Effectiveness of omalizumab in adolescent and adult patients with chronic idiopathic/spontaneous urticaria: a systematic review of ‘real-world’ evidence

ABSTRACT

Introduction: Chronic idiopathic/spontaneous urticaria (CIU/CSU) is a dermatological condition characterized by itchy wheals and/or angioedema of continuous or intermittent duration of ≥6 weeks with a high burden of disease and impact on quality of life. Omalizumab is a recombinant humanized monoclonal antibody that inhibits the binding of IgE to high affinity receptors, and is approved for the CIU/CSU indication. The objective of this systematic review was to evaluate and synthesize the evidence on the real-world effectiveness of omalizumab in CIU/CSU in daily clinical practice.

Areas covered: This review of 84 observational effectiveness studies covers treatments (dosing, medication use), clinical outcomes (treatment response, disease activity, quality of life), and safety.

Expert opinion: The clinical outcomes observed across studies underscore the real-world effectiveness of omalizumab in the management of CIU/CSU. Continued treatment may assist patients showing an initial response to achieve a complete treatment response. Response rates are aligned with observed changes in disease activity, symptom experience, and quality of life, and this across subtypes of CIU/CSU. The positive therapeutic profile is complemented by a positive safety profile. The real-world evidence summarized here points convincingly at the high degree of effectiveness of omalizumab in the treatment of CIU/CSU in daily clinical practice.

KEYWORDS:

• Chronic idiopathic urticaria
• chronic spontaneous urticaria
• omalizumab
• effectiveness
• real-world evidence
• systematic review

1. Introduction

Chronic idiopathic urticaria (CIU), also known as chronic spontaneous urticaria (CSU), is a dermatological condition characterized by itchy wheals and/or angioedema of continuous or intermittent duration of 6 weeks or longer. CIU/CSU is a subtype of chronic urticaria (CU) and is differentiated from inducible forms of CU (CindU) in that CIU/CSU has no known external trigger [1–3]. The incidence of CU in the general population has been estimated at 1.4% per year with a prevalence ranging from 0.5% to 5% [1]. Point prevalence of CIU/CSU at any time in Europe is estimated to be 0.5–1% [4] while the one-year prevalence of CIU/CSU in a commercially insured US population of 5.8 million was 0.11% [5]. Women are disproportionately affected by approximately 2:1 [5–7].

The number, size, character, and duration of wheal flares affect symptom severity. Burden of disease associated with CIU/CSU can be significant and debilitating, even when treated, in terms of patient-reported symptoms (primarily pruritus); quality of life including sleep problems and physical limitations; and adverse impact on daily activities and work attendance and performance. In a recent seven-country observational study [7], magnitude of burden across all of these parameters positively correlated with disease severity. Cost of work productivity loss per month was estimated to range from US$545 ± $603 in France to US$1287 ± $1124 in Germany. Direct CSU-related healthcare costs per patient year (in 2014) were found to range from US$907 ± $2431 in Italy to US$2984 ± 8969 in France. Broder et al. [5] similarly assessed resource utilization of patients with CIU/CSU (n = 6350) in a US population and found that mean urticaria-related healthcare cost in 2012 totaled $997 ± $2322 per person (median $612). For comparison, annual per person expenditures for other commonly treated conditions in 2013 included $728 for hyperlipidemia, $776 for hypertension, $1792 for chronic obstructive pulmonary disease/asthma, and $2565 for diabetes mellitus [8].

Urticarial wheals occur when mast cell activation results in release of proinflammatory mediators, such as histamine, leukotrienes, and platelet-activating factor among others. Mast cell activation may be triggered by such factors as antigens, autoantibodies, neuropeptides, hormones, medications, physical stimuli, venoms, and radiocontrast media [9], yet the mechanisms of mast cell activation and pathogenesis in CIU/CSU are not thoroughly understood [10–12]. While the formation of autoantibodies (e.g. against the FcεR1 alpha subunit of the high-affinity IgE receptor or the thyroid, among others) may be a factor in a subset of CIU/CSU patients, only about half of CIU/CSU patients have some type of autoimmunity [13,14]. Hence, chronic autoimmune urticaria (CAU) is considered a subtype of CIU/CSU [1,12,15].

Historically, non-sedating H1 antihistamine (nsAH) monotherapy has been the first-line treatment for CU [9,16] followed by nsAH up-dosing, then adding either an H2-blocker, a leukotriene antagonist, oral corticosteroids, cyclosporine, or immunomodulators among other alternative treatments [16]. Omalizumab (Xolair®, Novartis), a recombinant humanized monoclonal antibody that inhibits binding of IgE to high-affinity receptors, was first approved in Australia in 2002, followed in 2003 by the US Food and Drug Administration (FDA), and in 2005 by the European Medicines Agency (EMA) for the treatment of moderate-to-severe persistent allergic asthma. Omalizumab binds to free IgE, preventing IgE from binding to IgE receptors thereby triggering a cellular downregulation of IgE receptors (FcεR1); however, the mechanism by which these effects of omalizumab result in improvement of CIU/CSU symptoms is unknown [17]. Following publication of early case reports and case series documenting the effectiveness of off-label use of omalizumab for CU, CIU, and CAU [18–22], omalizumab emerged as an optional fourth level treatment (albeit based on low level evidence) in the 2009 international guidelines on urticaria management [15]. Three randomized, double-blind, placebo-controlled phase III trials [23–25] subsequently demonstrated efficacy and safety of omalizumab in CIU/CSU.

Omalizumab was approved by the EMA in February 2014 for CSU and by the FDA in March 2014 for CIU in adults and adolescents 12 years of age and older who remain symptomatic despite nsAH treatment. Antihistamines remain the first-line treatment for CIU/CSU with omalizumab currently recommended as Step 4 by the Joint Task Force on Practice Parameters in the United States [1,14] and as third-line treatment in international guidelines [3]. The published body of evidence on omalizumab effectiveness in daily clinical practice for CIU/CSU has since grown. In line with our prior systematic review of 24 observational studies on omalizumab in adult patients with severe allergic asthma [26], we report here on a systematic review of 84 publications including case reports/series and observational studies of the real-world effectiveness of omalizumab for treatment of CIU/CSU. The objective was to synthesize the evidence on the real-world effectiveness of omalizumab in CIU/CSU; that is, under conditions of greater heterogeneity in patients, treatment patterns, and clinicians than typically seen in randomized controlled efficacy trials. Our review is intended to provide a comprehensive, critical, and rigorous synthesis of this body of evidence and to provide an informed opinion on the use of omalizumab across the diverse patient phenotypes affected by CIU/CSU. As a systematic review, it extends and updates the clinical and product reviews and summaries on omalizumab in CIU/CSU published to date [27–36], and provides guidance to clinicians.

2. Methodology

A protocol based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [37] guidance was developed and implemented.

2.1. Eligibility

Included in this systematic review were published real-world effectiveness studies of male or female adults or adolescents (12 years or older) with CIU/CSU treated with omalizumab meeting the following PRISMA-defined PICOS [37] criteria:

1. Participants: Male or female adults or adolescents (12 years or older) diagnosed with CIU/CSU

2. Intervention: Treated with omalizumab for CIU/CSU

3. Comparators: Permissible but not required

4. Outcomes: at least one measure of: treatment response, CIU/CSU disease activity (i.e. symptoms), quality of life, or safety.

5. Studies: any observational method including case reports, case series, registry, retrospective chart review, prospective observational study, or pragmatic trials.

2.2. Search strategy, screening, and data extraction

We searched PubMed, EMBASE, Web of Science, and the Cochrane Library database for published articles. Keywords included ‘chronic idiopathic urticaria’ or ‘chronic spontaneous urticaria’, and ‘omalizumab’. There were no restrictions on language, sample size, or date of publication; however, studies conducted prior to 2014 were considered off-label use. Studies as defined above were eligible if published as original research, case report/series, review, or letter (if other eligibility criteria were met). While there have been a plethora of abstracts published on use of omalizumab in CIU/CSU from immunology and/or dermatology congresses, abstract-only publications were not included due to lack of sufficiently detailed data. The reference lists of sources were reviewed for studies not previously identified. The search censoring date was 28 September 2017.

As shown in Figure 1, the database searches yielded 1341 records and 5 additional records were identified through citation analysis, for a total of 1346. This total reduced to 871 after removal of 475 duplicates. Of these, 3 were not retrievable and 678 records were not relevant, resulting in 190 articles retrieved for full-text review including publications in English, Dutch, German, Polish, and Spanish. Of these, 29 included duplicate reporting of cases, 75 did not meet PICOS eligibility criteria, and 2 did not sufficiently report the requisite treatment or outcome data.

Figure 1. Data identification, screening, eligibility and inclusion.

This yielded the 84 studies mentioned above. The following study-level data were extracted: year of publication, country, evaluable sample size, sample characteristics (demographics, relevant medical history, CIU/CSU history, prior CIU/CSU treatments), omalizumab treatment patterns, and outcomes.

Treatment response was generally reported in one of two ways: responder/nonresponder or complete/partial/no response. There was variation in timing of measurements (e.g. 1-week response, 1-month response, 3-month, etc.) with the majority of studies reporting response at the end of the observation period, which also varied across studies. We included for both response measurements whether patients showed an initial and/or a final treatment response. For final response measures, ‘non-responder’ and/or ‘no response’ also included patients who may have had an initial response but became refractory. A small subset of studies reported time to this response.

Disease activity outcomes encompassed ratings on either of the following scales:

1. Urticaria Activity Score (UAS) [38]: summed intensity rating of wheals and pruritus each on a scale of 0 (no disease activity) to 3 (intense activity) over the course of 1 day.

2. UAS7 [38]: summed daily UAS over 7 consecutive days.

3. Urticaria Control Test (UCT) [39]: 4-item survey to retrospectively assess urticaria control over a 4-week recall period.

Quality of life outcomes comprised data from the following scales:

1. Chronic Urticaria and Quality of Life Questionnaire (CU-Q₂oL) [40]

2. Dermatology Life Quality Index (DLQI) [41]

Safety data were recorded as stated in the articles. This included singular adverse (AE) or serious adverse events (SAE), but also combined safety entries (e.g. fatigue and mild pain in lower extremities). We did not attempt to parse these out into singular occurrences. Neither did we attempt to classify AEs and SAEs according to such systems as Medical Dictionary for Regulatory Activities (MedDRA).

Medication use referred to whether other CIU/CSU treatments were continued or discontinued after treatment with omalizumab was started. Methods for quantifying medication use comprised medication scoring systems, medication count (mg or tablets) for routine or rescue medications, and combined symptom and medication scoring systems.

Note that studies differed in terms of the clinical, safety, and outcomes measures included. We recorded for each study the outcomes included in the study.

Screening and data extraction were performed independently by two investigators. Discrepancies were resolved through discussion or, if not resolved, escalated to a third investigator for adjudication.

2.3. Other methodological considerations

When two or more studies containing the same subjects (either partially or wholly) were identified, the larger study was retained. For example, an older case study on one or two subjects was excluded if a more recent, larger publication contained these same subjects as part of a larger cohort.

A number of publications contained mixed samples with some CIU/CSU patients and some with CindU. Where possible, the data on CIU/CSU subjects meeting our eligibility criteria were extracted and CindU patients were censored. For this, we relied in first instance on stratified results reported in the publication. Alternately, we censored specific cases based on raw data obtained from tables in the manuscript or included in online supplemental materials. If this was not possible, we queried the authors to provide either stratified results on the CIU/CSU patients only or for access to the raw data so that we could extract the relevant cases.

