126 (70.3) 52 (29.7) Duration of AH use, months Mean ± SD (range) 4.90 ± 4.13 (1-24) Treatment discontinuation method†, n (%) 300 mg/4 weeks 300 mg/8 weeks 150 mg/4 weeks 109 (54.5) 59 (29.5) 32 (16) Relapse rate, n (%) Present Absent 100 (50) 100 (50) Time to relapse, months Median (range) 4 (1-40) Relapse time, n (%) 1-3 months 4-6 months 7-12 months >12 months 49 (49) 21 (21) 19 (19) 11 (11) Post-relapse treatment, n (%) AH Omalizumab 10 (10) 90 (90) †Patients were categorized based on their approach to discontinuing omalizumab treatment: cessation directly (300 mg every 4 weeks), pro- longing the dosing interval to 8 weeks (300 mg every 8 weeks), and reducing the dosage to 150 mg every 4 weeks. SD, standard deviation; AH, antihistamines Table 3. Relapse rates according to the method of discontinuing treatment. Relapsed, n (%) Non-relapsed, n(%) P value 300 mg/4 weeks 71 (65.1) 38 (34.9) < 0.001* 300 mg/8 weeks 24 (40.7) 35 (59.3) 150 mg/4 weeks 5 (15.6) 27 (84.4) *continuity correction test Figure 1. A statistically significant difference in the post-treat- ment relapse was observed according to the method of treat- ment discontinuation (P<0.001) in our study fell within the age range where the highest prev- alence has been reported in the literature. The relapse rate in this study is comparable to the 44.4% and 50% rates reported in the 6-month OPTIMA study and the 43.4% and 45.1% rates reported in the 24-to-48- week XTEND-CIU study [11]. Gradual tapering has been 6 Original Article | Dermatol Pract Concept. 2025;15(3):5196 Table 4. The association between characteristics of patients and relapse rate. Relapse rate, n (%) P valueRelapsed Non-relapsed Sex Female Male Total 64 (48.5) 36 (52.9) 100 (50) 68 (51.5) 32 (47.1) 100 (50) 0.550* Age Mean ± SD (years) Total 46.43 ± 14.15 100 (50) 45.30 ± 15.74 100 (50) 0.594** Angioedema Present Absent Total 54 (54.5) 46 (45.5) 100 (50) 45 (45.5) 55 (54.5) 100 (50) 0.203* Hypothyroidism Present Absent Total 6 (42.9) 94 (50.5) 100 (50) 8 (57.1) 92 (49.5) 100 (50) 0.782*** Duration of disease Mean ± SD (months) Total 7.67 ± 6.55 100 (50) 4.51 ± 4.40 100 (50) < 0.001** Previous treatments AH >1 agent Total 52 (47.3) 48 (53.3) 100 (50) 58 (52.7) 42 (46.7) 100 (50) 0.394* Treatment response time 1st month >1 month Total 65 (51.6) 21 (40.4) 86 (48.3) 61 (48.4) 31 (59.6) 92 (51.7) 0.174* Duration of AH use ≤3 months >3 months Total 22 (35.5) 38 (60.3) 60 (48) 40 (64.5) 25 (39.7) 65 (52) 0.005* Basopenia Present Absent Total 7 (35) 63 (52.1) 70 (49.6) 13 (65) 58 (47.9) 71 (50.4) 0.241*** Baseline UAS7 score Mean ± SD Total 39.21 ± 6.11 78 (50.65) 35.64 ± 8.66 76 (49.35) 0.004** The decrease in UAS7 score at the 1st month Mean ± SD (∆) Total 31.22 ± 12.32 76 (50.33) 27.84 ± 12.18 75 (49.66) 0.092** Baseline serum IgE level (IU/mL) Median Total 111 55 (51.88) 89 51 (48.12) 0.410** Ratio of serum IgE level at week 4 to baseline Mean ± SD Total 3.97 ± 1.73 25 (48.07) 4.31 ± 2.19 27 (51.93) 0.544** *Pearson chi-squared test; **Independent sample t-test; ***continuity correction test SD, standard deviation; AH, antihistamines; UAS7, urti- caria activity score over 7 days; IgE, Immunoglobulin E; IU, International unit. associated with better disease control and longer remissions [4]. Our study results support these findings. When compar- ing discontinuation methods, the lowest relapse rates were observed in patients who discontinued omalizumab treat- ment by reducing the dose, followed by those who gradually extended the dose intervals. The highest relapse rates were observed in patients who discontinued treatment directly without altering the dose or dose interval. Previous studies have shown that patients who gradually tapered treatment by extending the dose intervals to eight weeks had a lower relapse rate compared to those who discontinued treatment directly. In the OPTIMA study, patients who discontinued omalizumab treatment by reducing the dose to 150 mg/4 weeks had a relapse rate of 44%, while patients who discon- tinued treatment at a dose of 300 mg/4 weeks had a relapse rate of 50% [4,5]. This may be because patients who tapered were able to stop treatment in a more controlled manner. Some patients who discontinued treatment directly did so in- dependently of their physician, believing they had recovered, which likely contributed to higher relapse rates in this group. Patients who tolerate step therapy not only require less medication but are also more likely to discontinue treatment. The duration that patients can tolerate varies as dose inter- vals are increased. In one study, patients were followed at 12-week intervals, while in another study, 6-week intervals were found to be adequate for symptom control; however, Original Article | Dermatol Pract Concept. 