Benefits and Harms of Omalizumab Treatment in Adolescent and Adult Patients With Chronic Idiopathic (Spontaneous) Urticaria: A Meta-analysis of “Real-world” Evidence

Michael D Tharp; Jonathan A Bernstein; Abhishek Kavati; Benjamin Ortiz; Karen MacDonald; Kris Denhaerynck; Ivo Abraham; Christopher S Lee

doi:10.1001/jamadermatol.2018.3447

. 2018 Nov 14;155(1):29–38. doi: 10.1001/jamadermatol.2018.3447

Benefits and Harms of Omalizumab Treatment in Adolescent and Adult Patients With Chronic Idiopathic (Spontaneous) Urticaria

A Meta-analysis of “Real-world” Evidence

Michael D Tharp ¹, Jonathan A Bernstein ², Abhishek Kavati ³, Benjamin Ortiz ⁴, Karen MacDonald ⁵, Kris Denhaerynck ^5,⁶, Ivo Abraham ^5,^7,^8,⁹, Christopher S Lee ^5,^10,^✉

¹Department of Dermatology, Rush University Medical Center, Chicago, Illinois

²Division of Immunology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio

³US Health Economics & Outcomes Research, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey

⁴Respiratory Medical Unit, US Clinical Development and Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey

⁵Matrix45, Tucson, Arizona

⁶Department of Public Health, University of Basel, Basel, Switzerland

⁷Associate Editor for Quantitative Methods, JAMA Dermatology

⁸Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, Arizona

⁹Department of Family and Community Medicine, College of Medicine, University of Arizona, Tucson, Arizona

¹⁰Boston College Connell School of Nursing, Chestnut Hill, Massachusetts

^✉

Corresponding Author: Christopher S. Lee, PhD, Boston College Connell School of Nursing, 140 Commonwealth Ave, Chestnut Hill, MA 02467 (csleern@gmail.com).

Accepted for Publication: August 14, 2018.

Published Online: November 14, 2018. doi:10.1001/jamadermatol.2018.3447

Author Contributions: Drs MacDonald and Lee had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Tharp, Bernstein, Kavati, Ortiz, MacDonald, Abraham, Lee.

Acquisition, analysis, or interpretation of data: Tharp, Bernstein, MacDonald, Denhaerynck, Abraham, Lee.

Drafting of the manuscript: Bernstein, MacDonald, Abraham, Lee.

Critical revision of the manuscript for important intellectual content: Tharp, Bernstein, Kavati, Ortiz, Denhaerynck, Abraham, Lee.

Statistical analysis: MacDonald, Lee.

Obtained funding: MacDonald, Abraham.

Administrative, technical, or material support: Tharp, Kavati, MacDonald, Abraham, Lee.

Study supervision: Tharp, Abraham.

Conflict of Interest Disclosures: Dr Tharp served as a consultant to Novartis Pharmaceuticals Corporation for work on this study. Dr Bernstein served as a consultant to Novartis for work on this study; he is affiliated with Bernstein Clinical Research Center, LLC, which was under contract with Novartis as a primary investigator to conduct clinical research outside of the submitted work; he has received speaker fees from Novartis as well as consulting fees from Genentech; and he is an author on the Joint Task Force for Practice Parameters for Urticaria guideline and the GALEN international guideline for urticaria. Drs Kavati and Ortiz are employees and stockholders of Novartis. Drs MacDonald, Denhaerynck, Abraham, and Lee are affiliated with Matrix45; by company policy, they are prohibited from owning equity in client organizations (except through mutual funds or other independently administered collective investment instruments) or contracting independently with client organizations; Matrix45 provides services similar to those described in this article to other biopharmaceutical companies on a nonexclusivity basis. No other disclosures are reported.

Funding/Support: This study was supported by Novartis.

Role of the Funder/Sponsor: Novartis had a role in reviewing the manuscript, but had no role in its preparation and approval and no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and decision to submit the manuscript for publication.

