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Efficacy and safety of omalizumab against chronic spontaneous urticaria: Real-world study from China

  • Author Footnotes
    1 These authors contributed equally.
    Ao Wang
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, P.R. China
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  • Author Footnotes
    1 These authors contributed equally.
    Yuhui Yun
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou 510091, P.R. China
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  • Zhihua Wen
    Affiliations
    Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, P.R. China
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  • Yingxia Gao
    Affiliations
    Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, P.R. China
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  • Shuzhen Qi
    Affiliations
    STD Clinic, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, P.R. China
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  • Yu Zhang
    Correspondence
    Corresponding author. Department of Allergy and Rheumatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.12 Jiangwangmiao Street, Xuanwu District, Nanjing city, Jiangsu Province, China.
    Affiliations
    Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, P.R. China
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  • Yunsheng Liang
    Correspondence
    Corresponding author. Department of Dermatology, Dermatology Hospital, Southern Medical University, No.2, Lujing Rd, Guangzhou 510091, China.
    Affiliations
    Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou 510091, P.R. China
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  • Xu Yao
    Correspondence
    Corresponding author. Department of Allergy and Rheumatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.12 Jiangwangmiao Street, Xuanwu District, Nanjing city, Jiangsu Province, China.
    Affiliations
    Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, P.R. China
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  • Author Footnotes
    1 These authors contributed equally.
Open AccessPublished:November 15, 2022DOI:https://doi.org/10.1016/j.waojou.2022.100719

      Abstract

      Background

      Omalizumab is an effective treatment for chronic spontaneous urticaria (CSU) patients aged ≥12 years, but its efficacy in patients aged <12 years has not been fully documented. We evaluated the therapeutic efficacy and safety of omalizumab in Chinese CSU population across all age groups.

      Objectives

      To assess the efficacy and safety of omalizumab treatment against CSU in China.

      Methods

      This study was a retrospective and observational study, and the clinical data of CSU patients treated with omalizumab from October 2018 to August 2021 were collected and analyzed.

      Results

      We enrolled 235 patients in this study, and 54.0% (n = 127/235) of patients were female. All patients received at least three injections of omalizumab treatment, and the mean treatment duration was 3.4 ± 1.0 months. At the end of week-12, 98.7% (n = 232/235) of patients responded to omalizumab, among which 91.1% (n = 214/235) achieved a complete response (CR). An excellent response to omalizumab treatment was observed across all ages. All patients aged <12 years (n = 26) achieved a CR at the end of week-12, and clinical improvement was maintained until treatment cessation. Eighty-seven patients received 3–9-month follow-up after the end of treatment, with a mean duration of 5.7 ± 2.0 months, and 17.2% (n = 15/87) patients experienced recurrence after discontinuing treatment. No factors associated with therapeutic response and recurrence to omalizumab treatment were found in this study.

      Conclusion

      Omalizumab is a safe and efficacious therapy for CSU patients, including those aged <12 years. We recommend addition of omalizumab to the treatment regimen in CSU patients under 12 years of age.

      Trial registration number

      This study was registered in Chinese Clinical Trial Registry (www.chictr.org.cn, Registration number: ChiCTR2200056599).

