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Omalizumab treatment and outcomes in Chinese patients with chronic spontaneous urticaria, chronic inducible urticaria, or both

  • Yudi Chen
    Affiliations
    Department of Dermatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China

    Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China

    Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China

    National Clinical Research Center for Skin and Immune Diseases, Beijing, China
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  • Miao Yu
    Affiliations
    Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China

    Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China

    National Clinical Research Center for Skin and Immune Diseases, Beijing, China

    Peking University School of Nursing, Beijing, China
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  • Xiaojie Huang
    Affiliations
    Center for Infectious Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
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  • Ping Tu
    Affiliations
    Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China

    Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China

    National Clinical Research Center for Skin and Immune Diseases, Beijing, China
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  • Peikun Shi
    Affiliations
    Friends' Central School, PA, USA
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  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-senior authors.
    Marcus Maurer
    Correspondence
    Corresponding author. Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Charitéplatz 1, Berlin, D-10117, Germany.
    Footnotes
    1 These authors contributed equally to this work and should be considered co-senior authors.
    Affiliations
    Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité-Universitatsmedizin Berlin, Berlin, Germany
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  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-senior authors.
    Zuotao Zhao
    Correspondence
    Corresponding author. Department of Dermatology and Venereology, Peking University First Hospital, Xishiku Avenue No.8, Beijing, China.
    Footnotes
    1 These authors contributed equally to this work and should be considered co-senior authors.
    Affiliations
    Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China

    Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China

    National Clinical Research Center for Skin and Immune Diseases, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-senior authors.
Open AccessPublished:January 05, 2021DOI:https://doi.org/10.1016/j.waojou.2020.100501

      Abstract

      Background

      Chronic urticaria (CU) is a common skin disorder, which can be further divided into chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU). Omalizumab is effective and safe for difficult-to-treat CSU based on clinical trials. However, there are limited data comparing the therapeutic effect of omalizumab for patients with CSU, CIndU, and CSU plus CIndU. Meanwhile, there is still no reliable predictor for treatment response or relapse. Our study was conducted to collect real-world clinical data on omalizumab treatment in patients with CSU, CIndU, and both.

      Methods

      This was an observational, retrospective chart review of patients with CU initiating omalizumab treatment between February 2018 and May 2020 (maximum 28 months follow-up).

      Results

      A total of 138 patients were included, 87 with CSU alone, 33 with different forms of CIndU, and 18 with both. A total of 87.0% (n = 120/138) of the CU patients responded to omalizumab therapy, among which 65.2% (n = 90/138) of the patients showed complete response and 21.7% (n = 30/138) of the patients showed partial response. The therapeutic effect and speed of onset of effect for omalizumab were comparable among patients with CSU, CIndU, or both. Autologous serum skin test (ASST)-positive patients were more likely to show a slow response to omalizumab therapy (P = 0.043). Non-responders had lower baseline total IgE levels (35.0 vs 121.5 kU/L, P < 0.001). The proportion of patients with low total IgE levels in non-responders was significantly higher than that of responders (61.1% vs. 14.5%, P < 0.001). Also, more non-responder patients had elevated thyroid autoantibodies than responders (50.0% vs. 23.0%, P = 0.041). The median ratio of serum IgG-anti-TPO to serum total IgE in non-responders was significantly higher compared with responders (1.22 vs. 0.09, P < 0.001). Non-responders also had shorter treatment periods (4.5 vs 6.0 months, P = 0.035) compared with responders. Two of 3 patients (67.4%, n = 29/43) experienced relapse after ceasing omalizumab therapy. These patients had longer disease durations (52.0 vs. 15.0 months, P = 0.007) and higher baseline total IgE levels (179.9 vs. 72.5 kU/L, P = 0.020) than patients who did not relapse. We reinitiated omalizumab treatment for 10 relapsed patients, all of them reported a rapid response after the first injection within the first 4 weeks of retreatment.

      Conclusion

      Omalizumab is highly effective in patients with difficult-to-treat CSU, CIndU, or both. Responders tend to have unique immunological features and longer treatment periods. Patients with higher baseline total IgE levels and longer disease durations are more likely to experience rapid relapse after discontinuation of omalizumab.

      Keywords

      Introduction

      Chronic urticaria (CU) is characterized by the recurrence of itchy wheals, angioedema, or both for more than 6 weeks. The prevalence of CU in Asia is 1.4%, higher than that in Europe (0.5%) and North America (0.1%).
      • Fricke J.
      • Ávila G.
      • Keller T.
      • et al.
      Prevalence of chronic urticaria in children and adults across the globe: systematic review with meta-analysis.
      It is divided into 2 types, chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU)—the latter including, for example, cold urticaria, cholinergic urticaria, and symptomatic dermographism.
      • Zuberbier T.
      • Aberer W.
      • Asero R.
      • et al.
      The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.
      CU markedly impairs quality of life (QoL) with significant impact on sleep, work performance, and social interactions.
      The EAACI/GA2LEN/EDF/WAO urticaria guideline recommends approved doses of second-generation H1-antihistamines as the first-line treatment for CU, and up to 4 times the approved dose as the second-line treatment.
      • Zuberbier T.
      • Aberer W.
      • Asero R.
      • et al.
      The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.
      However, a significant proportion of patients continue to experience symptoms even with high-dose antihistamine treatment and require more effective therapies.
      • Maurer M.
      • Abuzakouk M.
      • Bérard F.
      • et al.
      The burden of chronic spontaneous urticaria is substantial: real-world evidence from ASSURE-CSU.
      ,
      • Maurer M.
      • Weller K.
      • Bindslev-Jensen C.
      • et al.
      Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report.
      According to the EAACI/GA2LEN/EDF/WAO urticaria guideline, omalizumab is recommended as the only third-line therapy option for patients with antihistamine-resistant CU.
      • Zuberbier T.
      • Aberer W.
      • Asero R.
      • et al.
      The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.
      Omalizumab (Xolair®) is a recombinant humanized monoclonal anti-IgE antibody that binds circulating free IgE and downregulates the high-affinity receptor for IgE (FcϵRI).
      • 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.
      ,
      • Kaplan A.P.
      • Giménez-Arnau A.M.
      • Saini S.S.
      Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticaria.
      The clinical efficacy and safety of omalizumab in CSU has been shown in several clinical trials and real-life studies.
      • 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.
      • Maurer M.
      • Rosén K.
      • Hsieh H.J.
      • et al.
      Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria.
      • Kaplan A.
      • Ledford D.
      • Ashby M.
      • et al.
      Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy.
      • Sussman G.
      • Hébert J.
      • Gulliver W.
      • et al.
      Omalizumab retreatment and step-up in patients with chronic spontaneous urticaria: OPTIMA trial.
      • Bernstein J.A.
      • Kavati A.
      • Tharp M.D.
      • et al.
      Effectiveness of omalizumab in adolescent and adult patients with chronic idiopathic/spontaneous urticaria: a systematic review of 'real-world' evidence.
      • Tharp M.D.
      • Bernstein J.A.
      • Kavati A.
      • et al.
      Benefits and harms of omalizumab treatment in adolescent and adult patients with chronic idiopathic (spontaneous) urticaria: a meta-analysis of "real-world" evidence.
      Our study was conducted to evaluate the efficacy and time of response to omalizumab in Chinese patients with CSU, CIndU, or both, who had an inadequate response to H1-antihistamine treatment. The recently validated Chinese version of urticaria control test (UCT) was used to assess disease control status in this retrospective clinical study.
      • Yu M.
      • Chen Y.
      • Liu B.
      • Song X.
      • Zhao Z.
      Validation of Chinese version of urticaria control test (UCT).
      Additionally, the present study provides information on drugs used in combination with omalizumab, relapse, retreatment and potential predictors of response and recurrence of symptoms after omalizumab discontinuation.