Calculations in all papers were validated, data permitting, to assess data integrity and derive common metrics for comparisons across studies. Hence, results in our analysis may diverge from originally reported data if recalculations were done using a different formula to permit cross-study comparisons or for studies where cases were censored. When missing, means and standard deviations were imputed from other measures of central tendency (median) and dispersion (either min/max or interquartile range) when available and if the variable was reasonably expected of being normally distributed. The titrated omalizumab dose was computed on patients remaining on omalizumab (i.e. denominator does not include those discontinued).

2.4. Classification of studies by urticaria subtype

Based on the subtype of urticaria in focus, the 84 studies were classified into five categories.

1. The ‘CIU/CSU studies’ category (n = 21; 25.0%) includes investigations focused on patients diagnosed specifically with CIU or CSU, with no mention of CindU [42–62]. Angioedema was an allowable comorbidity, but patients could not have any other reported relevant comorbid conditions.

2. The ‘CAU studies’ category is composed of three studies (3.6%) explicitly using the term chronic autoimmune urticaria to describe the sample [21,22,63]. All three studies were published in or prior to 2010. Since then, the term CSU has been used more frequently to characterize non-inducible CU whether autoimmune or non-autoimmune in nature, as proposed in the international guidelines on classification of CU [3,15]. CAU (also known as auto-antibody-associated urticaria) is also regarded as a subcategory of CIU [12]. Hence, it is likely that had these studies been published more recently, they would have used the term CIU or CSU. However, for both historical and scientific reasons, we have assessed them as a separate cohort.

3. Six studies (7.1%) include patients with chronic urticaria that is not further defined or specified [64–69]. These are classified as ‘CU studies’ and can be presumed to be CIU/CSU as the terms physical urticaria or CindU were not used to describe the sample.

4. The majority of studies (n = 51; 60.7%) were categorized as ‘CIU/CSU or CU with comorbidities/conditions’ [18–20,70–117]. These included CIU/CSU or CU patients with relevant comorbidities including inducible urticarias, asthma, allergic disorders (e.g. allergic rhinitis), autoimmune diseases (e.g. systemic lupus erythematosis), other rheumatoid diseases (e.g. psoriatic arthritis), or relevant infectious diseases (e.g. hepatitis C virus). Other comorbidities such as diabetes Type II or hypertension are not listed separately. A couple case studies on special circumstances or conditions of particular interest (e.g. omalizumab use during pregnancy [86,87,97,112]) are also included in this category.

5. There remained three studies (3.6%) with a mix of CIU/CSU patients as well as patients with types of urticaria outside the scope of this review where censoring was not possible [118–120]. We categorized these studies as ‘Mixed studies’ and included this category in our systematic review for the sake of completeness.

3. Evidence base

Table 1 presents the 84 publications published through the search date of 28 September 2017 stratified by the urticaria subtype of study. This table details for each study the country or countries in which it was conducted; the study design as specified in the publication; the censored cases and the resulting eligible sample size; and the comorbidities of patients in the study. Also included are such demographics as the mean (±SD) age of patients, the proportion of female subjects, and the mean (±SD) number of years since subjects’ CIU/CSU diagnosis. It summarizes prior treatments received by patients in the study (with rates if n ≥ 2) as well as the mean (±SD) duration of omalizumab treatment (in months). The table concludes with the disease activity (UAS, UAS7, and/or UCT) and quality of life (DLQI or CU-Q₂oL) outcomes reported; whether the proportions of responders versus nonresponders are reported; whether the proportions by degree of response (complete, partial, none/refractory) are detailed; and whether safety data are presented. Note that the two treatment response variables may have been assessed at either one of two occasions, or both: as an initial response (as defined by each study) and as a final response to treatment at end of study or observation period.

Table 1. Review of urticaria types evaluated, study design, patient characteristics, and effectiveness outcomes reported (stratified by urticaria type of study).