Disclaimer: Dr Abraham is Associate Editor for Quantitative Methods, JAMA Dermatology, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

^✉

Corresponding author.

PMCID: PMC6439579 PMID: 30427977

Key Points

Question

What is known about the benefits and harms of omalizumab as used in the real-world clinical management of chronic idiopathic urticaria (also known as chronic spontaneous urticaria)?

Findings

In this meta-analysis of 67 published reports on real-world effectiveness, omalizumab therapy was associated with an average 25.6-point improvement in weekly Urticaria Activity Score (vs a 14.9 to 22.1 point improvement reported in clinical trials), a 4.7 point improvement in Urticaria Activity Score, a complete response rate of 72.2%, a partial response rate of 17.8%, and an average adverse event rate of 4.0% (vs 2.9%-8.0% reported in clinical trials).

Meaning

Benefits and safety of omalizumab in the real-world treatment of chronic idiopathic urticaria meet or exceed the results gleaned from clinical trials.

Abstract

Importance

Omalizumab is indicated for the management of chronic idiopathic urticaria (CIU) (also known as chronic spontaneous urticaria) in adolescents and adults with persistent hives not controlled with antihistamines. The effectiveness of omalizumab in the real-world management of CIU is largely unknown.

Objective

To quantitatively synthesize what is known about the benefits and harms of omalizumab in the real-world clinical management of CIU regarding urticaria activity, treatment response, and adverse events.

Data Sources

Published observational studies (January 1, 2006, to January 1, 2018) and scientific abstracts on the effectiveness of omalizumab in CIU were identified using PubMed, Embase, Web of Science, and Cochrane search engines; references were searched to identify additional studies.

Study Selection

Included studies were observational in design and included at least 1 outcome in common with other studies and at a concurrent time point of exposure to omalizumab. A total of 67 articles (35.2% of those screened) were included in the analysis.

Data Extraction and Synthesis

PRISMA and MOOSE guidelines were followed; independent selection and data extraction were completed by 2 observers. Random-effects meta-analyses were performed.

Main Outcomes and Measures

Main outcomes were change in weekly Urticaria Activity Score (UAS7; range, 0-42), change in Urticaria Activity Score (UAS; range 0-6) (higher score indicating worse outcome in both scales), complete and partial response rates (percentages), and adverse event rate (percentage).

Results

Omalizumab therapy was associated with an improvement in UAS7 scores (−25.6 points, 95% CI, −28.2 to −23.0; P < .001; 15 studies, 294 patients), an improvement in UAS scores (−4.7 points, 95% CI, −5.0 to −4.4, P < .001; 10 studies, 1158 patients), an average complete response rate of 72.2% (95% CI, 66.1%-78.3%; P < .001; 45 studies, 1158 patients) with an additional average partial response rate of 17.8% (95% CI, 11.7%-23.9%; P < .001; 37 studies, 908 patients), and an average adverse event rate of 4.0% (95% CI, 1.0%-7.0%; P < .001; any level of severity, 47 studies, 1314 patients).

Conclusions and Relevance

Benefits and safety of omalizumab in the real-world treatment of CIU meet or exceed results gleaned from clinical trials. These real-world data on omalizumab in CIU may help inform both clinical treatment expectations and policy decision making.

This meta-analysis of 67 observational studies analyzes the effectiveness and adverse event rate of omalizumab therapy in patients with chronic idiopathic urticaria and compares these findings with those of randomized clinical trials conducted among similar patients.