      Keywords

      Introduction

      Chronic spontaneous urticaria (CSU) is an inflammatory disorder of the skin characterized by recurrent wheals, angioedema, and pruritus for more than 6 weeks. It has been reported that more than 80% of CSU patients could recover within 1 year, but >10% of CSU patients had disease lasting more than 5 years, which seriously impaired quality of life (QoL), interfered with routine daily activities, and mental health.
      • Sánchez-Borges M.
      • Ansotegui I.J.
      • Baiardini I.
      • et al.
      The challenges of chronic urticaria part 1: epidemiology, immunopathogenesis, comorbidities, quality of life, and management.
      The prevalence and clinical features of CSU vary among different ages. A recent meta-analysis indicated that the prevalence of chronic urticaria in patients under 19 years was slightly higher than adults.
      • Fricke J.
      • Ávila G.
      • Keller T.
      • et al.
      Prevalence of chronic urticaria in children and adults across the globe: systematic review with meta-analysis.
      In Europe, the prevalence of CSU was 0.75% in pediatric patients, and it was numerically higher in older age groups (aged 7–11 and 12–17 years) as compared with the youngest age group (aged 0–6 years).
      • Balp M.-M.
      • Weller K.
      • Carboni V.
      • et al.
      Prevalence and clinical characteristics of chronic spontaneous urticaria in pediatric patients.
      Another research of Korea showed the highest prevalence at 0–9 years and the lowest prevalence at 10–19 years.
      • Kim B.R.
      • Yang S.
      • Choi J.W.
      • Choi C.W.
      • Youn S.W.
      Epidemiology and comorbidities of patients with chronic urticaria in Korea: a nationwide population-based study.
      Compared with adults, angioedema was less common in children. It was also reported that nearly 5%–24% children with CSU were affected by angioedema, but this rate in adults was up to 67%.
      • Balp M.-M.
      • Weller K.
      • Carboni V.
      • et al.
      Prevalence and clinical characteristics of chronic spontaneous urticaria in pediatric patients.
      ,
      • Saini S.
      • Shams M.
      • Bernstein J.A.
      • Maurer M.
      Urticaria and angioedema across the ages.
      In addition, children may show a better response to treatment. A study including 198 children and 772 adults with CSU in Korea revealed that the improvement rates at 6, 12, and 24 months after treatment were 60.6, 77.8, and 89.2% in children and 45.7, 63.2, and 74.6% in adults, respectively.
      • Jo Y.H.
      • Yoo H.W.
      • Kim S.H.
      • Kim Y.M.
      • Kim H.Y.
      Clinical characteristics and treatment response of chronic spontaneous urticaria according to age: a single-center Korean study.
      Another study in China also exhibited 82.1% of response rate to antihistamines treatment in children, meanwhile it was 62.2% in adults.
      • Tang N.
      • Mao M.Y.
      • Zhai R.
      • et al.
      [Clinical characteristics of urticaria in children versus adults].
      Second-generation H1 antihistamines (sgAHs) are recommended as first-line treatment for CSU according to the EAACI/GA2LEN/EDF/WAO guidelines.
      • Zuberbier T.
      • Abdul Latiff A.H.
      • Abuzakouk M.
      • et al.
      The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria.
      A four-fold standard or licensed dose can be used if a standard dose is not adequate. However, not all patients respond clearly to the increased dose. One meta-analysis showed that the rate of response for CSU was 38.6% with the standard dose of AHs and 63.2% with the increased dose.
      • Guillén-Aguinaga S.
      • Jáuregui Presa I.
      • Aguinaga-Ontoso E.
      • Guillén-Grima F.
      • Ferrer M.
      Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta-analysis.
      Some patients continue to require additional treatments other than AHs.
      Omalizumab is a monoclonal antibody targeting free immunoglobulin (Ig)E and binding to the FcεRI on mast cells and basophils. Currently, it is the only biological therapy approved for the treatment of antihistamine-resistant CSU patients aged ≥12 years.
      • Zuberbier T.
      • Abdul Latiff A.H.
      • Abuzakouk M.
      • et al.
      The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria.
      ,
      • Agache I.
      • Akdis C.A.
      • Akdis M.
      • et al.
      EAACI Biologicals Guidelines-Omalizumab for the treatment of chronic spontaneous urticaria in adults and in the paediatric population 12-17 years old.
      Previous clinical trials and real-world studies have shown that omalizumab can effectively improve clinical symptoms in CSU.
      • Labrador-Horrillo M.
      • Valero A.
      • Velasco M.
      • et al.
      Efficacy of omalizumab in chronic spontaneous urticaria refractory to conventional therapy: analysis of 110 patients in real-life practice.
      • Maurer M.
      • Rosén K.
      • Hsieh H.-J.
      • et al.
      Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria.
      • Saini S.S.
      • Bindslev-Jensen C.
      • Maurer M.
      • et al.
      Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: a randomized, placebo-controlled study.
      • Unsel M.
      Efficacy of drug therapies in antihistamine refractory chronic spontaneous urticaria: real life data.
      A recent prospective study and several real-world studies in China showed that omalizumab was also a safe and efficacious therapeutic drug for Chinese patients with CSU.
      • Yuan W.
      • Hu S.
      • Li M.
      • et al.
      Efficacy and safety of omalizumab in Chinese patients with anti-histamine refractory chronic spontaneous urticaria.
      ,
      • Chen Y.
      • Yu M.
      • Huang X.
      • et al.
      Omalizumab treatment and outcomes in Chinese patients with chronic spontaneous urticaria, chronic inducible urticaria, or both.
      Nevertheless, participants in most clinical trials are adult patients with CSU. The evidence for omalizumab utilization in patients under 12 years of age are still inadequate.
      In this investigator-initiated retrospective study, we systematically evaluated the therapeutic effects of omalizumab in Chinese CSU patients and compared the therapeutic effects of omalizumab in different age groups. This study also presented information on drug changes during the treatment of omalizumab and explored the potential predictors of response and relapse. Owing to the lack of coverage by insurance in China, it is difficult for patients to adhere to the treatment guidelines completely. Therefore, in this study, the use of omalizumab was adjusted according to the symptoms of patient.