	Authors	Year	Country	Study design(per publication)	Censored cases	n	Comorbidities/conditions	Age in years (Mean ± SD)	Female (%)	Years since CIU/CSU diagnosis (Mean ± SD)	Prior Treatment(s)	Months of omalizumab treatment (Mean ± SD)	Starting dose omalizumab	Responder (yes/no)	Degree of response (complete, partial, none or refractory)	UAS	UAS7	UCT	DLQI	CU-Q2oL	Safety
CIU/CSU studies (n = 21)
	Iemoli et al. [42]	2010	Italy	Case study/case series		1	Angioedema	57 ± 0	100.00%	5 ± 0	Antihistamine corticosteroid cyclosporine IV immunoglobulin other immunomodulator	6 ± 0	300 mg Q2W	✔
	Vestergaard & Deleuran [43]	2010	Denmark	Case study/case series		2		45 ± 17	100.00%	6.5 ± 5	Antihistamine 100% cyclosporine 100% mycophenolate mofetil 100% corticosteroid 50% methotrexate 50% IV immunoglobulin 50% other immunomodulator 100%	7.3 ± 0.4	150 mg Q4W 50.0% 300 mg Q4W 50.0%				✔		✔
	Wieczorek et al [44].	2011	Germany	Case study/case series	10 total: 9 CindU, 1 with angioedema without hives	4					Antihistamine in combination with anti-leukotriene 100% corticosteroid 50%		doses, based on serum IgE, ranged from 150 mg Q4W to max dose 750 mg Q4W		✔
	Armengot-Carbo et al. [45]	2013	Spain	Retrospective		15		49 ± 49	73.30%	4.9 ± 6.5	H1-antihistamine 100% H2-antihistamine 80.0% corticosteroid 40% cyclosporine 33.3%	5 ± 1.5	150 mg Q2W 13.33% 150 mg Q4W 53.33% 300 mg Q4W 33.33%		✔						✔
	Song et al. [46]	2013	Canada	Retrospective		16		47.2 ± 13.7	68.70%	6.3 ± 4.7	Antihistamine 100% corticosteroid 81.3% various other 2nd &3rd line tx (% not reported)		150 mg Q4W 100%		✔						✔
	Kai et al. [47]	2014	UK	Retrospective	9 total: 8 with CindU, 1 with vasculitis	6					H1-antihistamine 100% cyclosporine 100% mycophenolate mofetil 100% methotrexate 100%	11.5 ± 9.4							✔		✔
	Romano et al. [48]	2015	Italy	Retrospective	3 with atopic dermatitis	6		53.2 ± 12.2	83.30%	5.7 ± 6.2	Antihistamine 100% corticosteroid 100% anti-leukotriene 83.3% cyclosporine 50%	32.8 ± 33.3	150 mg Q4W 33.33% 300 mg Q2W 33.33% 300 mg Q4W 33.33%		✔		✔				✔
	Tontini et al. [49]	2015	Italy	Prospective		8		47.5 ± 12.1	50.00%	6.5 ± 3.8	H1-antihistamine 100% corticosteroid 100% cyclosporine 37.5%	6 ± 0	300 mg Q4W 100%				✔
	Clark et al. [50]	2016	US	Retrospective		41	Angioedema 31.7%	43.8 ± 15.4	80.50%	4.8 ± 0	H1-antihistamine 100% corticosteroid 75.6% cyclosporine 51.2% methotrexate 36.6% anti-leukotriene 31.7% mycophenolate mofetil 26.8% dapsone 22.0% colchicin 14.6%	14.1 ± 6.4	150mg Q4W 19.5% 300mg Q2W 51.2% 300 mg Q4W 29.3%	✔							✔
	Denman et al. [51]	2016	UK	Retrospective		123						7 ± 4.5									✔
	Gimenez-Arnau et al. [52]	2016	Spain	Retrospective		38		48.1 ± 14	65.80%	6.6 ± 8.1	Antihistamine 100% corticosteroid 78.9% cyclosporine 39.5% anti-leukotriene 26.3%		300 mg Q4W 100%		✔		✔			✔	✔
	Gomez-Vera et al. [53]	2016	Mexico	Prospective	5 with CindU	21	Angioedema 76.2%	49.2 ± 9.1	85.70%	5.1 ± 1.2	Antihistamine 100%	6 ± 0	300 mg Q4W 100%				✔	✔			✔
	Gönül et al. [54]	2016	Turkey	Case study/case series		1	Angioedema 100%	37 ± 0	100.00%	2 ± 0	H1-antihistamine andcorticosteroid		300 mg Q4W								✔
	Konstantinou et al. [55]	2016	Greece	Case study/case series		3	Angioedema 100%	56.7 ± 16.7	100.00%	0.4 ± 0.13	Antihistamine 100% corticosteroid 100% montelukast 100%	4 ± 0					✔	✔			✔
	Moreira et al. [56]	2016	Portugal	Retrospective	1 with CindU	5	Angioedema 80%	34.4 ± 15.5	80.00%	9.2 ± 6.8	Antihistamine 80% corticosteroid 80% anti-leukotriene 20%	17.4 ± 1.1	300 mg Q4W 100%								✔
	Subramaniyan & Chopra [57]	2016	India	Case study/case series		4	Angioedema 25%	36.5 ± 11.2	25.00%	3 ± 1.4	Antihistamine 100% corticosteroid 100% cyclosporine 50%	1 ± 0	Single dose of 300 mg				✔		✔		✔
	Ertas et al. [58]	2017	Turkey	Prospective		93		35.9 ± 12.21	65.05%	4 ± 6.9		3 ± 0	300 mg Q4W 100%		✔
	Gericke et al. [59]	2017	Germany	Prospective		64		47 ± 15.5	71.90%	3 ± 9.93	H1-antihistamine 100%	3 ± 0	300 mg Q4W 100%	✔
	Kocaturk et al. [60]	2017	Turkey	Prospective		15		41.2 ± 13.5	69.70%	1.8 ± 3.3	Antihistamine 100%		All treated with either 150 mg Q2W or 300 mg Q4W	✔				✔			✔
	Kulthanan et al. [61]	2017	Thailand	Retrospective	1 with CindU	12		40.4 ± 13	66.70%	4.4 ± 2.3	Antihistamine 100%, anti-leukotriene100% corticosteroid 100% cyclosporine 100% hydroxychloroquine 16.7%	6.3 ± 2.6	150 mg Q4W 100%		✔		✔				✔
	Larrea-Baca et al. [62]	2017	Spain	Prospective		18		44.1 ± 18.52	72.20%								✔			✔	✔
CAU studies (n = 3)
	Kaplan et al. [21]	2008	US	Prospective		12		47.3 ± 12.1	66.70%	6.3 ± 9.3	Antihistamine 100%	4 ± 0	Dosed according to body weight and total serum IgE levels and administered every 2–4 weeks		✔	✔			✔
	Maspero et al. [22]	2009	Argentina	Case study/case series		1	Angioedema 100%	12 ± 0	100.00%	1.2 ± 0	Antihistamine, corticosteroidand anti-leukotriene	12 ± 0	150 mg Q4W		✔
	Al-Ahmad [63]	2010	Kuwait	Case study/case series		3	Angioedema 100%	37.3 ± 12.6	100.00%	4.3 ± 0.6	Antihistamine 100% corticosteroid 100% montelukast 100%	16 ± 0	300 mg Q4W 100%		✔	✔					✔
CU studies (n = 6)
	Korkmaz et al. [64]	2010	Germany	Case study/case series		1	Angioedema 100%	29 ± 0	0.00%	1 ± 0	Antihistamine corticosteroid anti-leukotriene cyclosporine	2 ± 0	300 mg Q2W		✔
	Ferrer et al. [65]	2011	Spain	Prospective		9	Angioedema 66.7%	43.8 ± 12.4	77.80%	6.6 ± 3	Antihistamines 100% corticosteroid 77.8% cyclosporine 22.2% Doxepin 22.2% anti-leukotriene 11.1% Proton pump inhibitor 11.1%		300 mg Q2W 11.1% 300 mg Q4W 55.6% 300 mg Q12W 33.3%		✔	✔
	Košnik et al. [66]	2014	Slovenia	Case study/case series	1 with CindU	3		50.3 ± 15		1.9 ± 2	Antihistamine 100% corticosteroid 66.7% cyclosporine 33.3% anti-leukotriene 66.7% methotrexate 33.3%	4.3 ± 4.9	150 mg Q4W 66.7% 150 mg Q6W 33.3%		✔						✔
	Har et al.^a [67]	2015	US	Retrospective		10		44.2 ± 13.1	50.00%	8.4 ± 7.4	Antihistamine + at least onealternative treatment 100% mycophenolate 60% tacrolimus 60% dapsone 40% hydroxychloroquine 30% anti-leukotriene 20% cyclosporine 10% IV immunoglobulin 10%	43.8 ± 33.6	150 mg Q4W 40.0% 300 mg Q4W 30.0% 375 mg Q2W 10.0% 375 mg Q4W 10.0% 450 mg Q2W 10.0%	✔	✔						✔
	Irani et al. [68]	2015	Lebanon	Prospective		14			85.70%			12 ± 0	300 mg Q4W 100%		✔						✔
	Seth & Khan [69]	2017	US	Retrospective		24		44 ± 12.75	77.00%	3.7 ± 9.21		15 ± 17	Most patients received 300 mg Q4W; other regimens included 150 mg Q4 and 375 mg Q2W		✔						✔
CI/CSU or CU with combordities studies (n = 51)
	Dreyfus & Randolph [70]	2006	US	Case study/case series		1	Angioedema, asthma, allergic rhinitis	32 ± 0	100.00%	2 ± 0	Antihistamine corticosteroid epinephrine anti-leukotriene cyclosporine budesonide	6 ± 0	300 mg at initial injection; all subsequent injections 150 mg	✔							✔
	Spector & Tan [18]	2007	US	Case study/case series		3	Angioedema 33% allergic rhinitis 33% asthma 33% Crohn’s disease 33%	35.7 ± 11	66.70%	8 ± 10.4	H1-antihistamine 100% corticosteroid 100% anti-leukotriene 100% 5-Lipoxygenase inhibitor 66.7% H2-antihistamine 66.7%	4 ± 2.8	300 mg Q2W 33.3% 375 mg Q2W 66.7%		✔
	Dreyfus [19]	2008	US	Case study/case series		1	Angioedema, allergies, asthma, thyroid auto-immunity	22 ± 0	100.00%		Antihistamine corticosteroid cyclosporine	6 ± 0		✔
	Godse [20]	2008	India	Case study/case series		1	Sarcoidosis, osteoporosis, bronchial asthma	45 ± 0	100.00%	10 ± 0	Antihistamine corticosteroid anti-leukotriene cyclosporine	2 ± 0	300 mg Q4W		✔
	Magerl et al. [71]	2010	Germany	Case study/case series		8	Angioedema 87.5% asthma 25.0% other allergies 50.0% CindU 12.5%	44.6 ± 8.5	87.50%	7.3 ± 4.9	H1-antihistamine 100%and either switchantihistamine or anti-leukotriene 100%		150 mg Q4W 14.3% 300 mg Q2W 28.6% 300 mg Q4W 42.9% 300 mg Q6W 14.3%				✔				✔
	Godse [72]	2011	India	Case study/case series		5	Asthma 40.0% dermographism 20.0%	45.2 ± 12.3	60.00%	10 ± 6.7	Antihistamine 100% corticosteroid 60% cyclosporine 20% herbal 20%	4 ± 0	300 mg Q2W 60.0% 300 mg Q4W 40.0%			✔					✔
	Groffik et al. [73]	2011	Germany	Case study/case series		9	Atopic dermatitis 33.3% CindU 22.2% angioedema 22.2% cholinergic urticaria 22.2% asthma 11.1% sinusitis 11.1%	41.8 ± 13.7	33.30%	11.8 ± 16.9	H1-antihistamine 100% corticosteroid 88.9% anti-leukotriene 66.7% H2-antihistamine 22.2% immunoglobulin 11.1%	2.3 ± 0.8	150 mg Q2W 11.1% 150 mg Q4W 44.4% 300 mg Q2W 33.3% 300 mg Q4W 11.1%		✔						✔
	Saavedra & Sur [74]	2011	US	Case study/case series		1	Asthma, allergic rhinitis and atopic dermatitis	51 ± 0	100.00%	3 ± 0	Antihistamine corticosteroid anti-leukotriene cyclosporine	7 ± 0	300 mg Q2W		✔						✔
	Sanchez-Machin et al. [75]	2011	Spain	Case study/case series		1	Angioedema, rhinoconjunctivitis, episodic asthma	35 ± 0	100.00%	9 ± 0	Antihistamine corticosteroid doxepin cyclosporine	4.5 ± 0	300 mg Q2W		✔
	Nam et al. [76]	2012	South Korea	Retrospective		26	Atopy 68% NSAID hypersensitivity 61.5% angioedema or CindU 50% anti-nuclear antibody 19.2% antithyroglobulin antibody 23.1% antimicrosomal antibody 7.7%	43.1 ± 8.4	46.20%	5.3 ± 6.1	Fourth-line therapy 100%	6 ± 0	dosed according to body weight and total serum IgE levels and administered every 2–4 weeks		✔	✔					✔
	Diez et al. [77]	2013	Colombia	Case study/case series		3	Vasculitis 100% angioedema 100% +plasma autologous serum 100% CindU 66.7%	44.3 ± 14.2	100.00%	16.3 ± 7.2	Antihistamine 100% anti-leukotriene 100% corticosteroid 66.7% immunosuppresant 66.7%	14 ± 4.4	150 mg Q4W 66.7% 300 mg Q4W 33.3%		✔						✔
	Labrador-Horrillo et al. [78]	2013	Spain	Retrospective		110	CSU 100% CAU 42.9% CindU 35.5% angioedema 6.4%	45 ± 14.25	66.40%		Antihistamine 76.4% corticosteroid 77.3% cyclosporine or tacrolimus 28.8% anti-leukotriene 13.6% Other (methotrexate, doxepin,H2-antihistamine, antimalarial,dapsone, etc.) 15.5%		150 mg Q2W 9.1% 150 mg Q4W 49.1% 300 mg Q2W 4.5% 300 mg Q4W 25.5% Other (150–300 mg Q6-24W) 11.8%		✔	✔					✔
	Lefevre et al. [79]	2013	Denmark	Case study/case series		14	Asthma 21.4% psoriatic arthritis & fibromyalgia 7.1% systemic lupus erythematosus 7.1%	43.4 ± 17.7	64.30%	6.4 ± 4.8	Antihistamine 100% corticosteroid 92.9% mycophenolate mofetil 71.4%cyclosporine 57.1%	14.6 ± 12	150 mg Q4W 57.1% 300 mg Q2W 7.1% 300 mg Q4W 35.7%	✔			✔		✔		✔
	Viswanathan et al. [80]	2013	US	Retrospective	2 total: 1 age 8, 1 with CindU	17	Autoimmunity 52.9% (remainder CU not further specified) angioedema 29.4%	41.3 ± 12.9	64.70%		Cyclosporine 52.9% tacrolimus 23.5% hydroxychloroquine 23.5% mycophenolate mofetil 11.8%	5.9 ± 4.5	150 mg Q2W 17.6% 187.5 mg Q2W 5.9% 225 mg Q2W 5.9% 300 mg Q2W 23.5% 300 mg Q4W 47.1%		✔						✔