Introduction

Chronic idiopathic urticaria (CIU), also known as chronic spontaneous urticaria (CSU), is defined as the development of wheals, angioedema, or both that lasts for at least 6 weeks.^1,2 Symptoms of CIU include swelling, itching, and pain in affected areas as well as general discomfort that negatively influence patients’ quality of life.^3,4 Many patients with CIU remain symptomatic for periods lasting up to 5 years despite approved or higher-than-approved doses of H1 antihistamines. Clearly, there is room for improvement in the treatment of CIU.⁴

Omalizumab is a recombinant humanized monoclonal antibody that reduces levels of free IgE and the high-affinity receptor for the Fc region of IgE that are essential in mast-cell and basophil activation in conditions like CIU. Several early, phase 2, randomized, placebo-controlled, multicenter studies of omalizumab have provided evidence of beneficial efficacy on symptoms in patients with CIU who were previously symptomatic despite the use of approved doses of H1 antihistamines.^5,6 In a pivotal phase 3 trial, omalizumab diminished signs and symptoms among patients with CIU who were symptomatic despite the use of approved doses of H1 antihistamines compared with placebo.⁷

While the efficacy of omalizumab for the treatment of CIU has been established, the clinical benefits and harms associated with omalizumab therapy in the real-world management of CIU are less well known, particularly since patients included in trials do not always reflect the complexity of patients with CIU seen in clinical practice. Efficacy-effectiveness gaps (ie, differences in outcomes reported in clinical trials vs real-world practice) are common and confound both clinical and policy-level decision making.^8,9

In line with our research group’s previous systematic review¹⁰ and meta-analysis¹¹ of omalizumab in severe allergic asthma, we recently completed a systematic review of omalizumab in CIU.¹² The purpose of the present report is to quantitatively synthesize what is known about the benefits and harms of omalizumab as used in real-world management of CIU using meta-analytic techniques, and to provide insight into potential efficacy-effectiveness gaps.

Methods

Published observational studies and scientific abstracts on the effectiveness of omalizumab in CIU were identified using the PubMed, Embase, Web of Science, and Cochrane search engines and combinations of the search terms “chronic idiopathic urticaria,” “chronic spontaneous urticaria,” and “omalizumab” (as a MeSH Term and in all fields). To our knowledge, the first reports on omalizumab effectiveness in CIU were published in 2006; thus, the search was conducted for studies published from January 1, 2006, to January 1, 2018.

Reference lists of each report were searched to identify additional omalizumab studies in the context of CIU. The search process was conducted independently by 2 experts in systematic review and observational methodology (K.M. and K.D.). Studies included in this analysis were those that (1) were observational in design, (2) included at least 1 effectiveness metric in common with other studies, and (3) were judged to meet inclusion criteria by consensus of the expert reviewers. This meta-analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA),¹³ and the MOOSE guidelines for Meta-analyses and Systematic Reviews of Observational Studies (see eChecklist in the Supplement).¹⁴

A total of 67 observational studies on the effectiveness of omalizumab in CIU (with or without angioedema) were identified (Figure 1).^{15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81} As detailed in eTable 1 in the Supplement, there were 19 studies of patients with CIU or CSU specified, 2 of patients with chronic autoimmune urticaria (CAU), 5 of patients with chronic urticaria not otherwise specified (CU NOS), 38 of patients with CIU, CSU, or CU NOS with comorbidities, and another 3 of mixed samples of patients with urticaria. These articles on the effectiveness of omalizumab in CIU were included in our group’s systematic review, which also contains additional study description, narrative analysis, and tables of evidence.¹²

Reported Outcomes

Changes in the weekly Urticaria Activity Score (UAS7) (mainly using the daily method) were reported in studies included in the present meta-analysis. The UAS7 asked respondents to rate the number of wheals they have and the intensity of pruritus daily for 1 week. Scores on the UAS7 range from 0 to 42, with higher scores indicating worse CIU.⁸² Several studies also reported change in Urticaria Activity Score (UAS) collected at 1 time point; the UAS ranges from 0-6, with higher scores indicating worse CIU. Pretreatment and posttreatment scores were provided such that change in scores could be calculated if not reported. The ranges of minimally important difference on the UAS7 and UAS have been reported as 9.5 to 10.5 and 4.5 to 5.5, respectively.⁸³

