Key Points
Question
What is the drug survival of omalizumab in patients with chronic urticaria, and what are the potential predictors for discontinuation?
Findings
In this cohort study of 2325 patients with chronic urticaria, fast response and disease duration of more than 2 years were associated with higher and lower risk for omalizumab discontinuation due to well-controlled disease, respectively. Immunosuppressive cotreatment at the start of omalizumab and autoimmune disease predicted a higher risk for discontinuation due to ineffectiveness, while spontaneous wheals and access to higher dosages predicted a lower risk.
Meaning
Understanding omalizumab survival rates as well as reasons and potential predictors for discontinuation provides important daily practice information for guiding clinical decision-making and managing expectations in patients with chronic urticaria.
Abstract
Importance
Treating patients with chronic urticaria using omalizumab has been shown to be safe and effective in randomized clinical trials. Multinational studies on long-term omalizumab performance in chronic urticaria in clinical practice settings are lacking, especially on drug survival. Drug survival, which refers to the length of time that patients are treated with a specific drug, is a comprehensive outcome covering effectiveness, safety, and patient and physician preferences. Furthermore, little is known about the reasons and potential predictors for omalizumab discontinuation.
Objective
To investigate omalizumab drug survival as well as reasons and potential predictors for discontinuation in a large, diverse population.
Design, Setting, and Participants
This international multicenter cohort study was conducted at 14 Urticaria Centers of Reference and Excellence in 10 countries, including all patients with chronic urticaria from these centers who were ever treated with omalizumab.
Main Outcomes and Measures
Drug survival analysis was performed to assess time to discontinuation. Patient characteristics and treatment protocols were investigated by Cox regression analysis to identify potential predictors for omalizumab discontinuation.
Results
In 2325 patients with chronic urticaria who started omalizumab between June 2009 and July 2022, the mean (SD) age of the cohort was 42 (6) years, and 1650 participants (71%) were female. Overall omalizumab survival rates decreased from 76% to 39% after 1 to 7 years, respectively (median survival time, 3.3 [95 % CI, 2.9-4.0] years), primarily due to discontinuation from well-controlled disease in 576 patients (65%). Ineffectiveness and adverse effects were reasons for discontinuation in a far smaller proportion of patients, totaling 164 patients (18%) and 31 patients (4%), respectively. Fast treatment response was associated with higher rates of omalizumab discontinuation due to well-controlled disease (hazard ratio, 1.45 [95% CI, 1.20-1.75]), and disease duration of more than 2 years was associated with lower rates of discontinuation due to well-controlled disease (HR, 0.81 [95% CI, 0.67-0.98]). Immunosuppressive cotreatment at the start of omalizumab and autoimmune disease was associated with a higher risk for discontinuation due to ineffectiveness (HR, 1.65 [95% CI, 1.12-2.42]). The presence of spontaneous wheals (HR, 0.62 [95% CI, 0.41-0.93]) and access to higher dosages (HR, 0.40 [95% CI, 0.27-0.58) were both associated with a lower risk for discontinuation of omalizumab due to ineffectiveness.
Conclusion and Relevance
This multinational omalizumab drug survival cohort study demonstrated that treatment of chronic urticaria with omalizumab in a clinical setting is effective and safe, and well-controlled disease is the main reason for treatment discontinuation. These findings on omalizumab drug survival rates and reasons and potential predictors for discontinuation may guide patients and physicians in clinical decision-making and expectation management. These results may call for the identification of biomarkers for chronic urticaria remission in complete responders to omalizumab treatment.
This multinational cohort study investigates the length of time in which patients take omalizumab and the reasons and potential predictors for its discontinuation.