	Fiorino et al. [81]	2014	Italy	Case study/case series		2	Pressure urticaria 50%	52 ± 2.8	100.00%	9 ± 2.8	Antihistamine 100% corticosteroid 100% immunosuppressant 100% anti-leukotriene 50%	34.5 ± 19.1	150 mg Q4W 50.0% 300 mg Q4W 50.0%		✔		✔				✔
	Metz et al. J Derm Sci. [82]	2014	Germany	Retrospective	21 with CindU (without comorbid CIU/CSU)	30	CindU 33.3%		72.50%		Antihistamine 100% (many had also received2nd and 3rd line therapy[cannot tease out rates foronly CSU pts])		150 mg Q2W 12.0% 150 mg Q4W 60.0% 225 mg Q4W 4.0% 300 mg Q4W 24.0% (reported in n = 25)		✔						✔
	Rottem et al. [83]	2014	Israel	Retrospective		43	Allergic rhinitis 9.3% asthma 14.0%	45 ± 12	69.80%	4.3 ± 4	Antihistamine 97.7% corticosteroid 88.4% cyclosporine 25.6% anti-leukotriene 9.3% Other (methotrexate,mycophenolate mofetil,azatioprine, etc.) 14.0%		150 mg Q4W 74.4% 300 mg Q4W 25.6%		✔						✔
	Uysal et al. [84]	2014	Denmark	Prospective	5 total: 1 age 10, 4 with CindU (without comorbid CIU/CSU)	22	DPU 18.2% urticaria factitia 13.6% heat contact urticaria 4.6% contact urticaria 4.6% asthma 22.73% allergic rhinitis 18.18% drug allergy 18.18% hypothyroidism 9.09% anaphylaxis 4.55%	34.6 ± 17.5	72.70%	6.7 ± 6.5	Antihistamine 100% corticosteroid 40.9% anti-leukotriene 50.0% azathioprine 36.4% cyclosporine 13.6% methotrexate 9.1% dapsone 9.1% mycophenolate mofetil 4.6% ultraviolet B light 4.6%	15.2 ± 10.1	150 mg Q2W 100%	✔		✔
	Van Den Elzen et al. [85]	2014	Netherlands	Case study/case series	1 with CindU	4	Angioedema 75% DPU 25% anaphylaxis 25%	50 ± 6.7	75.00%	5 ± 2.9	Antihistamine 100% corticosteroid 75% cyclosporine 50% anti-leukotriene 50% azathioprine 25%		150 mg Q4W 75.0% 300 mg Q4W 25.0%		✔						✔
	Vieira Dos Santos et al. [86]	2014	Not specified	Case study/case series		1	Pressure urticaria anddermographism special circumstance: pregnancy	37 ± 0	100.00%	11 ± 0	Antihistamine corticosteroid anti-leukotriene cyclosporine	60 ± 0	150 mg Q4W		✔						✔
	Ghazanfar & Thomsen [87]	2015	Denmark	Case study/case series		1	Special circumstance: pregnancy	32 ± 0	100.00%		Antihistamine azathiorprine prednisolone TNF-inhibitor	36 ± 0	150 mg Q2W		✔						✔
	Klossowski et al. [88]	2015	Germany	Case study/case series		1	Acquired angioedema due to C1 inhibitor deficiency (C1-INH-AAE) and chronic lymphatic B cell leukemia 100%	57 ± 0		0.25 ± 0	Antihistamine corticosteroid		300 mg Q4W		✔
	Leiva-Salinas et al. [89]	2015	Spain	Case study/case series		1	HCV	49 ± 0	100.00%	0.42 ± 0	Antihistamine corticosteroid anti-leukotriene	8 ± 0	150 mg Q2W	✔							✔
	Lundberg et al. [90]	2015	US	Case study/case series		2	APECED 100%	12.5 ± 0.71	100.00%		Antihistamine 100% anti-leukotriene 100% doxepin 50%		150 mg Q4W		✔
	Netchiporouk et al. [91]	2015	Canada	Case study/case series	3 age <12	1	DPU	16 ± 0	0.00%	8 ± 0	Antihistamine anti-leukotrienes		300 mg Q4W		✔		✔
	Savic et al. [92]	2015	UK	Retrospective		46	CindU 21.7% angioedema 82.6% allergic condition 19.6% asthma 15.2% eczema 15.2%	43.3 ± 13.1	78.30%	3.8 ± 4.7	Antihistamines 100% corticosteroid 74.4% cyclosporine 71.7% leukotriene antagonists 50.0% methotrexate 37.0% mycophenolate mofetil 26.1% H2-antihistamines 21.7% tacrolimus 4.3%		150 or 300 mg Q2, 3 or 4W				✔		✔		✔
	Silva et al. [93]	2015	Portugal	Retrospective		7	Allergic asthma 42.9% allergic rhinitis 71.4%	40.6 ± 8	85.70%	6.9 ± 5.8	H1-antihistamine 100% H2-antihistamine 100% anti-leukotriene 100% corticosteroid 100% immunoglobulin 57.1% cyclosporine 42.9%	35 ± 2.75	150 mg Q2W 14.3% 150 mg Q4W 14.3% 225 mg Q2W 14.3% 225 mg Q4W 14.3% 300 mg Q2W 14.3% 300 mg Q4W 28.5%		✔	✔					✔
	Sussman et al. [94]	2015	Canada /Portugal	Case study/case series		3	DPU 33.3%	61.7 ± 17	33.30%	10.7 ± 7.6	Antihistamine 100% corticosteroid 100% anti-leukotriene 66.7% cyclosporine 66.7% immunoglobulin 66.7%	17 ± 16.5^b	150 mg Q4W 100%		✔						✔
	Wieder et al. [95]	2015	Not specified	Case study/case series		1	Asthma, angioedema, analphylaxis	51 ± 0	100.00%	3 ± 0	Antihistamine corticosteroid anti-leukotriene cyclosporine mycophenolate mofetil	29 ± 0	300 mg Q4W	✔							✔
	Bongiorno et al. [96]	2016	Italy	Case study/case series		14	Angioedema 50.0% asthma 28.6% atopic diathesis 28.6% CindU 14.3% IBS 7.1% contact dermatitis 7.1% psoriasis 7.1% autoimmune thyroiditis 7.1%	44.4 ± 15	64.30%	6 ± 7.9	Antihistamine 100% corticosteroid 78.6% cyclosporine 42.9% anti-leukotriene 14.3%	5.4 ± 2.7	300 mg Q4W 100%		✔		✔				✔
	Cuervo-Pardo et al. [97]	2016	US	Case study/case series		4	Special circumstance: pregnancy 100% asthma 75% allergic rhinitis 50%	Between 25 and 28	100.00%		H1-antihistamine 100% H2-antihistamine 100% anti-leukotriene 100% corticosteroid 100% immunosuppressant 75%	18.5 ± 5	300 mg Q4W 100%	✔							✔
	Dawicka et al. [98]	2016	Poland	Case study/case series		2	Hashimoto’s disease 50%	55 ± 12.7	100.00%	2 ± 0	Antihistamine 100% corticosteroid 100% anti-leukotriene 50% methotrexate 100%	3.3 ± 1.4	300 mg Q4W 100%				✔
	Ensina et al. [99]	2016	Brazil	Retrospective		47	CindU 21.3% autoimmunity 39.5%	38.9 ± 14.5	85.10%	4.5	Antihistamine 100% cyclosporine 4.3%		150mg Q4W 44.7% 300mg Q4W 55.3%		✔						✔
	Ertaş et al. [100]	2016	Turkey	Case study/case series		46	drug allergy 6.5% atopy 6.5% asthma 2.2% psoriasis 2.2% allergic rhinitis 2.2%	47 ± 13.4	50.00%	10.3 ± 8.6			300 mg Q4W 100%								✔
	Ghazanfar et al. [101]	2016	Denmark	Retrospective	17 with CindU	137	Angioedema 30.7% + histamine release test 34.3% other ‘significant comorbidities’ (including asthma, diabetes, HTN and hypothyroidism) 22.6%	39.7 ± 15	70.80%	3.8 ± 5.4	Anti-leukotriene 5.1% corticosteroid 42.3% immunosuppressant 27.0%		150 mg Q2W 45.3% 300 mg Q4W 54.7%		✔						✔^c
	Gozdzik-Spychalska et al. [102]	2016	Poland	Case study/case series		1	Asthma, idiopathic thrombocytopenic purpura	38 ± 0	100.00%	2 ± 0	Antihistamine 100% corticosteroid LABA anti-leukotriene theophylline SABA	36 ± 0	450 mg Q2W		✔						✔
	Kasperska-Zajac et al. [103]	2016	Poland	Retrospective		9	Angioedema only 66.7% DPU only 11.1% angioedema and DPU 22.2%	41.4 ± 15.1			Antihistamine 100% corticosteroid 100% anti-leukotriene 44.4% cyclosporine 22.2% methotrexate 11.1% other immunosuppressive/immunomodulatory 11.1%		300 mg Q4W 100%		✔						✔
	Olszowiec-Chlebna et al. [104]	2016	Poland	Case study/case series		1	Angioedema and idiopathic anaphylaxis	15 ± 0	100.00%	2 ± 0	Antihistamine corticosteroid self-injectable epinephrine	6 ± 0	300 mg Q4W		✔						✔
	Osmenda et al. [105]	2016	Poland	Case study/case series		1	Atopic asthma, allergic rhinitis	44 ± 0			Antihistamine fluticasone/salmeterol theophylline anti-leukotriene SABA methylprednisolone	29 ± 0	150 mg Q1W due to severe bronchial asthma		✔						✔
	Palacios et al. [106]	2016	US	Retrospective		41	Hypothyroidism 19.5% thyroid autoantibodies 19.5%	45.9 ± 17	80.50%		Antihistamine 100%		300 mg Q4W 100%	✔
	Shahzad H. [107]	2016	Pakistan	Case study/case series		1	Allergic rhinitis	52 ± 0	0.00%	15 ± 0	Antihistamine mast cell stabilizers corticosteroid anti-leukotriene xylometazoline nasal drops	12 ± 0	300 mg Q4W				✔			✔	✔
	Wilches et al. [108]	2016	Ecuador	Retrospective		26	Asthma 3.8% rhinitis 11.5%	47.8 ± 19.5	57.70%	1.9 ± 2.9	Antihistamine 100% corticosteroid 53.8% immunotherapy 3.8%	2.2 ± 1.6	150 mg Q4W 100%		✔	✔					✔
	Asero et al. [109]	2017	Italy	Prospective		32	Angioedema 37.5% thyroid autoimmunity 25% antinuclear antibody+ 15.6% NSAID-related exacerbations 12.5%	50.4 ± 18.5	65.60%	3.6 ± 3.2	Antihistamine 100% corticosteroid 71.9% cyclosporine 25% H2-antihistamine 9.4%	3 ± 0	300 mg Q4W 100%		✔
	Chicharro et al. [110]	2017	Spain	Case study/case series		1	HBV	56 ± 0	100.00%	15 ± 0	H1-antihistamine corticosteroid	6 ± 0	300 mg Q4W				✔				✔
	Deza et al. [111]	2017	Spain	Prospective		47	CindU 25.5% angioedema 42.6% +autologous serum skin test 68.2%	51 ± 5.75	78.70%	1.33 ± 3.58	Antihistamine 100% cyclosporine 53.2%	11 ± 0	300 mg Q4W 100%	✔
	Gonzalez-Medina et al. [112]	2017	Spain	Case study/case series		2	Special circumstance: pregnancy 100%	37 ± 0	100.00%	12.5 ± 6.4	Antihistamine 100% corticosteroid 100% cyclosporine 100%	19 ± 18.4	300 mg Q4W				✔				✔
	Iemoli et al. [113]	2017	Italy	Case study/case series		1	HIV	56 ± 0	0.00%	3 ± 0	Antihistamine cyclosporine	12 ± 0	150 mg Q4W				✔			✔	✔
	Marin-Cabanas et al. [114]	2017	Spain	Retrospective		16	CindU 45% angioedema 40% an autoimmune disease 20% atopy 17% HBV or HCV 4%	47.3	62.00%	1.9 ± 1.6	Second-line treatments 75% third-line treatments (including cyclosporine) 25%		doses ranged from 150 mg Q4W to 375 mg Q2W	✔							✔
	Pinto Gouveia et al. [115]	2017	Portugal	Prospective		13	angeioedema 100% DPU 53.8% Solar urticaria 7.7% atopy 7.7% psoriasis 7.7%	49.3 ± 16.2	84.62%	9.4 ± 10.1		15.3 ± 10.9	150 mg Q4W 100%		✔		✔				✔
	Porcaro et al. [116]	2017	Italy	Case study/case series		1	Chronic rhinosinusitis and severe asthma	15 ± 0	100.00%		Inhaled budesonide formoterol anti-leukotriene loratadine intranasal fluticasone furoate corticosteroid	6 ± 0	300 mg Q4W		✔		✔
	Türk et al. [117]	2017	Turkey	Retrospective		25	Asthma 16% rheumatologic disorder 4%	39 ± 12.74	72.00%	3.67 ± 3.52		6 ± 4.44	300 mg Q4W 100%		✔	✔					✔
Mixed studies (n = 3)
	Buyukozturk et al. [118]	2012	Turkey	Not specified		14	Mixed urticarias: CSU 85.7% idiopathic angeioedema 14.3% Comorbid: asthma 14.3% CSU & angioedema 7.1%	43.1 ± 9.8	71.40%	9.3 ± 8.5	Antihistamine 100% cyclosporine 21.4%	9.3 ± 4.1	150 mg Q4W 28.6% 225 mg Q4W 7.1% 300 mg Q2W 14.3% 300 mg Q4W 35.7% 375 mg Q2W 7.1% 375 mg Q4W 7.1%				✔			✔	✔
	Metz et al. JAMA Derm.^d [119]	2014	Germany	Retrospective		25	Mixed urticarias: CSU 36.0% CindU 40.0% CSU & CindU 24.0%	45 ± 14	72.00%		100% previously treated with omalizumab (with ≥90% improvement in symptoms without the need for concurrent antihistamines) with relapse of urticaria symptoms despite antihistamine treatment		Doses ranged from 150 to 600 mg Q2–4W		✔						✔
	Sussman et al. [120]	2014	Canada	Prospective	6 with CindU	62	Mixed urticarias: CSU 98.4% urticarial vasculitis 1.6%	44.7 ± 17.75	73.50%		Antihistamine 100% corticosteroid 97.1% anti-leukotriene 16.2% cyclosporine 10.3% hydroxychloroquine or methotrexate 20.6%	8.2 ± 7	150 mg Q2W 1.6% 150 mg Q4W 83.9% 300 mg Q4W 14.5%		✔		✔				✔