2025;15(3):5196 7 Marzano et al. found that high baseline UAS7 scores and longer disease duration were associated with higher relapse rates, while Salman et al. identified younger age (<40 years) as a factor contributing to more frequent relapses [4,16]. In a study of 152 patients, Su et al. found that longer disease du- ration was significantly associated with higher relapse rates, whereas duration of omalizumab treatment did not affect the occurrence of relapses [15]. Similarly, Sardana et al. con- cluded that omalizumab administration for longer than 6–12 months did not reduce relapse rates [17]. These findings un- derscore the lack of consensus among researchers regarding the factors influencing relapse rates. Recent studies have reported that even when treatment was continued for at least one year, symptoms returned in approximately 61% of patients after omalizumab discon- tinuation. When symptoms worsened, AHs often proved to be inadequate, prompting the majority of patients to resume omalizumab treatment. Türk et al. reported that 91% of pa- tients who achieved a complete response to omalizumab and experienced relapse after discontinuation needed to restart omalizumab [11,18]. Similarly, most patients in our study restarted omalizumab due to an inadequate response to AHs. When considering retreatment with omalizumab in relapsing patients, the clinician’s assessment and the patient’s expecta- tions are important. According to an established algorithm, omalizumab should be reinitiated in relapsing patients if the UAS7 score is >6 or the UCT is <12. Furthermore, disease severity and history of angioedema are also important fac- tors. From another perspective, if the patient’s symptoms are milder, the patient should be followed and omalizumab treatment should be considered if the UAS7 score is >16 [19]. Limitations There are several limitations to this study, including its ret- rospective nature, small sample size, lack of a control group, and short follow-up period. Extending the follow-up period might have provided more comprehensive results, particu- larly with regard to the occurrence of relapses beyond the initial 15 months. Conclusion The present study found a higher relapse rate in patients with longer disease duration, higher baseline UAS7 scores, and prolonged use of AHs with omalizumab for more than three months. These factors may serve as useful indicators for patient monitoring and treatment decisions. Gradual ta- pering of treatment rather than direct discontinuation has been shown to prolong remission. Achieving the lowest re- lapse rate by reducing the treatment dose to 150 mg/4 weeks is crucial to designing the omalizumab discontinuation pro- tocol and provides valuable insights for future studies. patients could not tolerate further increases in dose intervals [3]. In our study, patients whose symptoms remained con- trolled or were well controlled (UAS7 <6) for at least two months were discontinued after tolerating 8-week dose inter- vals. To date, no study has compared relapse rates in patients who were tapered to 150 mg/4 weeks versus those who had their intervals extended to eight weeks. The observation of the lowest relapse rate after dose reduction in our study is an important finding for omalizumab discontinuation strat- egies. Further comprehensive studies are needed to support this hypothesis. When analyzing the results of our study, no significant correlation was found between the relapse rates and the clinical and demographic characteristics of the patients. In a study conducted in China involving 235 patients, sex, age, disease duration, baseline IgE level, and, unlike in our study, baseline UAS7 score did not differ significantly between the relapse and non-relapse groups [12]. However, Chen et al. found that shorter disease duration and low baseline IgE lev- els (<100 IU/ml) were associated with a lower relapse rate [13]. Similarly, Ertaş et al. suggested that high baseline IgE levels (>100 IU/ml) correlated with faster relapse compared to normal serum IgE levels. They also found that IgE levels did not influence the response to omalizumab. It has been hypothesized that in patients with high baseline IgE levels, IgE is cleared from the blood within a few days after treat- ment discontinuation, leading to a faster onset of relapse due to rapid IgE synthesis [14]. In contrast to analyses suggesting that baseline serum IgE levels influence both relapse rate and frequency, our study found no significant association be- tween baseline serum IgE levels and these outcomes. Further comprehensive studies are needed to fully elucidate the effect of IgE levels on relapse. There is limited knowledge in the literature regarding the factors that influence relapse after omalizumab treatment. Predicting relapse duration is crucial to assessing disease prognosis and determining appropriate follow-up and treat- ment plans for patients [15]. Factors such as disease dura- tion, baseline UAS7 score, and duration of concomitant AH use with omalizumab have been significantly associated with relapse. Higher relapse rates have been observed in patients with longer disease duration [15,16], which aligns with our findings that more severe clinical presentations are linked to a higher risk of relapse. Similarly, patients with high baseline UAS7 scores demonstrated significantly higher relapse rates. Additionally, those who used AHs with omalizumab for more than three months had a higher relapse rate than did those who used AHs for three months or less. This suggests that prolonged use of AHs may indicate a more severe course of CU and an increased risk of relapse. Notably, no study has been found in the literature that specifically compared the duration of concomitant AH use with relapse frequency. 8 Original Article | Dermatol Pract Concept. 2025;15(3):5196 population analysis. J Am Acad Dermatol. 2019; 81:152- 156. DOI: 10.1016/j.jaad.2019.02.064. PMID: 30872154. 11. Türk M, Carneiro-Leão L, Kolkhir P, Bonnekoh H, Buttge- reit T, Maurer M. 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