Several articles have reported quality of life as measured by the Dermatology Life Quality Index (DLQI).⁸⁴ The DLQI is a 10-item self-administered questionnaire. A DLQI score is calculated by summing the results of each question to a total between 0 (no effect) and 30 (extremely large effect on quality of life). The range of minimally important difference on the DLQI has been reported as 2.24 to 3.10.⁸⁵ Several additional articles reported pretreatment and posttreatment quality of life measured by the Chronic Urticaria Quality of Life Questionnaire (CU-Q₂oL). The CU-Q₂oL is a self-administered 23-item questionnaire, with 5 response options on how much patients have been troubled by each problem (from 1, not at all, to 5, very much), with higher scores (ranging from 23 to 115) indicating worse quality of life.⁸⁶

Clinical response to omalizumab was reported in 2 different ways across studies. First, a vast majority of articles reported 3 categories of response: (1) complete response (reported in numbers of cases and most frequently defined as symptom disappearance that commonly could be followed by discontinuation of antihistamine treatment); (2) partial response (reported in numbers of cases and most frequently defined as incomplete symptom improvement, or symptom improvement followed by worsening after discontinuation of antihistamine treatment); and (3) nonresponse or refractory CIU (reported in numbers of cases with no significant improvement). Second, several articles reported response in 2 categories (response vs nonresponse) that were consistent with definitions already detailed such that results could be aggregated across studies.

Finally, adverse events were reported in most of the articles included in this meta-analysis. We synthesize the adverse event rate across studies using safety samples and the raw number of cases of adverse events as reported at any level of severity. As reported elsewhere,¹² the most common adverse events were headache, fatigue, and injection site reaction; anaphylaxis was experienced by 3 patients. See our group’s systematic review for more details on specific types of adverse events.¹²

Statistical Analysis

Our approach to this meta-analysis of observational studies of omalizumab in CIU was guided by analytic and reporting criteria.^13,14 Raw published data were extracted, verified in duplicate, and combined into a single database. Two effect size types were extracted from the literature. First, continuous outcomes, such as UAS7 scores, were extracted as mean and standard deviation (SD) prior to and after treatment. When not already calculated, changes in raw scores (eg, of UAS7) as well as in standardized mean difference (ie, Cohen d) were computed.⁸⁷ Second, counts of events and sample sizes were extracted to calculate rates of response and adverse events. In the case of UAS7 scores only, there were 9 case studies involving 1 or 2 patients that were aggregated into a single result for inclusion in the meta-analysis after sensitivity analyses indicated that doing so would not bias estimates.

Random-effects meta-analyses were performed to quantify pooled effectiveness estimates because this approach takes into account both within-study variance (ie, standard error) and between-study variance (ie, τ²). Studies were weighted by the inverse of within-study variance plus the between-study variance as calculated by the DerSimonian and Laird method.⁸⁸ Weighted pooled effectiveness estimates and 95% confidence interval (CIs) are reported. In addition, z scores (weighted mean divided by the standard error of the weighted mean) and associated P values are provided for each measure to judge the precision of the pooled estimate across studies. Variation in effectiveness estimates across studies attributed to heterogeneity was quantified using Q and its P value as well as I², a metric ranging from 0% (ie, all of the heterogeneity is spurious) to 100% (ie, all of the heterogeneity is real). Predictive intervals also were calculated to present the expected range of effects that may be observed in similar studies.⁸⁹

Traditional meta-analytic approaches are problematic when rates approach the limits of 0% or 100%, as several did in this analysis. Accordingly, the Stata command metaprop was used in this analysis, which pools proportions and uses the exact binomial method, with Freeman-Tukey double arcsine transformation, to compute precise 95% CIs.⁹⁰ Only studies that included more than 1 patient were included in the analyses of rates (clinical response and adverse events) so that CIs could be computed. There also are advantages to using multivariate meta-analysis (ie, simultaneously modeling 2 related outcomes) including being able to incorporate multiple outcomes into 1 model as opposed to conducting multiple meta-analyses wherein the outcomes are considered independent.⁹¹ Hence, we used multivariate meta-analysis⁹² for the clinical response to omalizumab wherein we report simultaneous estimates of complete and partial response using the mvmeta Stata command. Where possible, we also compared effectiveness estimates by sample inclusion (ie, CIU or CSU specified, CAU, CU NOS, CIU/CSU or CAU with comorbidities, or mixed samples) using a random-effects test for heterogeneity between subgroups. All analyses were performed using Comprehensive Meta-Analysis software, version 3.0 or StataMP, version 15.