APECED: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; CAU: chronic autoimmune urticaria; CindU: chronic inducible urticaria; CIU/CSU: chronic idiopathic/spontaneous urticaria; CU-Q2oL: Chronic Urticaria and Quality of Life Questionnaire; CU: chronic urticaria; DLQI: Dermatology Life Quality Index; DPU: delayed pressure urticaria; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; HTN: hypertension; ISB: irritable bowel syndrome; NSAID: nonsteroidal anti-inflammatory drug; SD: standard deviation; UAS: Urticaria Activity Score; UAS7: Urticaria Activity Score 7; UCT: Urticaria Control Test.

^aFrom 2005 to 2015, 17 patients with refractory CU were placed on a trial of omalizumab. Ten patients (58.8%) responded and 7 (41.2%) did not. This report is on the 10 responders who were treated ≥1 year.

^bOmalizumab treatment duration missing for one patient (case #2); however, duration for this patient was reported in a separate case study [Sussman GL, Hebert J, Simons ER. A 63-year-old man with chronic spontaneous urticaria. CMAJ. 2016;188(4):279–283.] and is included here.

^cSafety data are for the entire sample of n = 154 patients as the safety data on the 17 censored CindU patients could not be teased apart.

^dThe sample of n = 25 patients comprises a subset of patients who were previously treated and achieved complete response, as reported in Metz et al. 2014 J Derm Sci, who then subsequently relapsed. Results from 2014 JAMA Derm are unique and are related to re-treatment with omalizumab.

3.1. Study characteristics

Of the 84 studies, 25 (29.8%) were published before and 59 (70.2%) after the 2014 FDA and EMA approval of omalizumab for the CIU/CSU indication. This review concerns a total of 1507 patients.

In total, 41.7% of studies reported disease activity outcomes: 11.9% used the UAS, 26.2% the UAS7, and 1.2% the UCT; two studies (2.4%) included both the UAS7 and UCT. Further, 13.1% of studies evaluated quality of life outcomes, either with the DLQI (7.1% of studies) or the CU-Q₂oL (6.0% of studies). Treatment response was reported in 76.2% of studies, including 16.7% of studies that classified patients as responder versus non-responder, and 58.3% of studies that rated the degree of response (complete, partial, non/refractory); one study (1.2%) included both. Safety data were reported in 61 (72.6%) of studies and included 1327 patients.

Table 2 reveals that, on the aggregate, the majority of studies (n = 75 or 89.3%) were focused narrowly on CIU/CSU with or without angioedema, disease of autoimmune origin, and CIU/CSU or CU with relevant comorbidities. About half of the publications (n = 43 or 51.2%) described case studies or case series, about a third (n = 26 or 31.0%) were on retrospective studies, and the remainder (n = 14 or 16.7%) reported on prospective studies. In total, 68 (81.0%) studies had fewer than 30 patients, including 37 (44.0%) studies with fewer than 5 subjects (Table S2). About half of studies (n = 46 or 54.1%) were conducted in Europe, followed by the Americas (n = 22 or 25.9%; in particular North America with n = 18 or 21.2%) (Table S2).

Table 2. Summary of characteristics of studies included in the systematic review.

	Studies	%
Study design (as identified by authors)
Prospective study	14	16.7%
Retrospective study	26	31.0%
Case study/case series	43	51.2%
Not specified	1	1.2%
Subjects included^a
n = 1	22	26.2%
n = 2–4	15	17.9%
n = 5–14	18	21.4%
n = 15–29	13	15.5%
n = 30–44	6	7.1%
n = 45–137	10	11.9%
Urticaria subtypes included
Chronic idiopathic/spontaneous urticaria (CIU/CSU)	21	25.0%
Chronic auto-immune urticaria (CAU)	3	3.6%
Chronic urticaria not further specified (CU)	6	7.1%
CIU/CSU or CU with comorbidities	51	60.7%
Mixed	3	3.6%
Regions^b
Asia	15	17.6%
Europe	46	54.1%
North America	18	21.2%
South America	4	4.7%
Not specified	2	2.4%

^aSee Table S1 in Supplemental materials for detail.

^bSee Table S2 in Supplemental materials for detail. One study included subjects from both Canada and Portugal and is counted twice. Turkey and Israel are classified as Asia.

CAU: chronic autoimmune urticaria; CIU/CSU: chronic idiopathic/ spontaneous urticaria; CU: chronic urticaria not further specified.

3.2. Patients

Considering that these are study-level data and may be limited by the data reported in any given publication, most patients were women (70.6%) (Table 3). On average, patients were 43.7 (±14.6) years old; had been diagnosed with CIU/CSU 4.8 (±5.1) years prior; and were treated with omalizumab for 8.4 (±6.1) months. Virtually all patients had been previously treated with antihistamines (97.2%) and to a lesser extent with corticosteroids (55.1%), cyclosporine (29.4%), and anti-leukotriene agents (18.2%).

Table 3. Summary of demographics and clinical treatments of patients.

	Studies	Patients	Mean ± SD
Age (years)	78	1326	43.7 ± 14.6
Years since diagnosis of urticaria	66	1038	4.8 ± 5.1
Duration of omalizumab treatment (months)	61	840	8.4 ± 6.1
Omalizumab starting dose(mg/month)	72	1117	280.8 ± 74.5
Titrated omalizaumab dose(mg/month)	26	302	255.5 ± 112.8
	Studies	Patients	N	%
Female gender	77	1360	960	70.6%
Omalizumab initial dose	71	1188
150 mg Q2W			108	9.1%
150 mg Q4W			301	25.4%
300 mg Q2W			50	4.2%
300 mg Q4W			696	58.5%
Other^a			33	2.8%
Titrated omalizaumab dose	26	302
150 mg Q2W			5	1.6%
150 mg Q4W			108	35.8%
300 mg Q2W			31	10.3%
300 mg Q4W			91	30.1%
Other^a			67	22.2%
Prior treatments
Antihistamines	75	1010	982	97.2%
Corticosteroids	70	1016	560	55.1%
Cyclosporine	66	870	256	29.4%
Anti-leukotrienes	69	1009	184	18.2%
Methotrexate	61	638	48	7.5%
Mycophenolate mofetil	62	797	51	6.4%
IV-immunoglobulins	63	701	12	1.7%
Tacrolimus	62	797	12	1.5%
Other immunomodulators	69	916	90	9.8%

mg: milligrams; Q: ‘quaque’ or every; SD: standard deviation; W: weeks.

^aSee Table S3 in Supplemental materials for specification of other initial and titrated doses.

3.3. Dosing

Omalizumab was initiated at 150 mg/dose in 34.5% of patients including 9.1% at a frequency of every 2 weeks (Q2W) and 25.4% every 4 weeks (Q4W). More frequently, omalizumab was initiated at 300mg (in 62.7% of patients) at a frequency of Q2W (4.2%) or Q4W (58.5%). Only 2.8% received a different initial regimen in terms of dose (mg), frequency, or both. In the 23 publications reporting Q2W dosing at initiation with either 150 or 300 mg, 74% were published in or prior to 2014. In most reports, dose and/or frequency was titrated to the lowest dose with the longest interval to control symptoms. The optimal or end dose was 150 mg Q2W in 1.6% of patients, 150 mg Q4W in 35.8%, 300 mg Q2W in 10.3%, 300 mg Q4W in 30.1%; while 22.2% were titrated to another dose/frequency (computed on 26 studies).

3.4. Outcomes

For the disease activity and quality of life outcomes, we calculated the study pretreatment and end-of-study mean (±SD), the nominal change in mean value, and, as a standardized measure, the percent change in mean (Table 4). Next, we calculated, for the aggregate sample and stratified by urticaria subtype, the weighted pooled pretreatment and end-of-study mean (±SD) for the disease activity and quality of life outcomes, the nominal change in mean value, and, as a standardized measure, the percent change in mean as well as the range of this percent change across the studies under consideration (Table 5). Note that for scales where a lower score denotes a better outcome (UAS, UAS7, DLQI, and CU-Q₂oL), the mean percent improvement cannot exceed 100%. Conversely, for the UCT, where a higher score indicates a better outcome, this limit does not apply and mean percent improvement may exceed 100%. Also, end-of-study was per the definition in the study, which may have varied from study to study.

Table 4. Review of clinical outcomes and treatment response rates (stratified by urticaria type of study).