      Materials and methods

      Study design

      This was a retrospective, observational, investigator-initiated study examining real-world treatment scenarios of antihistamine-resistant CU in China. The data for this study were retrieved retrospectively from patients’ medical records. The study was approved by the China Ethics Committee of Registering Clinical Trials (IRB: ChiECRCT20190131). The review board waived the need for informed consent. The study was designed, implemented, and reported in accordance with the Guidelines for Good Pharmacoepidemiology Practices of the International Society for Pharmacoepidemiology and the STROBE guidelines.

      Patients

      We included 138 adult patients with CSU, CIndU, or both who had received at least 1 injection of omalizumab and had at least 1 follow-up visit between February 2018 and May 2020. Preliminary results on the outcome of omalizumab treatment in some of the patients analysed here were reported previously.
      • Chen Y.
      • Maurer M.
      • Yu M.
      • Tu P.
      • Zhao Z.
      Addition of omalizumab to antihistamine treatment in chronic urticaria: a real-world study in China.
      CU was diagnosed based on the patients' history and clinical picture according to the EAACI/GA2LEN/EDF/WAO urticaria guideline; other diseases and syndromes presenting with wheals, angioedema or both (eg, urticarial vasculitis, Schnitzler's syndrome, cryopyrin-associated periodic syndromes, bradykinin-mediated angioedema) were ruled out. In patients with CIndU, specific provocation tests were performed to verify the diagnosis. Provocation tests and threshold testing were performed using a FricTest® (Moxie, Berlin, Germany) for symptomatic dermographism, a TempTest® (Courage & Khazaka, Berlin, Germany) for cold and heat urticaria, and physical exercise provocation test for cholinergic urticaria. To be started on omalizumab therapy, patients had to be unresponsive to second generation H1-antihistamines (SGAHs). Patients were excluded if they were participating in any clinical trials for CU during the observation period or if they were treated with omalizumab for any other indication (eg, allergic asthma, allergic rhinitis).

      Assessment of treatment efficacy and relapse

      The urticaria control test (UCT) was applied to assess disease control status for all CU patients.
      • Yu M.
      • Chen Y.
      • Liu B.
      • Song X.
      • Zhao Z.
      Validation of Chinese version of urticaria control test (UCT).
      ,
      • Weller K.
      • Groffik A.
      • Church M.K.
      • et al.
      Development and validation of the urticaria control test: a patient-reported outcome instrument for assessing urticaria control.
      The UCT has a 4-week recall period and consists of 4 questions, each with 5 answer options (scored 0–4 points), where low points indicate high disease activity and poor disease control. The minimum and maximum UCT score is 0 and 16, respectively. A “complete response” was defined by UCT = 16 during the period of treatment with omalizumab, with/without H1-antihistamine therapy. A “partial response” was defined as UCT ≥12 during omalizumab treatment period, with/without H1-antihistamine therapy. “Non-response” was defined as UCT <12 during omalizumab treatment. Patients who showed complete response or partial response were considered as “responders”. Patients with CSU also completed the urticaria activity score (UAS) once daily, and the 7-day UAS (UAS7) was calculated.
      Patients' QoL was assessed by the dermatology life quality index (DLQI) during the study period.
      • Finlay A.Y.
      • Khan G.K.
      Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use.
      A DLQI of 21–30 indicates extremely large impairment of patients' QoL, 11–20 indicates very large impairment, 6–10 implies moderate impairment, 2–5 implies small effect on patients' QoL, and 0–1 marks no effect at all on patient's QoL.
      • Finlay A.Y.
      • Khan G.K.
      Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use.
      Relapse was defined as the reappearance of CU symptoms (UCT < 12) in complete responders after discontinuation of omalizumab treatment.

      Laboratory data

      Serum total IgE was measured by a chemiluminescent immunoassay (ImmunoCAP; ThermoFisher Scientific, Sweden), and levels of 100 kU/L or greater were defined as increased. Autologous serum skin test (ASST) was performed through the intracutaneous injection of autologous serum as described previously.
      • Konstantinou G.N.
      • Asero R.
      • Maurer M.
      • Sabroe R.A.
      • Schmid-Grendelmeier P.
      • Grattan C.E.
      EAACI/GA2LEN task force consensus report: the autologous serum skin test in urticaria.
      Thyroid autoantibodies including serum thyroid peroxidase antibody and thyroglobulin antibody were determined using an electrochemiluminescence immunoassay (Roche Elecsys-2010; Roche Diagnostics, U.S.) and the normal reference ranges were 0–34 IU/ml, and 0–115 IU/ml, respectively.

      Data collection

      Data were collected from clinical records of the patients. Demographics (age, sex), baseline urticaria profiles (disease duration, type of chronic urticaria, concomitant angioedema, total IgE level, levels of thyroid autoantibodies, ASST result, UCT, DLQI, and UAS scores) and omalizumab treatment patterns (treatment durations, drugs used in combination with omalizumab and adverse events) were retrieved.

      Statistical analysis

      Descriptive statistics included the mean ± standard deviation (SD) or median (interquartile range, IQR) as appropriate for continuous variables, as well as frequency (percentage) for categorical variables. Descriptive statistics were performed for demographic and different clinical variables including disease durations, concomitant angioedema, omalizumab treatment periods, types of urticaria, results of laboratory data, medications, relapse, and retreatment. For the analysis of clinical outcomes (UCT or DLQI), a Wilcoxon test was applied. Chi-square tests were used for group comparisons of categorical variables. The independent samples t-test or Mann–Whitney non-parametric test was used for comparisons of continuous variables between groups, as appropriate. Kaplan-Meier estimator and log-rank statistics were performed to analyse response time. Receiver-operator characteristic (ROC) curves were generated to compare the ratio of IgG-anti-TPO/IgE, IgG-anti-TPO and total IgE. The area under the curve (AUC) of the ROC value was calculated for the response evaluation of omalizumab treatment. ROC analyses were used to define cut-off points of IgG-anti-TPO/IgE, IgG-anti-TPO and total IgE to determine omalizumab response. A P value less than 0.05 was considered to indicate statistical significance.