Introduction
Chronic urticaria is characterized by recurrent, severely itching wheals, angioedema, or both, for longer than 6 weeks. Chronic urticaria is categorized further as chronic spontaneous urticaria and/or chronic inducible urticaria. Symptoms in chronic spontaneous urticaria develop spontaneously, and symptoms in chronic inducible urticaria are prompted by specific triggers.1 Chronic urticaria is self-limiting, but time until remission is highly unpredictable.2 All currently recommended therapies, such as antihistamines and omalizumab, are not considered disease-modifying drugs.1,3 In randomized clinical trials, omalizumab, an anti–immunoglobulin E monoclonal antibody, was safe and effective in patients with antihistamine-refractory chronic spontaneous urticaria or chronic inducible urticaria.3,4,5,6,7,8 However, patients included in randomized clinical trials are not entirely representative of those seen in clinical practice. Currently, little is known about the long-term performance of omalizumab in daily practice regarding the lengths of treatment duration and reasons and potential predictors for treatment discontinuation.
Drug survival analyses measure the performance of drugs in daily practice, incorporating effectiveness and safety as well as patient and physician preference,9,10 while estimating the length of time until an event occurs, such as the discontinuation of omalizumab treatment, reflecting the treatment duration of the drug. To date, 4 smaller omalizumab survival studies in patients with chronic urticaria have been performed.11,12,13,14 They showed a decrease in survival rates from 71% to 65% within 1 to 1.5 years12 and from 77% to 55% within 1 to 3 years, with well-controlled disease as a major reason for discontinuation.11 These previous studies were limited by small populations (range of sample sizes, 38-298 participants) and short follow-up (range, 32-72 months).11,12,14 Characterization of determinants of discontinuation is investigated in only 1 recent French study.13 All 4 studies were set in a single country, overall representing data from 3 countries, highlighting the remaining need for generalizable data.
We used the global network of Urticaria Centers of Reference and Excellence (UCARE)15 and performed this large international multicenter clinical cohort study, aiming to characterize the long-term performance of omalizumab in adults with chronic urticaria. Specifically, we assessed the reasons for omalizumab discontinuation and the determinants for omalizumab drug survival.
Methods
Patient Population, Data Collection, and Study Conduct
Fourteen international certified UCARE centers specializing in urticaria care15 from 10 countries participated in this cohort study (eTable 1 in Supplement 1). All patients with chronic urticaria who have ever been treated with omalizumab were included in the study population until the center-specific data lock. To avoid bias, patients with chronic inducible urticaria, including chronic inducible urticaria only, were included, as chronic inducible urticaria is often seen together with chronic spontaneous urticaria, and the distinction between sole/major/minor symptoms can be difficult. This study was approved by the Ethical Committee of Utrecht, Netherlands, and the ethics committees of the participating UCARE facilities as required. Exemption regarding obtaining informed consent was granted according to the General Data Protection Regulation.
All patients were treated according to their local treatment protocol primarily based on the international guideline.1 Local protocols were assessed by a questionnaire (eTable 2 in Supplement 1) as they differ in relevant details (eg, interval prolongation strategy, stop criteria, omalizumab up-dosing as per national health care policy) between UCARE facilities, possibly influencing omalizumab drug survival. The collected variables included the following:
Patient characteristics: These included age, sex, any concomitant autoimmune disease reported in patient history, time of chronic urticaria onset, and chronic urticaria diagnosis. Chronic spontaneous urticaria was defined as the presence of spontaneous wheals and/or angioedema. Chronic inducible urticaria was defined as the presence of inducible wheals. Chronic spontaneous urticaria with angioedema only was diagnosed based on the physician’s clinical assessment. When chronic spontaneous urticaria and chronic inducible urticaria were both present, the predominance of one was determined.
Treatment characteristics: These included antihistamine use during omalizumab treatment; use of immunosuppressive drugs at the start and during omalizumab treatment; time between start, stop, and (if applicable) restart of omalizumab treatment; occurrence of adverse effects; maximum omalizumab dosage; and reasons for discontinuation. Considering the half-life of omalizumab and clinical experience, treatment with an interruption of less than 90 days was considered continuous treatment.