Results

Changes in Urticaria Activity

Data on change in UAS7 in response to omalizumab in CIU were available from 15 studies, and aggregated results were available from 9 single- or double-patient case studies, collectively involving 294 patients (Table and Figure 2; eTable 2 in the Supplement). Across studies, omalizumab therapy was associated with a 25.6-point reduction in UAS7 scores (95% CI, 23.0-point to 28.2-point reduction; z = 19.47; P < .001). There was significant (Q₁₅ = 357.89, P < .001) and substantive (I² = 95.8%) heterogeneity in the improvement in UAS7 scores observed across studies; but, omalizumab was equally effective in reducing UAS7 scores across study subgroups (between-group Q = 0.5, P = .79; eFigure 1 in the Supplement). Using standardized mean differences, omalizumab had a large effect in improving urticaria activity as measured by the UAS7 (Cohen d = −4.4; 95% CI, −3.4 to −5.4); z = −8.8, P < .001; Q = 91.5, P < .001; I² = 84.7%) (data not shown).

Table. Meta-analysis of Benefits and Harms Summary of Omalizumab Treatment.

Characteristic	Patients, No.	Estimate (95% CI)	z Score	I², %
Change in UAS7	294	−25.6 (−23.0 to −28.2)	19.5	95.8
Change in UAS	245	−4.7 (−4.4 to −5.0)	27.6	75.1
Change in DLQI	84	−13.9 (−10.0 to −17.9)	6.9	94.8
Change in CU-Q₂oL	70	−42.3 (−18.9 to −65.8)	3.5	97.8
Complete response rate, %	1158	76.0 (70.0 to 82.0)	27.0	74.4
Partial response rate, %	908	15.0 (10.0 to 22.0)	7.6	73.8
Adverse events rate, %	1314	4.0 (1.0 to 7.0)	3.6	76.6

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Abbreviations: CU-Q₂oL, Chronic Urticaria Quality of Life Questionnaire; DLQI, Dermatology Life Quality Index; UAS, urticaria activity score; UAS7, weekly urticaria activity score.

Figure 2. — This forest plot represents the mean (95% CI) change in UAS7 results (squares [horizontal lines]) within individual studies. The size of each square represents the weight, by random effects analysis, of the contribution of each study; exact percentage weights are listed in the Weight column. The overall meta-analytic summary mean (95% CI) is represented by the vertical line (diamond), and the estimated predictive interval, by the solid horizontal lines extending from this diamond.

Data on change in UAS scores in response to omalizumab in CIU were available from 10 studies collectively involving 245 patients (Table; eFigure 2 and eTable 2 in the Supplement). Across studies, omalizumab therapy was associated with a 4.7-point reduction in UAS scores (95% CI, 4.4-point to 5.0-point reduction; z = 27.63, P < .001). There was significant (Q₉ = 36.14, P < .001) and substantive (I² = 75.1%) heterogeneity in the improvement in UAS scores observed across studies as well as significant differences across study subgroups (between-group Q = 11.1, P = .004). Specifically, omalizumab was more effective in reducing UAS scores in samples of patients with CU NOS (6.0-point reduction; 95% CI, 5.2-point to 6.8-point reduction; z = 14.0, P < .001) compared with samples of patients with CAU (5.0-point reduction; 95% CI, 4.5-point to 5.5-point reduction; z = 19.6, P < .001), and compared with samples where patients had CIU/CSU with comorbidities (4.6-point reduction; 95% CI, 4.5-point to 4.8-point reduction, z = 61.5, P < .001) (eFigure 3 in the Supplement). Using standardized mean differences overall, omalizumab had a large effect in improving urticaria activity as measured by the UAS (Cohen’s d = −3.4 (95% CI = -2.5 to −4.4); z = −7.2, P < .001; Q = 57.4, P < .001; I² = 84.3%) (data not shown).