      Results

      Antihistamine-resistant CU patients show poor disease control at baseline

      In total, 138 patients were included, and 63.0% (n = 87/138) of them had CSU only, 23.9% (n = 33/138) of them had CIndU only, 13.0% (n = 18/138) of them had both CSU and CIndU (Table 1). The majority of the patients were female (66.7%, n = 92/138), and the mean age was 39.6 ± 13.4 years (Table 1). The oldest patient was 84 years old. The median CU duration, assessed as the time from CU diagnosis to omalizumab initiation, was 24 months (IQR: 12–56 months). In total, 35.5% (n = 49/138) had a diagnosis of CU with angioedema at baseline (Table 1). The average omalizumab treatment period was 6.0 months (IQR: 4.0–11.0 months). All of the patients had a UCT<12 at baseline, indicative of uncontrolled disease, and the median baseline UCT was 3.0 (IQR: 0.0–4.0). Baseline DLQI was 18.0 (IQR:14.0–21.0), indicating a very large impact on patient QoL.
      Table 1Demographic data of patients with CSU, CIndU or both
      CharacteristicsOverall (n = 138)CSU (n = 87)CIndU (n = 33)CSU+CIndU (n = 18)
      Age (years)39.6 ± 13.444.3 ± 13.729.9 ± 7.634.8 ± 8.9
      Female, n (%)92 (66.7)62 (71.3)19 (57.6)11 (61.1)
      Disease duration (mo)24 (12–56)24 (12–66)15 (12–36)26 (18–51)
      Angioedema, n (%)
      All patients with angioedema also had wheals in this study.
      49 (35.5)35 (40.2)6 (18.2)8 (44.4)
      Omalizumab treatment periods (mo)6.0 (4.0–11.0)7.0 (4.0–12.0)5.0 (2.5–8.0)5.0 (3.5–7.0)
      Baseline UCT3.0 (0.0–4.0)2.0 (0.0–4.0)3.0 (1.5–5.0)3.5 (1.0–4.3)
      Baseline DLQI18.0 (14.0–21.0)18.0 (13.0–21.0)19.0 (16.0–21.0)18.5 (16.3–21.3)
      Total IgE (kU/L)
      Normal reference range: < 100 kU/L. IgE results were available for 128 patients.
      94.4 (48.9–309.0)95.1 (42.0–320.0)98.0 (68.5–313.0)90.1 (47.1–259.8)
      Elevated total IgE, n (%)
      The cutoff value to determine an elevated total IgE level: ≥100 kU/L. IgE results were available for 128 patients.
      61 (47.7)40 (48.2)13 (48.1)8 (44.4)
      ASST positive, n (%)
      ASST results were available for 88 patients.
      47 (53.4)30 (60.0)9 (37.5)8 (57.1)
      Elevated thyroid autoantibodies, n (%)
      Thyroid autoantibody levels were available for 105 patients
      29 (27.6)20 (26.7)2 (15.4)7 (41.2)
      Abbreviations: ASST: autologous serum skin test; CIndU: chronic inducible urticaria; CSU: chronic spontaneous urticaria; DLQI, dermatology life quality index; UCT: urticaria control test.
      a All patients with angioedema also had wheals in this study.
      b Normal reference range: < 100 kU/L. IgE results were available for 128 patients.
      c The cutoff value to determine an elevated total IgE level: ≥100 kU/L. IgE results were available for 128 patients.
      d ASST results were available for 88 patients.
      e Thyroid autoantibody levels were available for 105 patients
      The median IgE level was 94.4 (48.9–309.0) kU/L, and 47.7% (n = 61/128) of patients had elevated (>100 kU/L) levels of IgE. Blood levels of antithyroid autoantibodies were elevated in 29 of 105 patients (27.6%). More than half of the patients (53.4%, n = 47/88) were autologous serum skin test (ASST)-positive.

      Omalizumab treatment reduces the use of oral corticosteroids and immunosuppressive agents

      Before commencing omalizumab treatment, all of the patients had received a higher than standard dosed second-generation H1-antihistamine (SGAH) or a combination of different SGAHs. Omalizumab treatment was administered concurrently with antihistamines in 74.6% (n = 103/138) of patients, among which nearly half (n = 50/103, 48.5%) of the patients received standard-dosed SGAHs, 18.4% (n = 19/103) received updosed SGAHs, and 33.0% (n = 34/103) were treated with a combination of different SGAHs.
      Only very few patients used treatments other than antihistamines at the time when omalizumab therapy was started (traditional Chinese medicine: n = 15, methotrexate: n = 4, oral corticosteroid: n = 5, cyclosporine A: n = 5, antidepressant: n = 7).
      Before omalizumab treatment, oral corticosteroids were used by 24.6% (n = 34/138) of patients, and the use of oral corticosteroids significantly decreased to 3.6% (n = 5/138) after commencing omalizumab (P < 0.001). Similarly, the use of immunosuppressive agents (eg, azathioprine, cyclosporine A, methotrexate) also significantly decreased from 26.8% (n = 37/138) to 6.5% (n = 9/138) after initiating omalizumab (P < 0.001). There were 35 (25.4%, n = 35/138) patients who received no other medication when omalizumab therapy was started.