			Initial responder		Final responder		Initial response			Final response			UAS
	Authors	Year	Responder	Nonresponder	Responder	Nonresponder	Complete	Partial	None	Complete	Partial	None	PRE (mean ± SD)	EOS (mean ± SD)	Change PRE-EOS	% Change PRE-EOS
CIU/CSU studies (n = 21)
	Iemoli et al. [42]	2010	100.0%	0.0%	100.0%	0.0%
	Vestergaard & Deleuran [43]	2010
	Wieczorek et al [44].	2011								75.0%	0.0%	25.0%
	Armengot-Carbo et al. [45]	2013					20.0%	60.0%	20.0%	66.7%	20.0%	13.3%
	Song et al. [46]	2013					87.5%	0.0%	12.5%	68.8%	0.0%	31.3%
	Kai et al. [47]	2014
	Romano et al. [48]	2015								66.7%	0.0%	33.3%
	Tontini et al. [49]	2015
	Clark et al. [50]	2016	82.9%	17.1%	90.2%	9.8%
	Denman et al. [51]	2016
	Gimenez-Arnau et al. [52]	2016								83.8%	6.5%	9.7%
	Gomez-Vera et al. [53]	2016
	Gönül et al. [54]	2016
	Konstantinou et al. [54]	2016
	Moreira et al. [56]	2016
	Subramaniyan & Chopra [57]	2016
	Ertas et al. [58]	2017								47.3%	38.7%	14.0%
	Gericke et al. [59]	2017			87.5%	12.5%
	Kocaturk et al. [60]	2017	66.7%	33.3%	84.6%	15.4%
	Kulthanan et al. [61]	2016					50.0%	25.0%	25.0%	75.0%	8.3%	16.7%
	Larrea-Baca et al. [62]	2017
CAU studies (n = 3)
	Kaplan et al. [21]	2008								58.3%	33.3%	8.3%	7.5 ± 1.78	2.66 ± 3.31	−4.84	64.5%
	Maspero et al. [22]	2009					0.0%	100.0%	0.0%	100.0%	0.0%	0.0%
	Al-Ahmad [63]	2010								100.0%	0.0%	0.0%	5.47 ± 0.34	0.47 ± 0.53	−5	91.5%
CU studies (n = 6)
	Korkmaz et al. [64]	2010					0.0%	100.0%	0.0%	100.0%	0.0%	0.0%
	Ferrer et al. [65]	2011								44.4%	55.6%	0.0%	6 ± 0.74	0 ± 1.48	−6	100.0%
	Košnik et al. [66]	2014								100.0%	0.0%	0.0%
	Har et al.^a [67]	2015	100.0%	0.0%						80.0%	20.0%	0.0%
	Irani et al. [68]	2015								71.4%	21.4%	7.1%
	Seth & Khan [69]	2017								57.7%	19.2%	23.1%
CI/CSU or CU with combordities studies (n = 51)
	Dreyfus & Randolph [70]	2006			100.0%	0.0%
	Spector & Tan [18]	2007								100.0%	0.0%	0.0%
	Dreyfus [19]	2008			100.0%	0.0%
	Godse [20]	2008					0.0%	100.0%	0.0%	100.0%	0.0%	0.0%
	Magerl et al. [71]	2010
	Godse [72]	2011											5.1 ± 0.2	0.4 ± 0.5	−4.7	92.2%
	Groffik et al. [73]	2011								100.0%	0.0%	0.0%
	Saavedra & Sur [74]	2011					0.0%	100.0%	0.0%	100.0%	0.0%	0.0%
	Sanchez-Machin et al. [75]	2011								100.0%	0.0%	0.0%
	Nam et al. [76]	2012								84.6%	7.7%	7.7%	4.84 ± 0.79	1.08 ± 1.69	−3.76	77.7%
	Diez et al. [77]	2013								66.7%	33.3%	0.0%
	Labrador-Horrillo et al. [78]	2013								81.8%	10.9%	7.2%	5.34 ± 0.88	0.66 ± 1.3	−4.68	87.6%
	Lefevre et al. [79]	2013	92.9%	7.1%
	Viswanathan et al. [80]	2013								52.9%	41.2%	5.9%
	Fiorino et al. [81]	2014								100.0%	0.0%	0.0%
	Metz et al. J Derm Sci. [82]	2014								83.0%	10.0%	7.0%
	Rottem et al. [83]	2014								48.8%	37.2%	14.0%
	Uysal et al. [84]	2014			86.4%	13.6%							6 ± 0	1.5 ± 2.2	−4.5	75.0%
	Van Den Elzen et al. [85]	2014								75.0%	0.0%	25.0%
	Vieira Dos Santos et al. [86]	2014					100.0%	0.0%	0.0%	100.0%	0.0%	0.0%
	Ghazanfar & Thomsen [87]	2015								100.0%	0.0%	0.0%
	Klossowski et al. [88]	2015					0.0%	100.0%	0.0%	100.0%	0.0%	0.0%
	Leiva-Salinas et al. [89]	2015			100.0%	0.0%
	Lundberg et al. [90]	2015								100.0%	0.0%	0.0%
	Netchiporouk et al. [91]	2015								100.0%	0.0%	0.0%
	Savic et al. [92]	2015
	Silva et al. [93]	2015								100.0%	0.0%	0.0%	5.3 ± 1	0 ± 0	−5.3	100.0%
	Sussman et al. [94]	2015								100.0%	0.0%	0.0%
	Wieder et al. [95]	2015			100.0%	0.0%
	Bongiorno et al. [96]	2016								35.7%	50.0%	14.3%
	Cuervo-Pardo et al. [97]	2016			100.0%	0.0%
	Dawicka et al. [98]	2016
	Ensina et al. [99]	2016					72.3%	25.5%	2.1%	72.3%	25.5%	2.1%
	Ertaş et al. [100]	2016
	Ghazanfar et al. [101]	2016								67.0%	22.0%	11.0%
	Gozdzik-Spychalska et al. [102]	2016					100.0%	0.0%	0.0%	100.0%	0.0%	0.0%
	Kasperska-Zajac et al. [103]	2016								66.7%	22.2%	11.1%
	Olszowiec-Chlebna et al. [104]	2016								100.0%	0.0%	0.0%
	Osmenda et al. [105]	2016								100.0%	0.0%	0.0%
	Palacios et al. [106]	2016			70.7%	29.3%
	Shahzad [107]	2016
	Wilches et al. [108]	2016					7.7%	15.4%	76.9%	75.0%	0.0%	25.0%	5.6 ± 0.6	2 ± 2	−3.6	64.3%
	Asero et al. [109]	2017								56.3%	21.9%	21.9%
	Chicharro et al. [110]	2017
	Deza et al. [111]	2017			80.9%	19.1%
	Gonzalez-Medina et al. [112]	2017
	Iemoli et al. [113]	2017
	Marin-Cabanas et al. [114]	2017			100.0%	0.0%
	Pinto Gouveia et al. [115]	2017								30.8%	61.5%	7.7%
	Porcaro et al. [116]	2017					100.0%	0.0%	0.0%	100.0%	0.0%	0.0%
	Türk et al.^b [117]	2017								32.0%	60.0%	8.0%	6 ± 0.37	1 ± 0.96	−5	83.3%
Mixed studies (n = 3)
	Buyukozturk et al. [118]	2012
	Metz et al. JAMA Derm. [119]	2014								100.0%	0.0%	0.0%
	Sussman et al. [120]	2014					57.1%	39.9%	3.2%	66.1%	25.8%	8.1%
			UAS7				UCT				DLQI				CU-Q2oL
	Authors	Year	PRE (mean ± SD)	EOS (mean ± SD)	Change PRE-EOS	% Change PRE-EOS	PRE (mean ± SD)	EOS (mean ± SD)	Change PRE-EOS	% Change PRE-EOS	PRE (mean ± SD)	EOS (mean ± SD)	Change PRE-EOS	% Change PRE-EOS	PRE (mean ± SD)	EOS (mean ± SD)	Change PRE-EOS	% Change PRE-EOS
CIU/CSU studies (n = 21)
	Iemoli et al. [42]	2010
	Vestergaard & Deleuran [43]	2010	35 ± 0	0 ± 0	−35	100.0%					16.5 ± 12	0 ± 0	−16.5	100.0%
	Wieczorek et al [44].	2011
	Armengot-Carbo et al. [45]	2013
	Song et al. [46]	2013
	Kai et al. [47]	2014									22.8 ± 3.6	4.3 ± 6.1	−18.5	81.1%
	Romano et al. [48]	2015	38.2 ± 5.7	11.7 ± 18.6	−26.5	69.4%
	Tontini et al. [49]	2015	34.6 ± 5	1.4 ± 2.6	−33.2	96.0%
	Clark et al. [50]	2016
	Denman et al. [51]	2016
	Gimenez-Arnau et al. [52]	2016	29.1 ± 7.7	1.4 ± 2.9	−27.7	95.2%									72.7 ± 18.9	12.8 ± 10.3	−59.9	82.4%
	Gomez-Vera et al. [53]	2016	32.1 ± 3.9	2.7 ± 0.6	−29.4	91.6%	6.1 ± 1.2	13.3 ± 0.6	7.2	118.0%
	Gönül et al. [54]	2016
	Konstantinou et al. [54]	2016	27.3 ± 2.5	16 ± 0	−11.3	41.4%	5.7 ± 0.6	12	6.3	110.5%
	Moreira et al. [56]	2016
	Subramaniyan & Chopra [57]	2016	30 ± 7.1	6.5 ± 1.9	−23.5	78.3%					22.3 ± 2.1	6 ± 1.6	−16.3	73.1%
	Ertas et al. [58]	2017
	Gericke et al. [59]	2017
	Kocaturk et al. [60]	2017					6.5 ± 2.9	13.5 ± 3.1	7	107.7%
	Kulthanan et al. [61]	2016	22.9 ± 12.9	3.1 ± 6.4	−19.8	86.5%
	Larrea-Baca et al. [62]	2017	24.1 ± 5.6	5.3 ± 3.5	−18.8	78.0%									52 ± 15.5	32.2 ± 11.2	−19.8	38.1%
CAU studies (n = 3)
	Kaplan et al. [21]	2008									14 ± 6	6 ± 10	−8	57.1%
	Maspero et al. [22]	2009
	Al-Ahmad [63]	2010
CU studies (n = 6)
	Korkmaz et al. [64]	2010
	Ferrer et al. [65]	2011
	Košnik et al. [66]	2014
	Har et al.^a [67]	2015
	Irani et al. [68]	2015
	Seth & Khan [69]	2017
CI/CSU or CU with combordities studies (n = 51)
	Dreyfus & Randolph [70]	2006
	Spector & Tan [18]	2007
	Dreyfus [19]	2008
	Godse [20]	2008
	Magerl et al. [71]	2010	27.8 ± 8.6	4.3 ± 8.9	−23.5	84.5%
	Godse [72]	2011
	Groffik et al. [73]	2011
	Saavedra & Sur [74]	2011
	Sanchez-Machin et al. [75]	2011
	Nam et al. [76]	2012
	Diez et al. [77]	2013
	Labrador-Horrillo et al. [78]	2013
	Lefevre et al. [79]	2013	31.1 ± 2.3	8 ± 3.5	−23.1	74.3%					13.4 ± 1.75	3.8 ± 1.3	−9.6	71.6%
	Viswanathan et al. [80]	2013
	Fiorino et al. [81]	2014	39 ± 1.4	0 ± 0	−39	100.0%
	Metz et al. J Derm Sci. [82]	2014
	Rottem et al. [83]	2014
	Uysal et al. [84]	2014
	Van Den Elzen et al. [85]	2014
	Vieira Dos Santos et al. [86]	2014
	Ghazanfar & Thomsen [87]	2015
	Klossowski et al. [88]	2015
	Leiva-Salinas et al. [89]	2015
	Lundberg et al. [90]	2015
	Netchiporouk et al. [91]	2015	28 ± 0	0 ± 0	−28	100.0%
	Savic et al. [92]	2015	27.5 ± 10.4	3.1 ± 6.3	−24.4	88.7%					19.5 ± 5.2	3.2 ± 5.2	−16.3	83.6%
	Silva et al. [93]	2015
	Sussman et al. [94]	2015
	Wieder et al. [95]	2015
	Bongiorno et al. [96]	2016	31.1 ± 7	2.3 ± 3.2	−28.8	92.6%
	Cuervo-Pardo et al. [97]	2016
	Dawicka et al. [98]	2016	37.5 ± 4.9	8.8 ± 4.3	−28.7	76.5%
	Ensina et al. [99]	2016
	Ertaş et al. [100]	2016
	Ghazanfar et al. [101]	2016
	Gozdzik-Spychalska et al. [102]	2016
	Kasperska-Zajac et al. [103]	2016
	Olszowiec-Chlebna et al. [104]	2016
	Osmenda et al. [105]	2016
	Palacios et al. [106]	2016
	Shahzad [107]	2016	30 ± 0	4 ± 0	−26	86.7%									67 ± 0	30 ± 0	−37	55.2%
	Wilches et al. [108]	2016
	Asero et al. [109]	2017
	Chicharro et al. [110]	2017	37 ± 0	1 ± 0	−36	97.3%
	Deza et al. [111]	2017
	Gonzalez-Medina et al. [112]	2017	42 ± 0	0 ± 0	−42	100.0%
	Iemoli et al. [113]	2017	42 ± 0	14 ± 0	−28	66.7%									49 ± 0	0 ± 0	−49	100.0%
	Marin-Cabanas et al. [114]	2017
	Pinto Gouveia et al. [115]	2017	36.3 ± 5.4	5.1 ± 5.3	−31.2	86.0%
	Porcaro et al. [116]	2017	20 ± 0	6 ± 0	−14	70.0%
	Türk et al.^b [117]	2017
Mixed studies (n = 3)
	Buyukozturk et al. [118]	2012	34.4 ± 6.8	2.9 ± 1.5	−31.5	91.6%									57.5 ± 13.8	10.3 ± 10.4	−47.2	82.1%
	Metz et al. JAMA Derm. [119]	2014
	Sussman et al. [120]	2014	28.3	4	−24.3	85.9%

CAU: chronic auto-immune urticaria; CIU/CSU: chronic idiopathic/spontaneous urticaria; CU-Q2oL: Chronic Urticaria and Quality of Life Questionnaire; CU: chronic urticaria; DLQI: Dermatology Life Quality Index; EOS: end-of-study; PRE: pre-omalizumab; SD: standard deviation; UAS: Urticaria Activity Score; UAS7: Urticaria Activity Score 7; UCT: Urticaria Control Test.