Disease-activity scores16: These included the Urticaria Control Test (UCT); Urticaria Activity Score (UAS7); and Angioedema Activity Score (AAS) at baseline, second administration (within 4 weeks after initial treatment), and the end of treatment. Treatment end was defined as date of treatment discontinuation or in case of continuous treatment, the last visit before data lock or loss to follow-up. The UAS7 gives a score of the severity of the hives and the itch over 7 days. The UAS7 produces a numeric score ranging from 0 to 42, with higher values reflecting higher urticaria activity. The AAS consists of 5 questions with 4 answer options (scored 0 to 3) for each item, with a minimum score of 0 and a maximum score of 15 per day. Lower scores and higher scores represent low and high disease activity, respectively.
All data from 13 centers were obtained from in-hospital electronic medical records. One center retrieved part of the data from a questionnaire sent to patients (eMethods in Supplement 1; Supplement 2). All data were collected and stored in an electronic data capture system. Data from 142 patients from 1 center have been published previously.11
Treatment response was classified as complete (UAS7 = 0; UCT = 16), good (UAS7 = 1-6; UCT = 12-15),16 partial (UAS7 ≥ 7 and improvement of ≥1017; UCT = 0-11 and improvement ≥3),18 or no response (UAS7 ≥ 716 and improvement of <10; UCT = 0-11 and improvement of <3) and was evaluated at second administration and treatment end. In case of a discrepancy between the UAS7 and UCT scores, the better outcome was selected to define the response. Fast response was defined as UAS7 < 7 or UCT > 11 at the second administration, confirmed with expert consensus.16,19 When disease activity scores were missing, the onset of treatment response was determined based on the physicians’ description in patients’ medical records and categorized as complete or good (symptom-free or satisfied with minor symptoms only), partial (insufficient), or no response.
Statistical Analysis
Drug survival rates were calculated by Kaplan-Meier analysis and displayed in survival curves differentiated by reason for discontinuation: (1) any reason (overall survival), (2) well-controlled disease (ie, being symptom-free), (3) adverse effects, or (4) ineffectiveness. When patients discontinued due to both ineffectiveness and adverse effects, they were considered to have an event in both subanalyses. When patients discontinued for other reasons, they were considered to have an event in the overall drug survival analysis but were censored in the subanalyses. Patients who continuously used omalizumab at the time of data lock or were lost to follow-up were followed up until their last contact and censored thereafter. When omalizumab treatment was discontinued at least 90 days before restart, the subsequent treatment course was considered a second treatment episode.
To identify determinants of drug survival, a univariate Cox regression analysis was performed on patient characteristics and protocol aspects that were deemed clinically relevant (ie, all patient characteristics and protocol aspects). Determinants with a P value ≤ .20 were entered into a multivariate Cox regression model with manual backward selection omitting the variable with the highest P value in each step. In the multivariate Cox regression model, determinants with a P value ≤ .05 were considered statistically significant with 2-sided testing. Before analyzing the determinants of drug survival, we noted missing values in potential predictors of time to discontinuation. Consequently, we used the multiple imputation method (eMethods in Supplement 1).20,21 Statistical analyses were performed in SPSS Statistics software, version 27 (IBM). Graphs were made using GraphPad Prism 8.3 (GraphPad Software Inc).
Results
Patient and Treatment Characteristics
A total of 2325 patients with chronic urticaria (mean [SD] age, 42 [6] years; 1650 [71%] female participants), who started omalizumab treatment between June 2009 and July 2022 (13-year overall study period), were included (Table 1; eTable 3 in Supplement 1). Omalizumab start criteria were fairly similar across all centers, whereas stop criteria were different between centers concerning maximum treatment interval before discontinuation and limitation of available omalizumab administrations (eTable 2 in Supplement 1).
Table 1. Patient and Treatment Characteristics.