      Methods

      Patients

      Medical records of 347 patients treated with omalizumab were surveyed from October 2018 to August 2021. A diagnosis of CSU was established based on medical history and clinical symptoms according to EAACI/GA2LEN/EDF/WAO guidelines.
      • Balp M.-M.
      • Weller K.
      • Carboni V.
      • et al.
      Prevalence and clinical characteristics of chronic spontaneous urticaria in pediatric patients.
      Forty-four patients were excluded from the study because they were diagnosed with other diseases, and 68 patients were excluded because they did not follow the course of treatment (Fig. 1). Before initiation of omalizumab, patients had to be refractory to at least double dose of AHs or could not tolerate the side effect of AHs.
      A total of 235 patients diagnosed with CSU formed the study cohort. Patients were divided into 4 groups based on their age in years: 0–11, 12–17, 18–59, and ≥60. Patients were started on 150 or 300 mg of omalizumab administered every 4 weeks and completed at least 3 follow-up visits at an interval of 4 weeks. Besides omalizumab, original regimens were retained upon enrollment and were adjusted according to changes in disease condition.

      Data collection

      The detailed information for data collection is provided in supplementary files.

      Assessment of efficacy and relapse

      The Urticaria Activity Score over 7 days (UAS7) was applied to evaluate disease activity and the treatment effect of omalizumab. The Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Dermatology Life Quality Index (DLQI) and Children's Dermatology Life Quality Index (CDLQI) were utilized to assess QoL impairment. The detailed assessment of efficacy and definition of relapse are provided in supplementary files.

      Statistical analysis

      The detailed procedure of statistical analysis and software are listed in the supplementary files.

      Results

      Clinical features of enrolled patients

      A total of 235 CSU patients formed the study cohort, and 54.0% (n = 127/235) of them were female. The mean age of patients was 33.5 ± 15.7 (range: 4–72) years. The mean disease duration was 25.9 ± 33.0 months, assessed as the time from the diagnosis to initiation of omalizumab treatment. The score of UAS7, CU-Q2oL, DLQI and CDLQI was 24.8 ± 8.6, 40.2 ± 14.0, 11.6 ± 4.7 and 9.5 ± 4.8, respectively, upon treatment initiation (Table 1). All patients received at least 3 injections of omalizumab treatment, and the average treatment period was 3.4 ± 1.0 months (Table 1). The medication schedules of omalizumab were shown in Fig. S1. The median level of serum tIgE among 116 patients were 125.0 (IQR:54.1–248.9) kU/L. A total of 71.6% (n = 83/116) of cases had an increased level of serum tIgE (tIgE >60kU/L). ASST was carried out among 105 patients and 52.4% of them (n = 55/105) were positive (Table 1).
      Table 1Clinical features of study population.
      CharacteristicsTotal (n = 235)
      Gender, male, n (%)108(46.0%)
      Ages (year), mean ± SD (range)33.5 ± 15.7 (4–72)
      Disease Duration (month), mean ± SD25.9 ± 33.0
      Baseline of UAS7, mean ± SD24.8 ± 8.6
      Baseline of CU-Q2oL, mean ± SD
      CU-Q2oL and DLQI scores were available for 168 patients aged ≥18 years.
      40.2 ± 14.0
      Baseline of DLQI, mean ± SD
      CU-Q2oL and DLQI scores were available for 168 patients aged ≥18 years.
      11.6 ± 4.7
      Baseline of CDLQI, mean ± SD
      CDLQI scores were available for 44 patients aged <18 years.
      9.5 ± 4.8
      Treatment period, mean ± SD3.4 ± 1.0
      Total IgE (kU/L), median (IQR)
      Total IgE was available for 116 patients. The cut-off value to define a high level of total IgE was >60kU/L.
      125.0 (54.1–248.9)
      Elevated total IgE, n (%)
      Total IgE was available for 116 patients. The cut-off value to define a high level of total IgE was >60kU/L.
      76 (65.5%)
      ASST positive, n (%)
      ASST test was available for 105 patients
      55 (52.4%)
      SD: standard deviation; IQR: inter-quartile range; UAS7: Urticaria Activity Score over 7 days; CU-Q2oL: Chronic Urticaria Quality of Life Questionnaire; DLQI: Dermatology Life Quality Index; CDLQI: Children's Dermatology Life Quality Index; IgE: immunoglobulin E; ASST: autologous serum skin test.
      a CU-Q2oL and DLQI scores were available for 168 patients aged ≥18 years.
      b CDLQI scores were available for 44 patients aged <18 years.
      c Total IgE was available for 116 patients. The cut-off value to define a high level of total IgE was >60kU/L.
      d ASST test was available for 105 patients
      We found that 11.1% (n = 26/235) of patients were under 12 years of age, and the mean age was 8.1 ± 2.0 (range: 4–11) years (Table S1). The clinical characteristics and medication regimen were summarized in Table S1 and Fig. S2.