Changes in Quality of Life

Data on change in DLQI scores following omalizumab treatment of CIU were available from 6 studies collectively involving 84 patients (Table; eTable 2 in the Supplement). Across studies, omalizumab therapy was associated with a 13.9-point reduction in DLQI scores (95% CI, 10.0-point to 17.9-point reduction; z = 6.9, P < .001). There was significant (Q₅ = 96.3, P < .001) and substantive (I² = 94.8%) heterogeneity in the improvement in DLQI scores observed across studies. Data on change in CU-Q₂oL scores in following omalizumab treatment of CIU were available from 3 studies collectively involving 70 patients (Table; eTable 2 in the Supplement). Across studies, omalizumab therapy was associated with a 42.3-point improvement in CU-Q₂oL scores (95% CI, 18.9-point to 65.8-point reduction; z = 3.5, P < .001). There was significant (Q₂ = 97.3, P < .001) and substantive (I² = 97.8%) heterogeneity in the improvement in CU-Q₂oL scores observed across studies.

Clinical Response to Omalizumab

Data on complete response was available from 45 studies involving 1158 patients (Table and Figure 3; eTable 2 in the Supplement). Across studies, the average complete response rate was 76.0% (95% CI, 70.0%-82.0%; z = 27.0, P < .001). Although there was significant heterogeneity in complete response rates across studies (Q = 172.0, P < .001, I² = 74.4%), there were no significant differences in complete response rate across study subgroups (between-subgroup Q₄ = 3.48, P = .48) (eFigure 4 in the Supplement). Based on the same 45 studies, the average nonresponse rate was 7.0% (95% CI, 5.0%-10.0%; z = 8.9, P < .001). Although there was significant heterogeneity in nonresponse rates across studies (Q = 71.9, P < .001, I² = 37.4%), there were no significant differences in nonresponse rates across study subgroups (between-subgroup Q₄ = 7.2, P = .130) (data not shown).

Data on partial response was available from 37 studies involving 908 patients (Table; eTable 2 and eFigure 5 in the Supplement). Across studies, the average partial response rate was 15.0% (95% CI, 10.0%-22.0%; z = 7.6, P < .001). Although there was significant heterogeneity in partial response rates across studies (Q = 137.3, P < .001, I² = 73.8%), there were no significant differences in partial response rates across study subgroups (between-subgroup Q₄ = 3.8, P = .44) (data not shown). When modeled jointly using multivariate metaregression, the complete response rate was 72.2% (95% CI, 66.1%-78.3%; z = 23.3, P < .001, I² = 5%), and the partial response rate was 17.8% (95% CI, 11.7%-23.9%; z = 5.7, P < .001, I² = 4%) (eFigure 6 in the Supplement).

Adverse Events Following Omalizumab Treatment

Data on adverse events was available from 47 studies involving 1314 patients (Table and Figure 4; eTable 2 in the Supplement). Across studies, the average adverse event rate (any level of seriousness/severity) was 4.0% (95% CI, 1.0%-7.0%; z = 3.6, P < .001). There was significant heterogeneity in adverse event rates across studies (Q = 196.1, P < .001, I² = 76.6%). The adverse event rate was lower in studies of patients with mixed urticaria compared with other study subgroups (between-subgroup Q₃ = 14.5, P < .001) (eFigure 7 in the Supplement).