      Most of the CU patients benefit from omalizumab therapy

      A total of 87.0% (n = 120/138) of the CU patients responded to omalizumab therapy, among which 65.2% (n = 90/138) of the patients showed complete response and 21.7% (n = 30/138) of the patients showed partial response (Table 2). Patients with CSU, CIndU, or both responded to omalizumab therapy in 86.2% (n = 75/87), 90.9% (n = 30/33) and 83.3% (n = 15/18) of cases, respectively (Table 2). The proportions of complete response in patients with CSU only (69.0%, n = 60/87) or CIndU only (72.7%, n = 24/33) were significantly higher (P = 0.009) than that of patients with both CSU and CIndU (33.3%, n = 6/18). Meanwhile, the proportions of patients who achieved DLQI≤1 indicating no QoL impairment in patients with CSU only (74.7%, n = 65/87) or CIndU only (69.7%, n = 23/33) were also significantly higher (P = 0.040) than that of patients with both CSU and CIndU (44.4%, n = 8/18). The improvements of UCT and DLQI at week 12 or throughout the treatment period were comparable between patients with CSU, CIndU and both (Table 3).
      Table 2Response to omalizumab in patients with different types of urticaria
      Types of CUNComplete responsePartial responseNon-response
      CSU8760 (69.0%)15 (17.2%)12 (13.8%)
      CIndU3324 (72.7%)6 (18.2%)3 (9.1%)
       SDerm2317 (73.9%)5 (21.7%)1 (4.3%)
       ColdU11 (100.0%)00
       CholU85 (62.5%)1 (12.5%)2 (25.0%)
       SDerm+ColdU11 (100.0%)00
      CSU+CIndU186 (33.3%)9 (50.0%)3 (16.7%)
       CSU+SDerm145 (35.7%)7 (50.0%)2 (14.3%)
       CSU+ColdU201 (50.0%)1 (50.0%)
       CSU+ColdU+HU11 (100.0%)00
       CSU+SDerm+CholU101 (100.0%)0
      Total13890 (65.2%)30 (21.7%)18 (13.1%)
      Abbreviations: CholU: cholinergic urticaria; CIndU: chronic inducible urticaria; ColdU: cold urticaria; CSU: chronic spontaneous urticaria; CU: chronic urticaria; HU: heat urticaria; SDerm: symptomatic dermographism
      Table 3Treatment outcomes with omalizumab in patients with different types of urticaria
      OutcomesCSU (n = 87)CIndU (n = 33)CSU+CIndU (n = 18)P value
      Change from baseline to week 12 in UCT
      UCT scores at week 12 were available for 73 patients with CSU, for 21 patients with CIndU, and for 14 patients with both CSU and CIndU.
      11.0 (7.0–13.0)11.0 (9.0–12.5)8.0 (4.8–11.3)0.111
      Change in UCT throughout treatment period12.0 (10.0–15.0)12.0 (9.0–14.0)11.0 (9.8–12.0)0.243
      Patients achieved UCT ≥ 12, n (%)75 (86.2)30 (90.9)15 (83.3)0.756
      Patients achieved UCT = 16, n (%)60 (69.0)24 (72.7)6 (33.3)0.009
      Change from baseline to week 12 in DLQI
      DLQI scores at week 12 were available for 72 patients with CSU, for 21 patients with CIndU, and for 14 patients with both CSU and CIndU
      11.5 (7.3–17.0)14.0 (11.0–17.0)11.5 (5.8–14.5)0.442
      Change in DLQI throughout treatment period15.0 (11.0–20.0)17.0 (13.0–20.5)14.5 (10.8–20.3)0.309
      Patients achieved DLQI ≤ 1, n (%)65 (74.7)23 (69.7)8 (44.4)0.040
      Abbreviations: CIndU: chronic inducible urticaria; CSU: chronic spontaneous urticaria; DLQI: dermatology life quality index; UCT: urticaria control test. The significance of bold indicates a P value <0.05.
      a UCT scores at week 12 were available for 73 patients with CSU, for 21 patients with CIndU, and for 14 patients with both CSU and CIndU.
      b DLQI scores at week 12 were available for 72 patients with CSU, for 21 patients with CIndU, and for 14 patients with both CSU and CIndU
      Before commencing omalizumab, all of the patients had uncontrolled CU (UCT score <12). During the first month of omalizumab treatment, 55.1% (n = 76/138) of the patients achieved well-controlled disease (defined as a UCT score ≥ 12; Fig. 1A). At the third month, a well-controlled disease status was achieved by 70.4% (n = 76/108) of the patients (Fig. 1A). The response rate continued to increase and maintained a high level during the treatment period (Fig. 1A). The UCT score significantly increased from 3.0 (IQR: 0.0–4.0) at baseline to 12.0 (IQR: 6.8–15.0) at the first month (P < 0.001), and achieved 14.0 (IQR: 10.3–16.0) at the third month. Patients’ UCT scores continued to improve and retained a high level during the treatment period.
      Fig. 1
      Fig. 1A. The proportion of CU patients with uncontrolled (UCT<12) or controlled (UCT ≥ 12) disease. B. The proportion of CU patients with different QoL impairment status according to DLQI score. Abbreviations: CU: chronic urticaria; QoL: quality of life; UCT: urticaria control test
      No prespecified dosing protocol was followed, and dosing varied in our study. The doses of omalizumab given to all patients are shown in Supplemental Figure 1. Initial doses chosen and adjustment of the dosage were based on disease activity and disease control status.

      Time to respond to omalizumab therapy

      Benefits of omalizumab treatment were evident early (soon after the first treatment before week 4) in most patients. However, the speed of onset of effect can vary among individuals.
      The median time to respond to omalizumab therapy was 4, 4, and 8 weeks for patients with CSU only, CIndU only and for patients with both CSU and CIndU, respectively (Fig. 2A). The speed of onset of effects was comparable among patients with CSU, CIndU, or both (P = 0.477; Fig. 2A).
      Fig. 2
      Fig. 2A. The proportion of responders in patients with CSU, CIndU, or both during treatment period (n = 138). B. Kaplan-Meier curves showing the proportion of responders with positive and negative ASST over time. Abbreviations: ASST: autologous serum skin test; CSU: chronic spontaneous urticaria; CIndU: chronic inducible urticaria
      The median time to achieve well-controlled urticaria was 8 and 4 weeks for patients with positive and negative ASST results, respectively (Fig. 2B). ASST-positive omalizumab responders are more likely to have a slow response to treatment compared with ASST-negative responders (P = 0.043; Fig. 2B).

      Omalizumab treatment results in substantial quality of life improvement

      Omalizumab treatment led to a notable improvement in the QoL of patients as assessed by DLQI. Patients' median DLQI score significantly decreased from 18.0 (IQR:14.0–21.0) to 7.0 (IQR:1.0–12.3) during the first month of treatment (P < 0.001), and it continued to decrease to 2.0 (IQR: 0.0–8.0) at the third month (P < 0.001). Patients’ median DLQI score could achieve 1.0 (IQR: 0.0–4.0) at the end of the treatment period. The median DLQI improvement was 15.0 (IQR: 11.0–20.0), which decreased by 83.7% compared to baseline.
      As assessed by DLQI, before commencing omalizumab, CU showed an extremely large impact and a very large impact on the lives of 34.8% (n = 48/138) and 57.2% (n = 79/138) of patients, respectively (Fig. 1B). After the first month of treatment, the percentage of patients suffering from an extremely large and very large impact on QoL dropped markedly, to 6.5% (n = 9/138) and to 24.6% (34/138), respectively (Fig. 1B). For the first month of treatment, 31.9% (n = 44/138) of patients reported to have no QoL impairment (Fig. 1B). Low levels of QoL impairment were maintained during the treatment period.

      Omalizumab non-responders have unique immunological features and shorter treatment periods