      Most patients could benefit from omalizumab treatment

      In accordance with other studies, patients showed a rapid response to omalizumab therapy. Within the first 4 weeks of treatment, 96.2% (n = 226/235) of patients achieved a response, and 76.6% (n = 180/235) of them achieved a complete response (CR) (Fig. 2A). At the end of week-12, the proportion of treatment responders had increased to 98.7% (n = 232/235). Among all patients, 91.1% (n = 214/235) showed CR, 7.7% (n = 18/235) showed partial response (PR), and 1.3% (n = 3/235) showed non-response (NR) to omalizumab therapy (Fig. 2A). Consisted with the response to omalizumab, 95.3% (n = 224/235) of patients achieved UAS7 < 7 (“asymptomatic” and “well controlled”) at the end of week-12.
      Fig. 2
      Fig. 2A. The percentage of patients with non-response, partial response, or complete response during omalizumab treatment. B. The percentage of patients under 12 years of age with non-response, partial response, or complete response during omalizumab treatment.
      Patients across all ages responded well to omalizumab treatment (Table 2). A total of 98.4% (n = 186/189) of patients aged ≥18 years had a response to omalizumab treatment and 89.9% (n = 170/189) achieved CR at the end of week-12. Twenty-six patients aged <12 years also showed an excellent response to omalizumab. A total of 84.6% (n = 22/26) of them achieved a CR at the end of week-4. All patients aged <12 years showed CR at the end of week-8 and maintained it during treatment (Fig. 2B).
      Table 2Treatment outcomes of omalizumab in different age groups.
      Characteristic0–11 years (n = 26)12–17 years (n = 20)18–59 years (n = 179)≧60 years (n = 10)
      UAS7, mean ± SD
       Baseline20.9 ± 8.921.2 ± 8.925.9 ± 8.321.0 ± 9.1
       Week 1200.7 ± 2.01.2 ± 4.30
      CU-Q2oL, mean ± SD
      CU-Q2oL were available for 168 patients aged ≥18 years.
       BaselineN/AN/A40.5 ± 14.134.3 ± 10.8
       Week 12N/AN/A0.9 ± 4.50
      CDLQI/DLQI, mean ± SD
      DLQI scores were available for 168 patients aged ≥18 years; CDLQI scores were available for 44 patients aged <18 years
       Baseline9.3 ± 5.09.8 ± 4.611.6 ± 4.810.9 ± 2.7
       Week 1200.3 ± 0.80.4 ± 1.80
      Response, n (%)26 (100%)20 (100%)176 (98.3%)10 (100%)
      Drug discontinuation at the end of entire treatment, n (%)19 (73.1%)12 (60%)119 (66.5%)5 (50%)
      UAS7: Urticaria Activity Score over 7 days; CU-Q2oL: Chronic Urticaria Quality of Life Questionnaire; CDLQI: Children's Dermatology Life Quality Index; DLQI: Dermatology Life Quality Index.
      a CU-Q2oL were available for 168 patients aged ≥18 years.
      b DLQI scores were available for 168 patients aged ≥18 years; CDLQI scores were available for 44 patients aged <18 years

      Omalizumab improved the clinical symptoms and QoL of patients

      A distinct improvement in clinical symptoms and QoL was noted at the end of week-4 and persisted during omalizumab treatment, as assessed by UAS7 and CU-Q2oL scores (Fig. 3, Fig. S3). At the end of week-4, the mean UAS7 score and CU-Q2oL score significantly decreased to 2.5 ± 5.8 (p < 0.0001) and 2.6 ± 7.4 (p < 0.0001) (Fig. 3, Fig. S3). After 12 weeks of treatment, UAS7, CU-Q2oL, DLQI and CDLQI scores decreased to 0.9 ± 3.8 (p < 0.0001), 0.9 ± 4.4 (p < 0.0001), 0.4 ± 1.7 (p < 0.0001) and 0.1 ± 0.5 (p < 0.0001), respectively (Fig. 3, Fig. S3). All clinical scores retained a low-level during the treatment.
      Fig. 3
      Fig. 3Change of UAS7, CU-Q2oL, DLQI and CDLQI scores of all patients from baseline during treatment duration. CU-Q2oL and DLQI were available for 168 patients aged ≥18 years. CDLQI were available for 44 patients aged <18 years. UAS7: Urticaria Activity Score over 7 days; CU-Q2oL: Chronic Urticaria Quality of Life Questionnaire; DLQI: Dermatology Life Quality Index; CDLQI: Children's Dermatology Life Quality Index.
      At the end of week-12, UAS7, CU-Q2oL, DLQI, and CDLQI scores of patients across all ages significantly improved compared with those at the baseline (Table 2). In patients under 12 years of age, UAS7 score fell to 0 at week-8 and were maintained throughout the treatment period (Table 2, Fig. S4).