^aFrom 2005 to 2015, 17 patients with refractory CU were placed on a trial of omalizumab. Ten patients (58.8%) responded and 7 (41.2%) did not. This report is on the 10 responders who were treated ≥1 year.

^bOf 18 responders (complete or partial) who subsequently discontinued omalizumab after at least 6 months of treatment, 11 (61.1%) relapsed and 7 (38.9%) sustained remission. Of the 11 who relapsed, 10 were re-treated with omalizumab; all responded to re-treatment, 50% completely, 50% partially.

Table 5. Treatment response rates and clinical outcomes, across all studies and stratified by urticaria subtype.

All studies (n = 84)
	Responder vs. nonresponder				Degree of response
Treatment response	Studies	Patients	Responder	Nonresponder	Studies	Patients	Complete	Partial	None/refractory
Initial response	5	81	83.9%	16.1%	14	186	56.5%	26.9%	16.6%
Final response	13	255	85.0%	15.0%	50	921	67.9%	21.6%	10.5%
		Pretreatment	End-of-study^a
Clinical outcomes	Studies	Patients	Mean ± SD	Mean ± SD	Change	Mean % change	Range of % change
UAS	10	245	5.6 ± 0.8	1.0 ± 1.6	−4.6	82.4%	64.3%	100.0%
UAS7	24	275	29.8 ± 7.4	3.8 ± 5.2	−26.0	86.9%	41.4%	100.0%
UCT	3	39	6.2 ± 2.0	13.3 ± 2.0	7.1	113.5%	107.7%	118.0%
DLQI	6	70	17.7 ± 4.8	4.0 ± 5.8	−13.7	76.2%	57.1%	100.0%
CU-Q2oL	5	72	64.1 ± 17.2	17.2 ± 10.6	−46.9	71.1%	38.1%	100.0%
CIU/CSU studies (n = 21)
	Responder vs. nonresponder				Degree of response
Treatment response	Studies	Patients	Responder	Nonresponder	Studies	Patients	Complete	Partial	None/refractory
Initial response	3	57	78.9%	21.1%	3	43	53.5%	27.9%	18.6%
Final response	4	121	88.2%	11.8%	7	184	61.3%	23.1%	15.6%
		Pretreatment	End-of-study
Clinical outcomes	Studies	Patients	Mean ± SD	Mean ± SD	Change	Mean % change	Range of % change
UAS	1	25	6.0 ± 0.4	1.0 ± 1.0	−5.0	83.3%
UAS7	9	112	29.2 ± 7.2	3.6 ± 5.2	−25.6	87.5%	41.4%	100.0%
UCT	3	39	6.2 ± 2.0	13.3 ± 2.0	7.1	113.5%	107.7%	118.0%
DLQI	3	12	21.6 ± 5.0	4.2 ± 4.6	−17.4	81.6%	73.1%	100.0%
CU-Q2oL	2	56	66.1 ± 17.9	19.0 ± 10.6	−47.0	68.1%	38.1%	82.4%
CAU studies (n = 3)
					Degree of response
Treatment response					Studies	Patients	Complete	Partial	None/refractory
Initial response					1	1	-	100.0%	-
Final response					3	16	68.7%	25.0%	6.3%
		Pretreatment	End-of-study
Clinical outcomes	Studies	Patients	Mean ± SD	Mean ± SD	Change	Mean % change	Range of % change
UAS	2	15	7.1 ± 1.6	2.0 ± 3.1	−4.9	69.9%	64.5%	91.5%
DLQI	1	12	14.0 ± 6.0	6.0 ± 10.0	−8.0	57.1%	-	-
CU studies (n = 6)
	Responder vs. nonresponder				Degree of response
Treatment response	Studies	Patients	Responder	Nonresponder	Studies	Patients	Complete	Partial	None/refractory
Initial response	1	10	100.0%	0.0%	1	1	-	100.0%	-
Final response					6	61	65.3%	24.0%	10.7%
		Pretreatment	End-of-study
Clinical outcomes	Studies	Patients	Mean ± SD	Mean ± SD	Change	Mean % change	Range of % change
UAS	1	9	6.0 ± 0.7	0.0 ± 1.5	−6.0	100.0%	-	-
CIU/CSU or CU with comorbidities or conditions studies (n = 51)
	Responder vs. nonresponder				Degree of response
Treatment response	Studies	Patients	Responder	Nonresponder	Studies	Patients	Complete	Partial	None/refractory
Initial response	1	14	92.9%	7.1%	8	79	49.4%	24.0%	26.6%
Final response	9	134	82.1%	17.9%	32	573	69.0%	21.3%	9.7%
		Pretreatment	End-of-study
Clinical outcomes	Studies	Patients	Mean ± SD	Mean ± SD	Change	Mean % change	Range of % change
UAS	7	221	5.4 ± 0.7	1.0 ± 1.5	−4.5	82.5%	64.3%	100.0%
UAS7	13	87	31.1 ± 7.7	4.3 ± 5.5	−26.8	86.2%	66.7%	100.0%
DLQI	2	46	17.6 ± 4.5	3.4 ± 4.4	−14.2	79.9%	71.6%	83.6%
CU-Q2oL	2	2	58.0 ± 12.7	15.0 ± 21.2	−43.0	77.6%	55.2%	100.0%
Mixed studies (n = 3)
					Degree of response
Treatment response					Studies	Patients	Complete	Partial	None/refractory
Initial response					1	62	69.4%	27.4%	3.2%
Final response					2	87	75.8%	18.4%	5.8%
		Pretreatment	End-of-study
Clinical outcomes	Studies	Patients	Mean ± SD	Mean ± SD	Change	Mean % change	Range of % change
UAS7	2	76	29.4 ± 6.8	3.8 ± 1.5	−25.6	86.9%	85.9%	91.6%
CU-Q2oL	1	14	57.5 ± 13.8	10.3 ± 10.4	−47.2	82.1%	-	-

^aAs defined in study. Study end ranged from 2 to 70 months.

CU-Q2oL: Chronic Urticaria and Quality of Life Questionnaire; DLQI: Dermatology Life Quality Index; SD: standard deviation; UAS: Urticaria Activity Score; UAS7: Urticaria Activity Score 7; UCT: Urticaria Control Test.

In 5 studies with 81 patients, 83.9% of patients were rated to be an initial responder (Table 5). In 14 studies with 186 patients, the initial response was rated as complete for 56.5% of patients and as partial for an additional 26.9%, leaving 16.6% judged to have shown no response. As to final response, in 13 studies with 255 patients, 85% were rated to have shown a final response. In 50 studies with 921 patients, 67.9% were evaluated as having a complete response, 21.6% a partial response, and 10.5% to had no response or being refractory.

In the overall weighted pooled analyses (Table 5), disease activity decreased by 82.4% (UAS; 10 studies and 245 patients) and 86.9% (UAS7; 24 studies and 275 patients), while disease control increased by 113.5% (UCT; 3 studies and 39 patients). Quality of life outcomes improved by 76.2% (DLQI; 6 studies and 70 patients) and 71.1% (CU-Q2oL; 5 studies and 72 patients).

Table 5 also presents the clinical outcomes and treatment responses rates for the different categories of studies based on urticaria subtype. We compared the mean % change statistics, responder versus nonresponder rates, and degree of treatment response rates of each of these five urticaria subtypes to the overall results. For the 2 categories with the most studies – the 21 CIU/CSU studies and the 51 CIU/CSU with comorbidities studies – all results were statistically similar to the overall results, which is not surprising considering that, combined, these two categories accounted for 85.7% of studies. The three CAU studies, the six CU studies, and the three Mixed studies showed some occasional deviations from the corresponding results for all 84 studies, the 21 CIU/CSU studies, and the 51 CIU/CSU with comorbidities studies. Where such differences were observed, these can be reasonably attributed to the small number of studies involved.

3.5. Safety

Safety data, summarized in Table S4, were derived from 61 of the studies and involved 1327 patients. A total of 88 patients (6.6%) experienced an AE of which the majority were described as mild and transient. Included in this overall AE count and rate is one study [101] that reported that an aggregated nine patients experienced one or more of eight AEs without specifying counts/rates per AE. Another study [50] with 41 patients provided a nonnumerical summary of 4 mild AEs without reporting counts; hence, these AEs are not included in the overall count/rate. The most frequently reported events were headache (n = 11), fatigue (n = 8), and injection site reaction (n = 8). Three patients (0.2%) experience SAE, all anaphylaxis [54,92]; although in two patients [92] it is unclear if the SAE is treatment- or disease-related and omalizumab treatment was continued in both cases. In total, nine patients (0.7%) discontinued treatment due to AE/SAE. One of the reported AEs characterized as ‘an anaphylactoid reaction’ [70] is not classified as a SAE as omalizumab treatment for comorbid CIU and asthma was effective in managing both urticaria flares and wheezing and was continued for 6 months despite AE symptoms before being discontinued.

3.6. Other

3.6.1. Time to response

Eighteen of the studies reported time to response (Table S5). Of note is the rapid response in some patients reported in hours or days.

3.6.2. Medication use

Several studies evaluated continued use and discontinuation of other CIU/CSU treatments following initiation of omalizumab. These assessments included medication scoring systems [61,117,120], medication counts (e.g. number of tablets or mg) for routine medications [65,76] or rescue medications [21,63], and treatment scoring systems that combined symptom and medication scoring [73,93]. Variation in assessment methods coupled with low counts of studies using each method precluded aggregation of these assessments. More frequently, only the discontinuation rate of medications was reported. Discontinuation of routine antihistamines following omalizumab treatment was achieved in 60.0% of 251 patients from 16 studies (data not shown). Of patients taking corticosteroids at the time of omalizumab initiation, 75.3% were able to discontinue corticosteroid therapy after omalizumab treatment (n = 263 patients from 15 studies); 72.3% discontinued anti-leukotriene therapy (n = 166 from 7 studies); and 71.7% discontinued immunomodulatory treatment (n = 186 from 6 studies) (data not shown).

4. Comments

Real-world evidence has become critical to better understand the effectiveness of medications, previously shown to be efficacious in randomized clinical trials, under conditions of heterogeneity in patients, treatment regimens, clinicians, and settings. Whereas many effectiveness studies focus on the question of whether a medication works or does not work under such heterogeneity, it is just as essential to answer the following questions, especially in the case omalizumab [26]: in which patients with CIU/CSU does omalizumab work, and in which does it not? To what degree does omalizumab work in these patients? In which CIU/CSU treatment patterns and combinations does omalizumab work well, and in which less so or not? In which settings does omalizumab work well, less so, or not? Who responds to the medication and treatment, and who responds poorly or not? And, in whom is omalizumab safe, and in whom is it not? Our systematic review aimed to provide at least partial answers to these questions.

Typically, effectiveness studies are undertaken after a new agent has received regulatory approval. This certainly applies to first indications, as was the case when omalizumab was approved for severe allergic asthma. To date at least 25 prospective and retrospective effectiveness studies with evaluable samples as large as 925 patients have been conducted to answer the above questions [26,121]. Where the trajectory of a second indication, such as omalizumab for CIU/CSU, differs from the planned post-approval trajectory for the initial indication, is in its mix of exploratory and planned investigations. In the setting of CIU/CSU, the trajectory has been one of initial case reports and case series prior to and concurrent with registration trials, followed by small sample investigations and formal post-approval studies. Half of the 84 studies included in this systematic review were case reports and case series, about one-third were retrospective studies, but only 14 (16.7%) were prospective. Compare this to the 24 studies in the systematic review of omalizumab in severe allergic asthma, where 18 (75.0%) were prospective and the remainder retrospective [26].