      There were 18 patients (13.1%, n = 18/138) who did not respond to omalizumab during the treatment period. Non-responders had some unique immunological features (Table 4) including lower baseline total IgE levels (35.0 vs. 121.5 kU/L, P < 0.001). The proportion of non-responders with elevated total IgE levels was markedly lower than that of responders (11.1% vs. 53.6%, P = 0.001); the rate of patients with low total IgE levels was significantly higher in non-responders than responders (61.1% vs. 14.5%, P < 0.001). Also, more non-responders than responders had elevated thyroid autoantibodies (50.0% vs. 23.0%, P = 0.041). The proportion of patients with elevated IgG-anti-TPO was significantly higher in non-responders than in responders (44.4% vs. 14.9%, P = 0.012). As determined by ROC analyses (area under the curve), the most significant difference between non-responders and responders was in their median ratio of serum IgG-anti-TPO to serum total IgE (1.22 vs. 0.09, P < 0.001; Supplemental Fig. 2 and Supplemental Table 2). And rates of patients with ratios higher than 0.24 also showed significant difference between responders and non-responders (23.8% vs. 77.8%, P < 0.001).
      Table 4The demographic, clinical, and immunological features of responders and non-responders
      CharacteristicsResponders (n = 120)Non-responders (n = 18)P value
      Demographic features
       Sex: female, n (%)79 (65.8)13 (72.2)0.592
       Age (y), mean ± SD39.59 ± 13.4139.83 ± 13.850.943
      Clinical features
       Types of CU, n (%)
      CSU75 (62.5)12 (66.7)0.760
      CIndU30 (25.0)3 (16.7)
      CSU+CIndU15 (12.5)3 (16.7)
       Disease duration (mo), median (IQR)24 (12–51)39 (18–81)0.084
       Concomitant angioedema, n (%)
      All patients with angioedema also had wheals in this study.
      39 (32.5)10 (55.6)0.057
       Baseline UCT, median (IQR)3.0 (1.0–4.8)1.5 (0.0–3.0)0.120
       Baseline UAS7, median (IQR)
      Baseline UAS7 was available for 99 patients.
      28.0 (24.0–31.0)30.0 (23.5–35.0)0.249
       Treatment period (mo), median (IQR)6.0 (4.0–12.0)4.5 (3.8–5.5)0.035
      Immunological features
       Total IgE (kU/L), median (IQR)121.5 (62.5–320.3)35.0 (12.7–86.5)<0.001
       Elevated total IgE, n (%)
      The cutoff value to determine an elevated total IgE level: ≥ 100 kU/L.
      59 (53.6)2 (11.1)0.001
       Low total IgE, n (%)
      The cutoff value to determine a low total IgE level: < 40 kU/L.
      16 (14.5)11 (61.1)<0.001
       Elevated thyroid autoantibodies, n (%)
      Thyroid autoantibody levels were available for 105 patients.
      20 (23.0)9 (50.0)0.041
      Elevated IgG-anti-TPO, n (%)
      Normal reference range for IgG-anti-TPO: 0–34 IU/ml.
      13 (14.9)8 (44.4)0.012
      Elevated IgG-anti-TG, n (%)
      Normal reference range for IgG-anti-TG: 0–115 IU/ml.
      15 (17.2)6 (33.3)0.219
       IgG-anti-TPO: total IgE, median (IQR)0.09 (0.03–0.23)1.22 (0.26–5.48)<0.001
       Positive ASST, n (%)
      ASST results were available for 88 patients
      39 (51.3)8 (66.7)0.322
      Abbreviations: ASST: autologous serum skin test; CIndU: chronic inducible urticaria; CSU: chronic spontaneous urticaria; IQR: interquartile range; SD: standard deviation; TG: thyroglobin; TPO: thyroid peroxidase; UAS7: urticaria activity score 7; UCT: urticaria control test. The significance of bold indicates a P value <0.05.
      a All patients with angioedema also had wheals in this study.
      b Baseline UAS7 was available for 99 patients.
      c The cutoff value to determine an elevated total IgE level: ≥ 100 kU/L.
      d The cutoff value to determine a low total IgE level: < 40 kU/L.
      e Thyroid autoantibody levels were available for 105 patients.
      f Normal reference range for IgG-anti-TPO: 0–34 IU/ml.
      g Normal reference range for IgG-anti-TG: 0–115 IU/ml.
      h ASST results were available for 88 patients
      Non-responders also had shorter treatment durations (4.5 vs. 6.0 months, P = 0.035) compared with responders (Table 4). There was no significant difference between non-responders and responders in terms of demographic features, types of urticaria, disease duration, concomitant angioedema, baseline UCT and UAS7 score, positivity for autologous serum skin test (ASST) or IgG-anti-TG (Table 4). The response rate showed no major difference between patients with and without angioedema (79.6% vs. 91.0%, P = 0.057).

      CU patients who relapse after omalizumab discontinuation have higher total IgE levels and longer disease duration

      We discontinued omalizumab therapy in 43 patients with CU who showed complete response defined as UCT = 16 during the period of omalizumab treatment. Their median treatment duration was 12.0 (IQR: 7.0–13.0) months. The strategies of omalizumab discontinuation in these patients are presented in Supplemental Table 1.
      Two of 3 patients (67.4%, n = 29/43) experienced a relapse despite continued antihistamine treatment within 3–16 weeks after their last omalizumab injection. The median relapse time was 9.0 weeks (95%CI: 6.5–11.5 weeks). The other 14 patients had sustained well-controlled disease for a minimum of 12 weeks and up to 14 months (the duration of the study period) after their last omalizumab injection.
      Patients with disease relapse had higher baseline total IgE levels (179.9 vs 72.5 kU/L, P = 0.020) and longer disease duration (52.0 vs 15.0 months, P = 0.007) than patients without disease relapse (Table 5). Demographic features, types of urticaria, concomitant angioedema, baseline UCT and UAS7 scores, treatment period, patients with elevated thyroid autoantibodies, the ratio of IgG-anti-TPO to total IgE, or positivity for ASST did not significantly differ between patients with or without relapse (Table 5).
      Table 5Comparison of the clinical features and laboratory results between patients with and without disease relapse.
      CharacteristicsRelapsed (n = 29)Non-relapsed (n = 14)P value
      Demographic features
       Sex: female, n (%)19 (63.3)11 (73.3)0.502
       Age (y), mean ± SD40.07 ± 16.1137.71 ± 11.470.627
      Clinical features
       Types of CU, n (%)
      CSU18 (62.1)8 (53.3)0.121
      CIndU7 (24.1)6 (42.9)
      CSU+CIndU4 (13.8)0 (0.0)
       Disease duration (mo), median (IQR)52.0 (17.0–96.0)15.0 (11.8–24.0)0.007
       Concomitant angioedema, n (%)10 (34.5)5 (35.7)1.000
       Baseline UCT, median (IQR)3.0 (1.5–4.0)3.0 (0.8–4.3)0.947
       Baseline UAS7, median (IQR)
      Baseline UAS7 was available for 31 patients.
      30.0 (24.5–32.3)26.5 (24.3–29.8)0.311
       Treatment period (mo), median (IQR)12.0 (6.5–13.5)10.5 (7.8–12.3)0.548
      Immunological features
       Total IgE (kU/L), median (IQR)
      Normal reference range: < 100 kU/L.
      179.9 (75.9–468.5)72.5 (51.3–109.5)0.020
       Elevated total IgE, n (%)
      The cutoff value to determine an elevated total IgE level: ≥ 100 kU/L.
      19 (65.5)3 (21.4)0.007
       Low total IgE, n (%)
      The cutoff value to determine a low total IgE level: < 40 kU/L.
      2 (6.9)2 (14.3)0.825
       Elevated thyroid autoantibodies, n (%)
      Thyroid autoantibody levels (including IgG-anti-TPO and IgG-anti-TG) were available for 30 patients. Normal reference range for IgG-anti-TPO: 0–34 IU/ml. Normal reference range for IgG-anti-TG: 0–115 IU/ml.
      6 (26.1)0 (0.0)0.290
       IgG-anti-TPO: total IgE, median (IQR)0.07 (0.03–0.47)0.18 (0.17–0.23)0.201
       Positive ASST, n (%)
      ASST results were available for 32 patients.
      10 (47.6)5 (45.5)0.907
      Abbreviations: ASST: autologous serum skin test; CIndU: chronic inducible urticaria; CSU: chronic spontaneous urticaria; IQR: interquartile range; SD: standard deviation; TG: thyroglobin; TPO: thyroid peroxidase; UAS7: urticaria activity score 7; UCT: urticaria control test. The significance of bold indicates a P value <0.05.
      a Baseline UAS7 was available for 31 patients.
      b Normal reference range: < 100 kU/L.
      c The cutoff value to determine an elevated total IgE level: ≥ 100 kU/L.
      d The cutoff value to determine a low total IgE level: < 40 kU/L.
      e Thyroid autoantibody levels (including IgG-anti-TPO and IgG-anti-TG) were available for 30 patients. Normal reference range for IgG-anti-TPO: 0–34 IU/ml. Normal reference range for IgG-anti-TG: 0–115 IU/ml.
      f ASST results were available for 32 patients.