      Responders and non-responders had similar clinical features

      Only 1.3% (n = 3/235) of patients did not respond to omalizumab treatment at the end of week-12. There were no significant differences in demographic data, disease duration, or baseline scores of UAS7 between responders and non-responders (Table 3). Differences in immunological features were also not found. Because there was only 1 available data for non-responders (Table 3), the comparison for tIgE could not be applicable between treatment responders and non-responders. The proportion of patients with a positive ASST was similar between responders and non-responders (52.0% vs. 66.7%, p > 0.9999) (Table 3), and the speed of efficacy onset was also concordant between the ASST-positive group and ASST-negative group (p = 0.1754) (Fig. S5).
      Table 3The comparison of clinical features and laboratory tests between responders and non-responders.
      CharacteristicsResponder (n = 232)Non-responder (n = 3)P value
      Gender: Female n (%)126 (54.3%)1 (33.3%)0.5953
      Age (year), mean ± SD33.4 ± 15.741.0 ± 12.10.4030
      Disease duration (month), mean ± SD26.0 ± 33.220.0 ± 13.90.7949
      Baseline of UAS7, mean ± SD24.7 ± 8.632.7 ± 9.00.1286
      Elevated total IgE, n (%)
      Total IgE was available for 116 patients. The cut-off value to define a high level of total IgE was >60kU/L. As only one data was available for non-responders, statistical analysis was not applicable.
      76 (66.1%)1 (100%)N/A
      ASST: positive, n (%)
      ASST test was available for 105 patients.
      53 (52.0%)2 (66.7%)>0.9999
      SD: standard deviation; UAS7: Urticaria Activity Score over 7 days; IgE: immunoglobulin E; ASST: autologous serum skin test. ∗ P value for comparisons between responders and non-responders.
      a Total IgE was available for 116 patients. The cut-off value to define a high level of total IgE was >60kU/L. As only one data was available for non-responders, statistical analysis was not applicable.
      b ASST test was available for 105 patients.

      Omalizumab treatment reduced the drug burden of patients

      Before initiating omalizumab treatment, 73.2% (n = 172/235) of patients received double doses of AH, 20.4% (n = 48/235) received AHs and oral glucocorticoid, 2.6% (n = 6/235) received AH and immunosuppressant, and 3.0% (n = 7/235) received a combination of 3 AHs (Table S2). At the end of omalizumab treatment, the proportion of patients using glucocorticoid decreased to 0.4% (n = 1/235, p < 0.0001), and no patient received immunosuppressant (p = 0.0303) (Table S2). Omalizumab treatment also reduced the use of AHs. The use of double dose AHs and a combination of 3 AHs decreased to 5.1% (n = 12/235, p < 0.0001) and 0.4% (n = 1/235, p = 0.0680) at the end of omalizumab treatment, respectively (Table S2). The proportion of patients treated with standard-dose AHs increased to 28.1% (n = 66/235, p < 0.0001) (Table S2). Notably, a significant proportion of patients discontinued treatments other than omalizumab when therapy started. After the first administration, this proportion was 33.6% (n = 79/235, p < 0.0001) and increased to 66.0% (n = 155/235, p < 0.0001) at the end of omalizumab treatment (Table S2).
      Among all age groups, a rate of discontinuation of 73.1% (n = 19/26) was reported in patients under 12 years of age, numerically higher than that of other age groups but without statistical difference (Table 2).