Discussion

The objective of this meta-analysis was to quantitatively synthesize what is known about the benefits and harms of omalizumab as used in the real-world clinical management of CIU. Synthesizing results from 67 published reports, we have provided evidence that omalizumab therapy results in large and significant improvements in UAS7, UAS, DLQI, and CU-Q₂oL scores. We also have provided evidence that omalizumab therapy is associated with complete and partial response rates of approximately 72.2% and 17.8%, respectively, when examined simultaneously. Finally, we have provided evidence that across real-world studies of omalizumab in CIU, the average adverse event rate at any level of severity is 4%. The results of this meta-analysis of observational research must be interpreted with an understanding of (1) what is already known about omalizumab in CIU from trials, (2) what these results add to our understanding of real-world use of omalizumab in CIU, and (3) what can be expected in clinical practice.

In the pivotal trial of omalizumab in CIU,⁷ patients experienced a 17.9- to 20.7-point average reduction in UAS7 scores and an 8.3- to 10.2-point average reduction in DLQI scores. In the ASTERIA I trial,⁹³ patients had a 14.9- to 22.1-point average reduction in UAS7 scores and a 6.1- to 10.3-point average reduction in DLQI scores. In the present meta-analysis of real-world studies of omalizumab in CIU, there was a 25.6-point reduction in UAS7 scores, and a 13.9-point reduction in DLQI scores on average. Of particular note, the average changes observed in urticaria activity and quality of life in following omalizumab treatment were numerically greater than the results of prior trials and were also above thresholds of minimally important difference in these outcomes. Thus, in the treatment of CIU, results may be better in real-world practice than in reports of clinical trials. Change in UAS7 assessed from daily vs twice-daily methods are similar enough that only the less burdensome UAS7 should be used in future research.^94,95

Clinical response has been operationalized in several ways in the CIU literature. Studies included in this meta-analysis most commonly defined complete response as symptom disappearance that could be followed by antihistamine discontinuation, and partial response as incomplete symptom improvement or symptom improvement followed by worsening when discontinuing antihistamines. The complete response rate in our analysis ranged from 70% to 82%, and the partial response rate ranged from 10% to 22%. Likely most informative to practice and policy are our results that the average complete response rate was 72.2% with a partial response rate of 17.8% when modeled together as opposed to considering these outcomes independently. Specifically, these results reflect what might be observed in clinical practice when looking for both complete and partial responses.

Serious adverse event rates from randomized clinical trials involving omalizumab and CIU range from 2.9% to 8% depending on the dosage.^7,93 In the present meta-analysis, there was an adverse event rate (any severity) of 4% with a confidence range of 1% to 7%. Hence, based on these real-world data, omalizumab has a safety profile that is similar to if not better than what was gleaned from prior trial results. Our results need to be interpreted with caution, however, because the monitoring and reporting of adverse events in real-world studies is not always comparable to how safety is evaluated in trials.

Even when protocols identify a complete body of research, meta-analysis results may represent a wide range of the population of interest, concomitant medications, and study characteristics, as well as true variation in treatment effects (ie, heterogeneity).⁹⁶ Hence, results of this meta-analysis are more variable than trial results, as evidenced by significant heterogeneity statistics and high I² values. Our observations of heterogeneity, however, do not impair our principal findings that across real-world settings treatment of CIU with omalizumab is associated with significant clinical improvement in several outcomes as well as clinical response. But, our findings also indicate that treatment effectiveness should be expected to vary in clinical practice. Hence, we also have included prediction intervals in our results such that clinicians can have a full understanding of the precision of our results as well as the full range of what might be expected in similar studies and in practice (ie, prediction interval).

There are several remaining questions about the real-world effectiveness of omalizumab in CIU. Dosing and duration of omalizumab was highly variable within studies (eTable 1 in the Supplement); as more evidence accumulates, the effect of study-level treatment variation on outcomes can be explored. Because other medications were not reported consistently across studies,¹² the influence of concomitant medications on real-world outcomes remains unknown. Studies in this meta-analysis included patients with and without angioedema¹²; we are hopeful to gain more insight into the effectiveness of omalizumab for angioedema with uptake of the new definition of CIU that includes angioedema,² and as more studies report angioedema activity. Finally, few studies in this meta-analysis included patients with CIU and inducible urticarias, but not in a way that could be synthesized to understand omalizumab effectiveness under both conditions.