      Retreatment with omalizumab results in rapid remission

      We reinitiated omalizumab treatment in 10 patients who experienced relapse, all patients reported a rapid response after the first injection within the first 4 weeks of retreatment.
      Patients’ median UCT score before retreatment was 5.0 (IQR: 4.0-5.3) and significantly increased to 14.0 (IQR: 10.5–15.3) after the first injection of retreatment (P = 0.005), and maintained at a high level during the retreatment period (Fig. 3A). All patients regained control of symptoms (defined as UCT ≥ 12) after the third injection of retreatment.
      Fig. 3
      Fig. 3A. UCT scores in patients re-treated with omalizumab (n = 10). B. UAS7 scores in patients re-treated with omalizumab (n = 9). Abbreviations: UAS7: urticaria activity score 7; UCT: urticaria control test
      Nine of the 10 patients who received retreatment had CSU, and their median UAS7 score was 24.0 (IQR: 23.0–25.8) before retreatment. These patients reported a significant decrease of their UAS7 score to 4.5 (IQR: 3.0–7.3) after the first injection of retreatment (P = 0.008), and they maintained a low level of disease activity during the retreatment period (Fig. 3B).

      Omalizumab was well tolerated

      During the study period, 138 patients received a total of more than 1000 treatments, and the longest treatment duration was 22 months. Adverse events reported were of mild-to-moderate intensity. No deaths or anaphylaxis was reported.
      However, 11 patients (8.0%, n = 11/138) experienced flare up of their urticaria after the first or the second injection of omalizumab. None of them reported extracutaneous signs or symptoms (eg, hypotension, tachycardia, dyspnea, oxygen desaturation, nausea, vomiting). Seven of them discontinued omalizumab due to ineffectiveness.
      Eight patients reported injection site reactions (eg, warmth, erythema, itching) after omalizumab treatment. One patient experienced headache and dizziness after the first treatment.