| Characteristic | No. (%) |
|---|---|
| Total patients, No. | 2325 |
| Sex | |
| Female | 1650 (71) |
| Male | 675 (29) |
| Age at start omalizumab, mean (SD); range, y (n = 2321) | 42 (16); 8-90 |
| <18 | 72 (3) |
| Disease duration >2 y before omalizumab (n = 2188) | 1050 (48) |
| Autoimmune disease (n = 1932) | 357 (18) |
| Chronic urticaria classification | |
| Chronic spontaneous urticaria only | 1552 (67) |
| Wheals | 777 (50) |
| Angioedema | 67 (4) |
| Wheals and angioedema | 707 (46) |
| Chronic inducible urticaria only | 179 (8) |
| Chronic spontaneous urticaria + chronic inducible urticaria | 594 (26) |
| Disease activity scores at baseline, median (IQR) | |
| UCT (n = 1449) | 5 (2-7) |
| UAS7 (n = 1565) | 28 (21-35) |
| AAS (n = 1629) | 12 (0-41) |
| Treatment characteristics | |
| High dose omalizumab useda (n = 1894) | 393 (21) |
| Immunosuppressive cotreatment at start of omalizumab (n = 1933) | 378 (20) |
| Prednisolone (n = 1967) | 300 (15) |
| Ciclosporin (n = 1967) | 68 (4) |
| Methotrexate (n = 1967) | 13 (0.7) |
| Other (n = 1967) | 27 (1) |
| Omalizumab response, No./total available (%) | |
| Fast responseb | 1068/1998 (54) |
| Response at treatment endc | 1659/2085 (80) |
| Partial response at treatment endd | 263/2085 (12) |
| No response at treatment ende | 163/2085 (8) |
Abbreviations: AAS, Angioedema Activity Score; UCT, Urticaria Control Test; UAS7, Urticaria Activity Score summed over 7 days.
High-dose omalizumab is defined as 450 mg or 600 mg.
These were the definitions for each response category: Fast response: UAS7 < 7 or UCT>11 at second administration.
Response at treatment end: UAS7 = 0-6 or UCT = 12-16 at treatment end.
Response at treatment end: UAS7 ≥ 7 and improvement of ≥10 or UCT 0-11 and improvement of ≥3.
No response at treatment end UAS7 ≥ 7 and improvement of <10 or UCT = 0-11 and improvement of <3.
Most patients, 1552 (67%), had chronic spontaneous urticaria only (777 [50%] wheals only, 67 [4%] angioedema only, 707 [46%] both), and 594 (26%) had a combination of chronic spontaneous urticaria and chronic inducible urticaria with 179 (8%) having chronic inducible urticaria only (Table 1). Approximately one-fifth of patients (357 patients [18%]) had concomitant autoimmune disease (mostly thyroid disease), and 1050 (48%) had chronic urticaria for more than 2 years before starting omalizumab. Almost all patients (1707 of 1952 patients [87%]) used antihistamines during omalizumab treatment, with 1504 of 1952 (77%) patients receiving higher than the standard dose. Immunosuppressive cotreatment of chronic urticaria at the start of omalizumab treatment was used in 378 patients (20%), mainly oral corticosteroids in 300 patients (15%).
Disease activity (Table 1) was high and disease control poor before the start of omalizumab, with median (IQR) baseline UAS7 and UCT values of 28 (21-35) and 5 (2-7) points, respectively. A fast response was achieved in 1068 patients (54%). At the end of treatment, 1659 patients (80%) had a complete or good response; 263 patients (12%) had a partial response, and 163 (8%) did not respond to treatment. The majority, 1501 of 1894 patients (79%), were treated with standard-dose omalizumab, while 393 of 1894 patients (21%) received a higher dosage due to insufficient response to the standard dosage. Higher dosages were available in 11 of 14 centers (3 centers did not allow higher dosages per national health care policy; eTable 2 in Supplement 1). Less than one-tenth of patients, 150 of 1967 (8%), used simultaneous immunosuppressive treatment, including 111 patients (74%) taking intermittent oral corticosteroids, 37 (25%) taking ciclosporin, or 2 (1%) taking methotrexate.