Strengths and Limitations

There are several strengths and limitations of this meta-analysis that must be considered. First, despite our focus on real-world data, our results may not be generalizable to all patient and clinician experiences with omalizumab in the treatment of CIU. Second, real-world study designs, data, and rigor vary considerably. Hence, despite our overall conclusions that omalizumab may be more effective in the real world than what is seen in randomized clinical trials, real-world practice results should be expected to vary, with many patients having complete response but some having less benefit. Third, 2 issues that often surface when examining meta-analyses are the influence of publication and small-sample bias. Regarding our synthesis of response rate, as a representative example, there was no evidence of publication bias when performing common trim and fill procedures,⁹⁷ and any bias from small studies⁹⁸ was nonsignificant (eFigure 8 in the Supplement). Finally, our goal was to quantitatively synthesize what is known about the benefits and harms of omalizumab as used in real-world clinical management of CIU. We acknowledge, however, potential publication bias favoring effective and safe treatment and the fact that few real-world studies included all outcomes of interest. Hence, the present analysis was based on what data were available, and not necessarily what would be most desirable analytically.

Conclusions

The benefits of omalizumab reported in the real-world treatment of CIU exceed those reported in clinical trials, and the real-world safety profile is similar or superior to that found in trials. These real-world data on the use of omalizumab in CIU may help inform clinical practice treatment expectations as well as policy decision making.

Supplement.

eTable 1. Studies Included

eTable 2. Table of Evidence

eFigure 1. Change in UAS7 by Study Sub-Groups

eFigure 2. Change in UAS in Response to Omalizumab

eFigure 3. Change in UAS by Study Sub-Groups

eFigure 4. Complete Response Rate by Study Sub-Groups

eFigure 5. Partial Response to Omalizumab in Urticaria

eFigure 6. Multivariate Meta-analysis of Complete and Partial Response

eFigure 7. Adverse Events (any Severity) by Study Sub-Group

eFigure 8. Publication and Small Sample Bias

eReferences. Reference List of Meta-Analysis Sample

eChecklist.

Click here for additional data file.^{(444.2KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eTable 1. Studies Included

eTable 2. Table of Evidence

eFigure 1. Change in UAS7 by Study Sub-Groups

eFigure 2. Change in UAS in Response to Omalizumab

eFigure 3. Change in UAS by Study Sub-Groups

eFigure 4. Complete Response Rate by Study Sub-Groups

eFigure 5. Partial Response to Omalizumab in Urticaria

eFigure 6. Multivariate Meta-analysis of Complete and Partial Response

eFigure 7. Adverse Events (any Severity) by Study Sub-Group

eFigure 8. Publication and Small Sample Bias

eReferences. Reference List of Meta-Analysis Sample

eChecklist.

Click here for additional data file.^{(444.2KB, pdf)}

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PERMALINK

Benefits and Harms of Omalizumab Treatment in Adolescent and Adult Patients With Chronic Idiopathic (Spontaneous) Urticaria

Michael D Tharp, MD

Jonathan A Bernstein, MD

Abhishek Kavati, PhD

Benjamin Ortiz, MD

Karen MacDonald, PhD

Kris Denhaerynck, PhD

Ivo Abraham, PhD

Christopher S Lee, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Data Sources

Study Selection

Data Extraction and Synthesis

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Figure 1. Study Inclusion Flowchart.

Reported Outcomes

Statistical Analysis

Results

Changes in Urticaria Activity

Table. Meta-analysis of Benefits and Harms Summary of Omalizumab Treatment.

Figure 2. Change in Weekly Urticaria Activity Score (UAS7) Following Omalizumab Treatment.

Changes in Quality of Life

Clinical Response to Omalizumab

Figure 3. Urticaria Complete Response Rate Following Omalizumab Treatment.

Adverse Events Following Omalizumab Treatment

Figure 4. Adverse Event Rate in Response to Omalizumab in Urticaria.

Discussion

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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