      Discussion

      This study is the first to confirm, in Chinese patients with CSU, CIndU, or both, the efficacy of omalizumab in controlling CU signs and symptoms and in improving QoL.
      Patient demographics and clinical characteristics in this study are representative of the general population of patients with CU. The arduous course of treatment for these difficult-to-treat patients with CU was confirmed by the long periods of time from diagnosis to omalizumab treatment initiation which was 24 months (IQR: 12–56 months). Treatments used prior to commencing and in combination with omalizumab did not always adhere to guidelines. Omalizumab could markedly reduce the usage of oral corticosteroids (P< 0.001) and immunosuppressive agents (P<0.001); and reduce the dosage of SGAHs used.
      A total of 87.0% (n = 120/138) of the CU patients responded to omalizumab therapy, among which 65.2% (n = 90/138) of the patients showed complete response. These numbers were somewhat higher than those observed in the randomized controlled phase III trials of CSU,
      • 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.
      • Maurer M.
      • Rosén K.
      • Hsieh H.J.
      • et al.
      Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria.
      • Kaplan A.
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      Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy.
      but are very much in accordance with the results of other real-life studies.
      • Bernstein J.A.
      • Kavati A.
      • Tharp M.D.
      • et al.
      Effectiveness of omalizumab in adolescent and adult patients with chronic idiopathic/spontaneous urticaria: a systematic review of 'real-world' evidence.
      ,
      • Cherrez-Ojeda I.
      • Maurer M.
      • Bernstein J.A.
      • et al.
      Learnings from real-life experience of using omalizumab for chronic urticaria in Latin America.
      ,
      • Vadasz Z.
      • Tal Y.
      • Rotem M.
      • et al.
      Omalizumab for severe chronic spontaneous urticaria: real-life experiences of 280 patients.
      Kocaturk E et al reported a total response rate of 76.1% and 83.3% in CIndU and CSU respectively in real-life clinical settings.
      • Kocatürk E.
      • Can P.K.
      • Akbas P.E.
      • et al.
      Management of chronic inducible urticaria according to the guidelines: a prospective controlled study.
      And Cherrez-Ojeda I et al reported a response rate of 80.0% in CU patients treated with omalizumab in Latin America.
      • Cherrez-Ojeda I.
      • Maurer M.
      • Bernstein J.A.
      • et al.
      Learnings from real-life experience of using omalizumab for chronic urticaria in Latin America.
      For CSU, an average complete response rate of 72.2% (95%CI: 66.1%–78.3%) was reported by Tharp M et al in a meta-analysis of real-world evidence including 45 real-world studies; and an additional average partial response rate of 17.8% (95%CI: 11.7%–23.9%) was reported by the same meta-analysis.
      • Tharp M.D.
      • Bernstein J.A.
      • Kavati A.
      • et al.
      Benefits and harms of omalizumab treatment in adolescent and adult patients with chronic idiopathic (spontaneous) urticaria: a meta-analysis of "real-world" evidence.
      CU has a detrimental impact on many aspects of patient QoL. Omalizumab can significantly improve patient QoL as assessed by DLQI. Improvement of DLQI score after omalizumab treatment ranges from 57.1% to 100.0%, and the change of DLQI score at the end of treatment compared to baseline was 9.6–18.5 in previous real-life studies.
      • Vestergaard C.
      • Deleuran M.
      Two cases of severe refractory chronic idiopathic urticaria treated with omalizumab.
      • Kai A.C.
      • Flohr C.
      • Grattan C.E.
      Improvement in quality of life impairment followed by relapse with 6-monthly periodic administration of omalizumab for severe treatment-refractory chronic urticaria and urticarial vasculitis.
      • Subramaniyan R.
      • Chopra A.
      Treatment of chronic spontaneous urticaria with a single dose of omalizumab: a study of four cases.
      • Lefévre A.C.
      • Deleuran M.
      • Vestergaard C.
      A long term case series study of the effect of omalizumab on chronic spontaneous urticaria.
      • Savic S.
      • Marsland A.
      • McKay D.
      • et al.
      Retrospective case note review of chronic spontaneous urticaria outcomes and adverse effects in patients treated with omalizumab or ciclosporin in UK secondary care.
      The decrease of DLQI score in our study was in compliance with the results of other studies. Low levels of QoL impairment were maintained throughout the treatment period in our study.
      Another finding is that patients with both CSU and CIndU simultaneously can also benefit from omalizumab therapy. The improvements of UCT and DLQI score at week 12 or throughout the treatment period were comparable between patients with CSU, CIndU, and both. In 10%–50% of patients, CSU occurs in combination with CIndU.
      • Türk M.
      • Carneiro-Leão L.
      • Kolkhir P.
      • Bonnekoh H.
      • Buttgereit T.
      • Maurer M.
      How to treat patients with chronic spontaneous urticaria with omalizumab: questions and answers.
      Patients who have CSU with comorbid CIndU were excluded from the omalizumab phase III trials and several other RCTs. However, comorbidity of CIndU is thought to be linked to longer disease duration and higher disease activity.
      • Türk M.
      • Carneiro-Leão L.
      • Kolkhir P.
      • Bonnekoh H.
      • Buttgereit T.
      • Maurer M.
      How to treat patients with chronic spontaneous urticaria with omalizumab: questions and answers.
      In our study, 83.3% (n = 15/18) of the patients with CSU plus CIndU benefited from omalizumab therapy, among which 33.3% (n = 6/18) of them showed complete response. In a retrospective study, Metz M and coworkers reported 5 patients with CSU plus delayed pressure urticaria and 1 patient with CSU plus SD had complete symptom control after the first use of omalizumab.
      • Metz M.
      • Ohanyan T.
      • Church M.K.
      • Maurer M.
      Retreatment with omalizumab results in rapid remission in chronic spontaneous and inducible urticaria.
      In another report, a woman with CSU plus pressure urticaria plus symptomatic dermographism experienced complete remission of her 3 urticarias after the first injection of omalizumab. Autoallergy has been postulated to be a cause of CIndU, the appropriate trigger (eg, friction, cold, heat, pressure, sunlight, passive warming/exercise) may result in de novo synthesized autoantigen, which is detected by IgE autoantibodies, resulting in mast cell degranulation.
      • Maurer M.
      • Metz M.
      • Brehler R.
      • et al.
      Omalizumab treatment in patients with chronic inducible urticaria: a systematic review of published evidence.
      ,
      • Kring Tannert L.
      • Stahl Skov P.
      • Bjerremann Jensen L.
      • Maurer M.
      • Bindslev-Jensen C.
      Cold urticaria patients exhibit normal skin levels of functional mast cells and histamine after tolerance induction.
      Omalizumab blocks binding of IgE to FcϵRI, therefore, it can intervene in this common pathway and block the mast cell-activating signal so as to improve the symptoms of both CSU and CIndU simultaneously.
      • Kaplan A.P.
      • Giménez-Arnau A.M.
      • Saini S.S.
      Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticaria.
      However, the complete response rate, as well as the proportion of patients who achieved a DLQI score ≤1, indicating no impairment of QoL, were significantly lower in patients with both CSU and CIndU in our study. We speculate that in patients with both CSU and CIndU, longer treatment duration and higher dosage can result in better therapeutic effect. Based on the findings of phase III clinical trials in CSU, some patients who had not met the definitions of complete response at primary endpoint at week 12 met those definitions with continued dosing at week 24: ASTERIA I (26%, 39%, and 55%, respectively, of the 75-, 150-, and 300-mg arms) and GLACIAL (49% in the 300-mg omalizumab arm).
      • Kaplan A.
      • Ferrer M.
      • Bernstein J.A.
      • et al.
      Timing and duration of omalizumab response in patients with chronic idiopathic/spontaneous urticaria.
      Although the international guideline recommends 300 mg/4 weeks of omalizumab as standard dose,
      • Zuberbier T.
      • Aberer W.
      • Asero R.
      • et al.
      The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.
      increasing real-world studies demonstrate that omalizumab updosing could be effective in partial responder or non-responder patients with CU. For example, Curto-Barredo and coworkers reported that 43 and 16 of the 79 previously partial responder or non-responder patients became responders after updosing to 450 and 600 mg/4 weeks, respectively.
      • Curto-Barredo L.
      • Spertino J.
      • Figueras-Nart I.
      • et al.
      Omalizumab updosing allows disease activity control in patients with refractory chronic spontaneous urticaria.
      Our study also suggested that a positive ASST might predict a slow response to omalizumab. ASST was easy to perform clinically and was designed to identify serum IgG autoantibodies to FcεRI/IgE. In CU patients with IgG autoantibodies against IgE or FcεRI, the effect of omalizumab might be associated with the decrease in mast cell–bound IgE levels and the subsequent downregulation of FcεRI on mast cells and basophils.
      • 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.
      Thus patients with IgG autoantibodies against IgE or FcεRI can be expected to show a slow response to omalizumab treatment. The finding of our study was consistent with the study from Nettis E et al and Gericke J et al.
      • Nettis E.
      • Cegolon L.
      • Dileo E.
      • et al.
      Omalizumab in chronic spontaneous urticaria: efficacy, safety, predictors of treatment outcome, and time to response.
      ,
      • Gericke J.
      • Metz M.
      • Ohanyan T.
      • et al.
      Serum autoreactivity predicts time to response to omalizumab therapy in chronic spontaneous urticaria.
      Non-responders in our study had higher rates of low IgE, elevated IgG-anti-TPO, and high ratios of IgG-anti-TPO to total IgE, all them being biomarkers for autoimmune chronic urticaria as demonstrated by the PURIST study.
      • Schoepke N.
      • Asero R.
      • Ellrich A.
      • et al.
      Biomarkers and clinical characteristics of autoimmune chronic spontaneous urticaria: results of the PURIST study.
      Therefore, we have good reason to speculate that CU patients with an autoimmune basis may respond differently to omalizumab. The pathogenesis of autoimmune chronic urticaria involves IgG autoantibodies to IgE or its high-affinity receptor FcεRI. Autoimmunity might be linked to delayed response as mentioned above and we may therefore infer that some of the “non-responders” are likely to respond if they continued their omalizumab therapy.
      • Gericke J.
      • Metz M.
      • Ohanyan T.
      • et al.
      Serum autoreactivity predicts time to response to omalizumab therapy in chronic spontaneous urticaria.
      The fact that responders tend to have longer treatment periods in our study supports this notion.
      Relapse rates after ceasing omalizumab are high in clinical trials and in real life, ranging from 17.6% to 67%.
      • Nettis E.
      • Cegolon L.
      • Dileo E.
      • et al.
      Omalizumab in chronic spontaneous urticaria: efficacy, safety, predictors of treatment outcome, and time to response.
      ,
      • Kulthanan K.
      • Tuchinda P.
      • Likitwattananurak C.
      • Weerasubpong P.
      • Chularojanamontri L.
      Does omalizumab modify a course of recalcitrant chronic spontaneous urticaria?: a retrospective study in Asian patients.
      • Maurer M.
      • Kaplan A.
      • Rosén K.
      • et al.
      The XTEND-CIU study: long-term use of omalizumab in chronic idiopathic urticaria.
      • Türk M.
      • Yılmaz İ.
      • Bahçecioğlu S.N.
      Treatment and retreatment with omalizumab in chronic spontaneous urticaria: real life experience with twenty-five patients.
      • Pinto Gouveia M.
      • Gameiro A.
      • Pinho A.
      • Gonçalo M.
      Long-term management of chronic spontaneous urticaria with omalizumab.
      • Niemeyer-van der Kolk T.
      • van Maaren M.S.
      • van Doorn M.B.A.
      Personalized omalizumab treatment improves clinical benefit in patients with chronic spontaneous urticaria.
      • 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.
      The OPTIMA study revealed a 44.4%–50.0% relapse rate after 6 months of omalizumab treatment.
      • Sussman G.
      • Hébert J.
      • Gulliver W.
      • et al.
      Omalizumab retreatment and step-up in patients with chronic spontaneous urticaria: OPTIMA trial.
      The XTEND-CIU study showed a relapse rate of 43.4% and 45.1% during the 12 weeks after discontinuation of omalizumab in patients treated for either 24 or 48 weeks.
      • Maurer M.
      • Kaplan A.
      • Rosén K.
      • et al.
      The XTEND-CIU study: long-term use of omalizumab in chronic idiopathic urticaria.
      The relapse rate in our study was 67.4% (n = 29/43). We found that patients with relapse had longer disease durations and higher baseline total IgE levels than that of patients without relapse.
      There was no rebound phenomenon after discontinuation of omalizumab in our study. The median UCT and UAS7 score before the second dosing period were comparable with the first dosing period. Basically, omalizumab is not a curative or disease-modifying treatment. Therefore, instead of treating patients for a fixed length of period, omalizumab should be used until the disease is gone. Insufficient duration of treatment might result in avoidable flare ups of urticaria. All relapsed patients who underwent retreatment were able to regain symptom control with a second course of treatment in our study indicating that retreatment with omalizumab is an effective therapy option for patients who previously benefited from this drug.
      Generally, omalizumab is a safe and well tolerated treatment. Adverse events reported were of mild-to-moderate intensity in our study. Clinical trials have shown that omalizumab was well tolerated in CSU patients older than 12 years old.
      • 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.
      • Maurer M.
      • Rosén K.
      • Hsieh H.J.
      • et al.
      Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria.
      • Kaplan A.
      • Ledford D.
      • Ashby M.
      • et al.
      Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy.
      However, we observed exacerbation of urticaria in 11 patients after the first or the second injection. Ertaş R et al also reported 4 patients who experienced flare up of urticaria during omalizumab administration, which led to discontinuation of the drug.
      • Ertaş R.
      • Özyurt K.
      • Yıldız S.
      • Ulaş Y.
      • Turasan A.
      • Avcı A.
      Adverse reaction to omalizumab in patients with chronic urticaria: flare up or ineffectiveness?.
      In our study, exacerbation of urticaria did not occur again during the remainder of the treatment period.
      Potential limitations of the present study are its retrospective design and the likelihood of patients lost to follow-up. Moreover, since the data were collected at a single specialized urticaria center, the results might not represent the general CU population in China due to limited numbers. Our study did not include CU patients with angioedema only, and the efficacy of omalizumab for angioedema was not systematically studied. Further studies should assess the effects of omalizumab on angioedema in CU patients with the help of validated tools and include CU patients who have angioedema but no wheals.
      In conclusion, our study indicates that omalizumab is highly effective and safe in patients with antihistamine-resistant CSU, CIndU or both. A total of 87.0% of the CU patients benefited from omalizumab treatment. The therapeutic effect and speed of onset of effect for omalizumab were comparable among patients with CSU, CIndU or both. ASST-positive patients were more likely to show a slow response to omalizumab therapy. Non-responders tend to have lower baseline total IgE levels, higher proportions of elevated IgG-anti-TPO, higher ratios of IgG-anti-TPO to total IgE and shorter treatment periods. Patients with higher baseline total IgE levels and longer disease durations are more likely to experience rapid relapse after discontinuation of omalizumab. However, omalizumab retreatment was an effective therapy option for those who had previously benefited from this drug.