      Relapse after discontinuation of omalizumab treatment

      Up to 92.3% (n = 217/235) of CSU patients achieved “UAS7 = 0” at the end of omalizumab therapy. One hundred and thirty patients dropped out when omalizumab treatment finished, and 40.1% (n = 87/217) of patients finished a 3–9-month follow-up (Fig. 1). The mean duration of follow-up was 5.7 ± 2.0 months. We found that 82.8% (n = 72/87) of patients did not relapse and 17.2% (n = 15/87) of patients experienced a relapse during follow-up. None of patients aged <12 years (17.2%, n = 15/87) had a relapse during follow-up, with a mean remission period of 5.4 ± 2.1 months. The mean relapse duration was 5.5 ± 1.9 months. There were no differences among demographic data, disease duration, baseline clinical scores, and laboratory tests between patients who relapsed and those who did not (Table 4).
      Table 4The comparison of clinical features and laboratory tests between relapsed patients and non-relapsed patients
      CharacteristicsRelapsed (n = 15)Non-relapsed (n = 72)P value
      Gender: Female n (%)7 (46.7%)42 (58.3%)0.5683
      Age (year), mean ± SD31.7 ± 15.730.0 ± 17.40.4637
      Disease duration (month), mean ± SD34.5 ± 47.126.8 ± 31.10.9517
      Baseline of UAS7, mean ± SD25.8 ± 9.322.5 ± 8.90.1790
      Baseline of CU-Q2oL, mean ± SD
      CU-Q2oL scores were available for 54 patients aged ≥18 years.
      42.1 ± 10.535.5 ± 13.30.0929
      Total IgE (kU/L), median (IQR)
      Total IgE was available for 43 patients. The cut-off value to define a high level of total IgE was >60kU/L.
      346.0 (25.9–707.3)129.1 (75.6–231.5)0.6691
      Elevated IgE, n (%)
      Total IgE was available for 43 patients. The cut-off value to define a high level of total IgE was >60kU/L.
      4 (66.7%)28 (75.7%)0.6367
      ASST: positive, n (%)
      ASST test was available for 36 patients.
      6 (75.0%)18 (64.3%)0.6910
      SD: standard deviation; IQR: inter-quartile range; UAS7: Urticaria Activity Score over 7 days; CU-Q2oL: Chronic Urticaria Quality of Life Questionnaire; IgE: immunoglobulin E; ASST: autologous serum skin test. ∗P value for comparisons between relapsed patients and non-relapsed patients.
      a CU-Q2oL scores were available for 54 patients aged ≥18 years.
      b Total IgE was available for 43 patients. The cut-off value to define a high level of total IgE was >60kU/L.
      c ASST test was available for 36 patients.

      Omalizumab was well tolerated

      A total of 84.7% (n = 199/235) of patients discontinued injection of omalizumab at the end of week 12, and the longest treatment duration was 28 weeks. During treatment period, only 2.6% (n = 6/235) of patients reported adverse events (AEs). The most common AE was injection-site reaction, which was reported by 3 patients. Two patients reported body weight gain and increased hair loss, respectively. One patient experienced joint pain. There were no serious AEs.