Reasons for Omalizumab Discontinuation and Omalizumab Survival Rates
Nearly one-half, 1129 patients (49%), used omalizumab continuously until data lock, and 299 patients (13%) were lost to follow-up. Approximately one-third, 890 patients (38%), discontinued omalizumab at least once, of which 253 (29%) restarted (second treatment episode) after a median (IQR) treatment-free period of 7 (4-15) months. The 1-year, 5-year, and 7-year overall omalizumab survival rates of the first treatment episode were 76%, 43%, and 39%, respectively, with unchanged survival rates after 7 years. The median survival time was 3.3 (95 % CI, 2.9-4.0) years (Figure 1; eTable 4 in Supplement 1). Overall median omalizumab survival was longer in patients with predominantly chronic inducible urticaria (exceeding 5 years) compared to patients with predominantly chronic spontaneous urticaria (Figure 1B; eTable 5 in Supplement 1). The omalizumab survival rates were mostly determined by well-controlled disease, as this was the major reason for discontinuation in 576 patients (65%) (Table 2; eTable 6 in Supplement 1). Omalizumab survival rates related to discontinuation due to ineffectiveness and adverse effects were 93% and 98% after 1 year, respectively (eTable 4 in Supplement 1), and decreased only marginally thereafter. Of the patients who discontinued omalizumab, 164 patients (18%) did so because of ineffectiveness, 31 patients (4%) because of adverse effects, and 13 (2%) because of a combination of both. Omalizumab survival rates overall and related to well-controlled disease, ineffectiveness, or adverse effects differed significantly between the 14 centers (eFigure 1 in Supplement 1).
Figure 1. Drug Survival of Omalizumab in Chronic Urticaria Patients.
A, Drug survival rates for overall drug survival (total) and the various reasons for discontinuation, including well-controlled disease, adverse effects, and ineffectiveness. B, The overall drug survival of omalizumab differentiated per subcategory of chronic urticaria. The survival curves are cut off at 7 years as the survival rates remain unchanged thereafter. CSU indicates chronic spontaneous urticaria; CIindU, chronic inducible urticaria.
Table 2. Reasons for Omalizumab Discontinuation in First Treatment Period.
| Reason for discontinuation | No. (%) |
|---|---|
| Well-controlled disease | 576 (65) |
| Adverse effects | 31 (4) |
| Ineffectiveness | 164 (18) |
| Combination of adverse effects and ineffectiveness | 13 (2) |
| Planning for pregnancy | 44 (5) |
| Other | 50 (9) |
| Patients’ preference | 16 (32) |
| Other medical condition | 9 (18) |
| COVID-19 pandemic | 7 (14) |
| Vacation | 5 (10) |
| Cold urticaria seasonal remission | 4 (8) |
| Costs/insurance | 3 (6) |
| Omalizumab use through clinical trial | 2 (4) |
| Other trial participation | 2 (4) |
| Fear of adverse effects | 1 (2) |
| Fear of biologic | 1 (2) |
| Unknown | 12 (1) |
| Total | 890 (100) |
Potential Predictors of Time to Omalizumab Discontinuation
The results of univariate Cox regression analyses are summarized in Table 3. Multivariate Cox regression analysis showed that a disease duration of more than 2 years (HR, 0.81 [95% CI, 0.67-0.98]) and the presence of chronic inducible urticaria (HR, 0.65 [95% CI, 0.54-0.80]) was associated with a lower chance of discontinuation due to well-controlled disease, whereas fast response (HR, 1.45 [95% CI, 1.20-1.75]) was associated with a higher chance of discontinuation due to well-controlled disease. Of the protocol aspects, a maximum dosing interval of more than 12 weeks (HR, 0.64 [95% CI, 0.51-0.81]) and access to higher than standard-dose omalizumab treatment (HR, 0.36 [95% CI, 0.29-0.44]) was associated with a lower chance of discontinuation due to well-controlled disease, whereas being limited to 6 consecutive administrations (HR, 1.87 [95% CI, 1.38-2.53]) was associated with a higher chance of discontinuation due to well-controlled disease (Figure 2A).