      Abbreviations

      ASST, autologous serum skin test; AUC, area under the curve; CholU, cholinergic urticaria; CIndU, chronic inducible urticaria; ColdU, cold urticaria; CSU, chronic spontaneous urticaria; CU, chronic urticaria; DLQI, dermatology life quality index; HU, heat urticaria; IgE, immunoglobulin E; IQR, interquartile range; QoL, quality of life; ROC, receiver-operator characteristic; SD, standard deviation; SDerm, symptomatic dermographism; SGAHs, second-generation H1-antihistamines; TG, thyroglobin; TPO, thyroid peroxidase; UAS7, urticaria activity score 7; UCARE, Urticaria Center of Reference and Excellence; UCT, urticaria control test.

      Author contributions

      Yudi Chen: substantial contributions to acquisition, analysis and interpretation of data; drafted the manuscript;
      Miao Yu: substantial contributions to acquisition of data; drafted the article;
      Xiaojie Huang: conception and design of the study; revising the manuscript critically for important intellectual content;
      Ping Tu: substantial contributions to conception and study design; revising the manuscript critically for important intellectual content;
      Peikun Shi: substantial contributions to acquisition of data; reviewed the article;
      Marcus Maurer: substantial contributions to conception and study design; reviewed the article critically for important intellectual content;
      Zuotao Zhao: substantial contributions to conception and study design; reviewed the article critically for important intellectual content.

      Funding source

      This study was funded by the Joint Sino-German Research Project of National Natural Science Foundation of China (grant no. GZ901 ).

      Availability of data and materials

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

      Ethics approval

      The study was approved by China Ethics Committee of Registering Clinical Trial (ChiECRCT20190131).

      Trial registration number

      The study was registered with the Chinese clinical trial registry (ChiCTR2000038085).

      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 its publication has been approved by the responsible authorities at the institution where the work is carried out.

      Submission declaration

      We confirm that the manuscript is original, has not been published before, is not currently being considered for publication elsewhere, and has not been posted to a preprint server.

      Declaration of competing interest

      Yudi Chen: none;
      Miao Yu: none;
      Xiaojie Huang: none;
      Ping Tu: none;
      Peikun Shi: none;
      Marcus Maurer: Speaker and/or advisor and recipient of institutional research funding from Genentech and Novartis ;
      Zuotao Zhao: research support from Novartis outside the submitted work.

      Acknowledgments

      We acknowledge the support of the GA2LEN network of Urticaria Centers of Reference and Excellence (UCAREs; www.ga2len-ucare.com). We thank Zhi-Yue Chu, Jia Yu, Bo Liu, and Xiao-Ting Song for assistance with patient follow-ups and data collection.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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