      Discussion

      Omalizumab is very efficacious and safe for the treatment of AH-resistant CSU. Several real-world studies have reported a rate of response 87.0–91.4% in CSU patients.
      • Unsel M.
      Efficacy of drug therapies in antihistamine refractory chronic spontaneous urticaria: real life data.
      ,
      • Chen Y.
      • Yu M.
      • Huang X.
      • et al.
      Omalizumab treatment and outcomes in Chinese patients with chronic spontaneous urticaria, chronic inducible urticaria, or both.
      • Marzano A.V.
      • Genovese G.
      • Casazza G.
      • et al.
      Predictors of response to omalizumab and relapse in chronic spontaneous urticaria: a study of 470 patients.
      • Ertas R.
      • Ozyurt K.
      • Atasoy M.
      • Hawro T.
      • Maurer M.
      The clinical response to omalizumab in chronic spontaneous urticaria patients is linked to and predicted by IgE levels and their change.
      • Ghazanfar M.N.
      • Sand C.
      • Thomsen S.F.
      Effectiveness and safety of omalizumab in chronic spontaneous or inducible urticaria: evaluation of 154 patients.
      • Salman A.
      • Ergun T.
      • Gimenez-Arnau A.M.
      Real-life data on the effectiveness and safety of omalizumab in monotherapy or combined for chronic spontaneous urticaria: a retrospective cohort study.
      • Ghazanfar M.N.
      • Holm J.G.
      • Thomsen S.F.
      Effectiveness of omalizumab in chronic spontaneous urticaria assessed with patient-reported outcomes: a prospective study.
      Consistent with the previous studies, rapid and effective improvement in clinical scores and QoL were also observed in our study. In our study, 98.7% (n = 232/235) of patients including patients aged <12 years achieved a response at the end of week-12, among which 91.1% (n = 214/235) reached a CR. There are very few studies to systemically evaluate the application of omalizumab in Chinese patients with CSU, especially for patients under 12 years of age.
      • Chen Y.
      • Yu M.
      • Huang X.
      • et al.
      Omalizumab treatment and outcomes in Chinese patients with chronic spontaneous urticaria, chronic inducible urticaria, or both.
      To our knowledge, this study includes the largest cohort of Chinese patients across all ages so far.
      The rate of response in our study was much higher in this study than that reported previously. A recent real-world study in China involving 133 adult CU patients treated with omalizumab reported a total response rate of 87.0% and a CR rate of 65.2%.
      • Chen Y.
      • Yu M.
      • Huang X.
      • et al.
      Omalizumab treatment and outcomes in Chinese patients with chronic spontaneous urticaria, chronic inducible urticaria, or both.
      This inconsistency may be due to the differences in the inclusion criteria. Compared with other studies that mainly included moderate to severe AH-resistant CU patients, 13.2% (n = 31/235) of patients with mild symptoms (UAS7 <16) were included in this study. The baseline UAS7 score in our study was lower than that of other studies. Furthermore, no patients received four doses of AHs prior to initiation of omalizumab treatment, because receiving such a high dose of AHs is usually challenging for Chinese patients. The mild symptoms and medication history may explain the high response rate noted in our study.
      An excellent response to omalizumab treatment in patients under 12 years of age was observed in our study. According to epidemiological studies, the prevalence of chronic urticaria in pediatric patients may be higher than other age groups;
      • Fricke J.
      • Ávila G.
      • Keller T.
      • et al.
      Prevalence of chronic urticaria in children and adults across the globe: systematic review with meta-analysis.
      ,
      • Saini S.
      • Shams M.
      • Bernstein J.A.
      • Maurer M.
      Urticaria and angioedema across the ages.
      whereas the treatment need is not met in patients under 12 years of age. Previous studies have demonstrated that omalizumab may also be an effective therapy in CSU patients under 12 years of age.
      • Song X.T.
      • Chen Y.D.
      • Yu M.
      • Liu B.
      • Zhao Z.T.
      • Maurer M.
      Omalizumab in children and adolescents with chronic urticaria: a 16-week real-world study.
      ,
      • Ari A.
      • Levy Y.
      • Segal N.
      • et al.
      Efficacy of omalizumab treatment for pediatric chronic spontaneous urticaria: a multi-center retrospective case series.
      In this study, all pediatric patients aged <12 years obtained rapid remission after omalizumab treatment, regardless of dose, or administration frequency of omalizumab. In addition, children showed a highest rate of discontinuation across all age groups. These data suggest that omalizumab is an effective treatment for CSU patients under 12 years of age. Treatment with 150 mg omalizumab every 4 weeks was very efficacious in controlling clinical symptoms for children.
      It has been suggested that patients with a high level of tIgE may respond better to omalizumab treatment.
      • Marzano A.V.
      • Genovese G.
      • Casazza G.
      • et al.
      Predictors of response to omalizumab and relapse in chronic spontaneous urticaria: a study of 470 patients.
      ,
      • Ertas R.
      • Ozyurt K.
      • Atasoy M.
      • Hawro T.
      • Maurer M.
      The clinical response to omalizumab in chronic spontaneous urticaria patients is linked to and predicted by IgE levels and their change.
      ,
      • Altrichter S.
      • Fok J.S.
      • Jiao Q.
      • et al.
      Total IgE as a marker for chronic spontaneous urticaria.
      ,
      • Fok J.S.
      • Kolkhir P.
      • Church M.K.
      • Maurer M.
      Predictors of treatment response in chronic spontaneous urticaria.
      Moreover, patients with positive ASST may show a slow response to omalizumab treatment in some studies.
      • Chen Y.
      • Yu M.
      • Huang X.
      • et al.
      Omalizumab treatment and outcomes in Chinese patients with chronic spontaneous urticaria, chronic inducible urticaria, or both.
      ,
      • Kolkhir P.
      • Church M.K.
      • Weller K.
      • Metz M.
      • Schmetzer O.
      • Maurer M.
      Autoimmune chronic spontaneous urticaria: what we know and what we do not know.
      However, our data do not support the notion that the serum tIgE level or positive ASST are predictors of response to omalizumab or the speed of efficacy onset. Another finding is that omalizumab decreased the usage of antihistamines, glucocorticoids and immunosuppressive agents in patients, and more than half of patients discontinued use of other drugs after treatment.
      The relapse rate after discontinuation of omalizumab treatment has been reported to be high, ranging from 17.6% to 67.4%.
      • Labrador-Horrillo M.
      • Valero A.
      • Velasco M.
      • et al.
      Efficacy of omalizumab in chronic spontaneous urticaria refractory to conventional therapy: analysis of 110 patients in real-life practice.
      ,
      • Unsel M.
      Efficacy of drug therapies in antihistamine refractory chronic spontaneous urticaria: real life data.
      ,
      • Chen Y.
      • Yu M.
      • Huang X.
      • et al.
      Omalizumab treatment and outcomes in Chinese patients with chronic spontaneous urticaria, chronic inducible urticaria, or both.
      ,
      • Mandel V.D.
      • Guanti M.B.
      • Liberati S.
      • Demonte A.
      • Pellacani G.
      • Pepe P.
      Omalizumab in chronic spontaneous urticaria refractory to conventional therapy: an Italian retrospective clinical analysis with suggestions for long-term maintenance strategies.
      ,
      • Türk M.
      • Yılmaz İ.
      • Bahçecioğlu S.N.
      Treatment and retreatment with omalizumab in chronic spontaneous urticaria: real life experience with twenty-five patients.
      In our study, the relapse rate was 17.2% (n = 15/87), and none of patients under 12 years of age (n = 15) experienced a relapse during follow-up. No significant differences in clinical features and laboratory tests were found between patients who relapsed and those who did not. The relapse rate was lower compared with that in another study undertaken in China, which reported a relapse rate of 67.4% in adult patients.
      • Chen Y.
      • Yu M.
      • Huang X.
      • et al.
      Omalizumab treatment and outcomes in Chinese patients with chronic spontaneous urticaria, chronic inducible urticaria, or both.
      A possible explanation for this difference is that the symptoms of patients in our study were mild, which resulted in a low relapse rate after discontinuation of omalizumab treatment.
      A potential limitation of this study was that the data was collected only from 2 specialist urticaria centers, which may not perfectly represent the clinical characteristics of all CSU patients in China. Moreover, the analysis of predictors of response to omalizumab treatment was limited because there were only 3 patients who did not respond to omalizumab treatment. Another limitation was that the drug cost of using omalizumab treatment was not recorded in detail, making it difficult to calculate the economic benefits to patients.
      In conclusion, we enrolled the largest number of CSU patients in China across all ages. Although most patients discontinued treatment of omalizumab after 3 injections, omalizumab appears to be a safe, rapid-acting, and efficacious drug for CSU treatment. Omalizumab treatment showed promising results in patients under 12 years of age. We recommend addition of omalizumab to the treatment regimen in patients under 12 years of age and recommend 150 mg every 4 weeks as the initial dose.