The exploratory trajectory of the use of omalizumab in CIU/CSU is also evidenced in the variability in the dosing patterns observed across studies. The most common initiation dose (62.7%) was 300 mg, whereas 34.5% of patients received 150 mg, and the remaining 2.8% other regimens. The most common frequency (83.9%) was every 4 weeks. This suggests that, certainly in the early evaluations of omalizumab in CIU/CSU, the dosing for the severe allergic asthma indication was followed. However, this changed markedly when, later in the treatment, doses were titrated. The proportion of patients dosed at 150 mg Q4W remained about the same (35.8%), the proportion of patients treated with 300 mg Q4W declined (30.1%), and almost a quarter of patients (22.2%) had other dose and frequency regimens. This underscores the importance of individualizing dose and frequency. This individualization of treatment may prove to be a significant marker of omalizumab therapy in CIU/CSU and should be investigated in future effectiveness studies.

The outcomes of interest included in the studies in this systematic review further document the trajectory from initial exploration of omalizumab in CIU/CSU to its later validation. Most studies reported on treatment response (76.2%) and safety (72.6%), reflecting a consistent assessment of overall effectiveness and safety across studies – and, by extension, time. A focus on disease activity was less prevalent (41.7% of studies). The attention to quality of life, a prominent variable in allergy research and practice, was assessed in only 13.1% of studies – when quality of life is intricately tied to patients’ symptom experience. This, too, is another area requiring further investigation so as to get a better view on the patient-centric aspects of managing CIU/CSU in general and with omalizumab.

Related to one study on 32 patients included in this systematic review [109], a separate case report on 2 of those patients who were treated with concomitant angiotensin-converting enzyme (ACE) inhibitors was subsequently published [122]. These patients experienced an initial response to omalizumab followed by loss of effectiveness; following discontinuation of ACE inhibitor treatment, urticarial symptoms were again controlled with omalizumab. Whether concomitant therapies that interfere with biologic pathways that can cause angioedema, such as ACE inhibitors, may result in a more resistant form of CIU/CSU and/or decreased response to omalizumab is still unclear and requires further investigation. In general, ACE inhibitors should be avoided or discontinued in patients with angioedema.

After the search for this systematic review was completed and while data were being aggregated, Wang et al. [123] published a retrospective study on omalizumab in CIU using US claims data. Of the 88 patients for whom data were available for 12 or more months, 75.4% were initiated on 300 mg, 18.8% on 150 mg, and 5.8% on other doses – mainly (96.2%) Q4W. Most (69.6%) patients remained on their initial dose, and about half (46.2%) on the initial frequency of administration. The treatment response rate was 83.7%. This recent study is consistent with the findings of this systematic review. Additional evidence of real-world use of omalizumab is anticipated from forthcoming results from the AWARE study (A World-wide Antihistamine-Refractory Chronic Urticaria Patient Evaluation), a multinational study designed to assess pharmacological treatment and outcomes in nsAH-refractory CU patients in the real-life setting [124,125].

5. Expert opinion

The clinical outcomes observed across studies underscore the effectiveness of omalizumab as treatment for CIU/CSU in the real-world setting. On the aggregate, across studies reporting specific outcomes, the rate of initial treatment response was 83.9%, with over half (56.5%) of patients classified as showing a complete response. The response rate at the end of the respective observation periods was similar (85.0%), with two-thirds (67.9%) of patients showing a complete response. In addition to demonstrating effectiveness, these rates also suggest that continued treatment may assist patients with an initial partial response to achieve a complete treatment response – though this needs to be documented in future studies. Further, these response rates are also aligned with the observed change in disease activity scores and urticaria symptoms. Scores on the UAS and UAS7 decreased by 82.4% and 86.9%, respectively, while scores on the (reversely scored) UCT improved by 113.5%. The high (clinician-rated) treatment response rates and the marked changes in (patient-reported) disease activity are reflected in the distinct improvements in (patient-reported) quality of life ratings.

The high and convincing effectiveness outcomes seen across the 84 publications were also observed when studies were classified by urticaria subtype – suggesting that the disease itself, not its subtypes, are positively impacted by treatment with omalizumab. Notably, omalizumab was found to be comparably effective in patients with comorbid allergic and immunologic diseases as well as those with comorbid CindU. Further, several case studies reported omalizumab treatment during pregnancy [86,97,112] and one case study concerned a patient treated through two consecutive pregnancies [87] – all with demonstrable effectiveness and no adverse effects to the mothers or newborns. Effectiveness and safety data were likewise reported in patients with hepatitis B [110] and hepatitis C virus [89], human immunodeficiency virus [113], and chronic lymphatic B-cell-leukemia undergoing chemotherapy [88].

To this should be added the time-to-response data reported by studies, which ranged from rapid-onset complete response within hours or days following the first injection in some patients to, generally, patients responding within weeks. For instance, in one study [49] 87.5% of patients responded within 4–8 weeks while another study reported a mean time-to-response of 9.27 weeks [76]. Relatedly, evidence is accumulating on the long-term effectiveness and safety of omalizumab use in CIU/CSU including treatment durations of >1 year [56], up to 2 years [46], > 2 years [93,95,105], up to 3 years [115], 3 years [87,102], 2–4 years [81], up to 5 years [69], 5 years [86], up to 6 years [48], and up to 9 years [67].

The positive therapeutic profile of omalizumab is also supported by the safety data. The AE rate of 6.6% and SAE rate of 0.2% are in line with phase III safety results [23–25] and the product label [17]. With regards to two (of the three) cases of anaphylaxis, the investigators noted that it was unclear whether the anaphylactic reactions were treatment- or disease-related and treatment with omalizumab was continued in both cases. While the potential for anaphylaxis may cause dermatologists to be reluctant about prescribing omalizumab, our review supports the general notion that anaphylaxis is a very rare event.

The findings on discontinuation of other medications following initiation of omalizumab therapy should be interpreted with some caution as there was significant variation in methods across studies. Nonetheless, the data are encouraging with over 70% of patients having treatment with corticosteroids, antileukotriene agents, or immunomodulatory agents discontinued; and 60% of patients being discontinued from routine antihistamine therapy. Medication use patterns should be evaluated more systematically in future studies.

Additionally, future real-world studies on omalizumab for CIU/CSU should focus on the following priorities. Prospective studies are preferred because greater attention can be given to design and data model, thus permitting investigations that are broader than what retrospective studies typically permit. The burden of CIU/CSU merits further investigation. Also, to better align CIU/CSU studies with those on omalizumab in severe allergic asthma, the impact of disease on social functioning, work or school performance, and healthcare resource utilization should be elucidated further. The interaction between symptom experience, symptom distress, treatment, and quality of life should also be examined. More generally, modeling of variables associated with treatment outcomes should be integrated as much as possible into future studies.

Despite the strong evidence on the real-world effectiveness and safety of omalizumab presented in our systematic review, some caution is warranted. About half of the studies included in our review were case studies and case series, which hold the inherent risk of emphasizing mainly positive experiences with omalizumab, and not balancing this with possible negative results. In addition, the studies with larger samples were based on convenience samples, not samples obtained by means of probabilistic methods. Further, studies varied in terms of level of detail in reporting, outcome measures assessed, and duration of treatment and follow-up. Lastly, it is possible that additional real-world evidence exists but was overlooked; use of other database search engines such as Scopus or Google Scholar may have identified such publications. Despite these limitations, the body of evidence as a whole presents compelling results from which conclusions about the real-world effectiveness and safety of omalizumab in the CIU/CSU indication can be drawn.

In conclusion, the real-world evidence aggregated in this systematic review points convincingly at the high degree of effectiveness of omalizumab in the treatment of patients with CIU/CSU with or without comorbidities or special conditions, CAU, or CU in daily clinical practice. The 84 publications included in the review represent patient samples with considerable heterogeneity in terms of demographics, comorbidities, disease history, and omalizumab treatment patterns; yet the findings in terms of outcomes, whether disease activity measures, response rates, or quality of life, are highly consistent.

While observational data from case reports, case series, and retrospective and prospective observational studies do not permit direct inferences of causality, the effectiveness and safety of omalizumab certainly meets the Mosteller [126] criteria for causal interpretations from nonexperimental data: (1) consistency, or that the same effects are achieved regularly, and across people and time; (2) responsiveness, or that variations in treatment precede variations in effects; (3) a mechanism that explains how the effect is created; and (4) uniqueness, or the ability to dismiss alternative explanations of the effect other than the treatment. Coupled with the fact that the safety findings are in line with those from phase III trials and as described in the product label, omalizumab should be considered a highly effective and safe treatment for CIU/CSU and related urticarial diseases.

Article highlights

• As there is no cure for chronic idiopathic/spontaneous urticaria (CIU/CSU), treatment is focused on improving clinical outcomes – from disease control and symptom management to quality of life. Omalizumab is a recombinant humanized monoclonal anti-IgE antibody approved initially for the treatment of severe allergic asthma, but since 2014 also for CIU/CSU in adults and adolescents 12 years of age and older who remain symptomatic despite treatment with non-sedating anti-histamines.

• A systematic review was conducted of 84 case reports, case series, and retrospective and prospective observational studies showing a trajectory from early exploration of the use of omalizumab in CIU/CSU to larger studies of treatment patterns and outcomes in daily clinical practice.

• There is strong and sustained real-world evidence that a broad range of CIU/CSU patients respond to treatment with omalizumab in terms of reductions in disease activity and improvement in disease control; translating into significant improvements in quality of life.

• The most commonly prescribed initiation and titration dose is 300mg, though about one-third of patients are started on 150mg. The most common frequency of administration is Q4W, though titrated dosing regimens may vary.

• The safety profile in daily clinical practice is in line with results of phase III trials and the product label.

• Most real-world studies reviewed here were case reports, case series, and retrospective observational studies. There is a continued need for prospective real-world effectiveness and safety studies.

This box summarizes key points contained in the article.

Declaration of interest

J. Bernstein received consultancy fees from Novartis Pharmaceuticals Corporation for work on this study. He is affiliated with Bernstein Clinical Research Center, LLC which was under contract with Novartis Pharmaceuticals Corporation as a PI to conduct clinical research outside of the submitted work. He has received speaker fees from Novartis Pharmaceuticals Corporation as well as consulting fees from Genentech. He is an author on the Joint Task Force for Practice Parameters for Urticaria guideline and the GALEN international guideline for urticaria. A. Kavati is an employee and stockholder of Novartis Pharmaceuticals Corporation. M. Tharp received consultancy fees from Novartis Pharmaceuticals Corporation for work on this study. B. Ortiz is an employee and stockholder of Novartis Pharmaceuticals Corporation. I. Abraham, K. MacDonald and K. Denhaerynck are affiliated with Matrix45. By company policy, employees 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 non-exclusivity basis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. A reviewer on this manuscript has disclosed working with all pharmaceutical companies involved in the field of urticaria and have ordered that the worldwide guidelines on urticaria. A reviewer on this manuscript disclosed having been speaker for Novartis and FAES Farma.

Supplemental material

Supplemental data for this article can be accessed here.

Additional information

Funding

This systematic review was sponsored by Novartis.