      Abbreviations

      AEs; adverse events, ASST; autologous serum skin test, CDLQI; Children's Dermatology Life Quality Index, CR; complete response, CSU; chronic spontaneous urticaria, CU-Q2oL; Chronic Urticaria Quality of Life Questionnaire, DLQI; Dermatology Life Quality Index, IgE; immunoglobulin E, IQR; inter-quartile range, NR; non-response, PR; partial response, QoL; quality of life, SD; standard deviation, sgAHs; second-generation H1 antihistamines, UAS7; Urticaria Activity Score over 7 days

      Author contributions

      A. Wang and Y. Yun performed the study, analyzed the data, and A. Wang wrote the manuscript; Z. Wen, Y. Gao and Q. Shu performed the study; Y. Liang, Y. Zhang, and X. Yao designed and performed the study, coordinated the research, and X. Yao wrote the manuscript.

      Funding source

      This study was support by National Natural Science Foundation of China ( 81703126 , 82073446 , 81972941 ); The Nanjing Incubation Program for National Clinical Research Center (2019060001); The Key Project of Social Development in Jiangsu Province ( BE2020632 ).

      Ethics approval

      The Ethics Committee of Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College (Nanjing, China), and Dermatology Hospital, Southern Medical University (Guangzhou, China) approved this study. This study was registered in Chinese Clinical Trial Registry (www.chictr.org.cn, Registration number: ChiCTR2200056599).

      Consent for publication

      The submission of the article and the publication of the article by World Allergy Organization Journal has been approved by all authors and the responsible authorities at the institution where the work is carried out.

      Availability of data and materials

      The datasets are available on ResMan (http://www.medresman.org.cn/uc/index.aspx).

      Submission declaration

      All authors have read and approved all versions of the manuscript, its content, and its submission to World Allergy Organization Journal. We confirm that the manuscript is original and has not been considered or published elsewhere.

      Declaration of competing interest

      X. Yao received speaker's fees from Novartis , Sanofi Regeneron , LEO, Pfizer , and AbbVie . Y. Liang received speaker's fees from Sanofi Regeneron , Lilly , Novartis , and LEO.

      Acknowledgements

      We would like to express our sincere gratitude to the funding support by National Natural Science Foundation of China ( 81703126 , 82073446 , 81972941 ); The Nanjing Incubation Program for National Clinical Research Center ( 2019060001 ); The Key Project of Social Development in Jiangsu Province ( BE2020632 ).

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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