Table 3. Univariate Analysis of Potential Predictors of Time to Discontinuation Due to Well-Controlled Disease, Ineffectiveness, and Adverse Effects.
| Variable | Well-controlled disease | Ineffectiveness | Adverse effects | |||
|---|---|---|---|---|---|---|
| HR (95% CI) | P valuea | HR (95% CI) | P valuea | HR (95% CI) | P valuea | |
| Sex | ||||||
| Female | 0.91 (0.76-1.08) | .28 | 1.18 (0.85-1.66) | .33 | 1.60 (0.77-3.32) | .21 |
| Disease duration >2 y before start of omalizumab | 0.70 (0.58-0.84) | <.001 | 0.97 (0.71-1.32) | .83 | 2.01 (1.06-3.82) | .03 |
| Age at start of treatment (scale, higher) | 1.00 (1.00-1.01) | .17 | 1.01 (1.00-1.02) | .13 | 1.01 (0.99-1.03) | .54 |
| Autoimmune disease | 1.09 (0.86-1.39) | .45 | 1.77 (1.19-2.61) | .01 | 1.69 (0.84-3.39) | .14 |
| Immunosuppressive cotreatment at start of omalizumab | 1.00 (0.80-1.25) | >.99 | 1.62 (1.11-2.38) | .01 | 1.43 (0.70-2.93) | .32 |
| Fast responseb | 1.46 (1.21-1.75) | <.001 | 0.30 (0.14-0.63) | .002 | ||
| Presence of spontaneous whealsc | 1.42 (1.06-1.91) | .02 | 0.71 (0.47-1.06) | .09 | 1.84 (0.57-5.93) | .31 |
| Presence of angioedemac | 0.98 (0.83-1.16) | .83 | 1.15 (0.86-1.55) | .34 | 1.73 (0.95-3.15) | .07 |
| Presence of chronic inducible urticariac | 0.57 (0.47-0.69) | <.001 | 0.92 (0.67-1.26) | .59 | 1.00 (0.53-1.86) | .99 |
| UAS7 at baseline | 0.99 (0.98-1.00) | .06 | 1.00 (0.98-1.03) | .72 | 1.00 (0.97-1.03) | .90 |
| UCT at baseline | 0.99 (0.96-1.02) | .60 | 0.95 (0.88-1.02) | .14 | 0.95 (0.84-1.07) | .37 |
| Access to higher than standard-dose omalizumabd | 0.32 (0.27-0.39) | <.001 | 0.34 (0.24-0.48) | <.001 | 5.14 (0.71-37.37) | .11 |
| Self-administration availablee | 1.34 (1.13-1.58) | .001 | 2.00 (1.43-2.80) | <.001 | 4.23 (1.79-10.02) | .001 |
| Maximum dosing interval >12 wkf | 0.81 (0.65-1.01) | .06 | 1.23 (0.86-1.76) | .27 | 0.22 (0.05-0.89) | .03 |
| Maximum of 6 administrationsg | 3.46 (2.62-4.58) | <.001 | 2.47 (1.45-4.20) | .001 | 1.16 (0.28-4.81) | .84 |
Abbreviations: UCT, Urticaria Control Test; UAS7, Urticaria Activity Score summed over 7 days.
Determinants with a P value ≤ 0.2 in univariate Cox regression analysis were included as candidate determinants in the multivariate Cox regression analysis.
UAS7-score <7 or UCT-score >11 within 4 weeks after first administration.
The chronic urticaria symptom could be present as a sole, major, or minor symptom.
The treating physician in a particular center was allowed to prescribe a dose higher than 300 mg.
Patients were allowed to administer omalizumab outside of the hospital (eg, by themselves or a home nurse).
Omalizumab was stopped after a symptom-free treatment interval of >12 weeks was reached.
A maximum of 6 consecutive administrations per patient per treatment episode as per national health care policy.
Figure 2. Multivariate Analysis of Determinants of Time to Discontinuation Due to Well-Controlled Disease, Ineffectiveness, and Adverse Effects.
All variables (patient and protocol aspects) with P ≤ .20 in the univariate Cox regression analysis were included in the multivariate Cox regression analysis. The multivariate Cox regression analyses were all performed on an imputed dataset. The analysis for determinants of adverse effects was performed only with patient characteristic variables as there were too few events (n = 44) to include protocol aspects.
Multivariate Cox regression analysis of discontinuation due to ineffectiveness showed that immunosuppressive cotreatment at start of omalizumab (HR, 1.65 [95% CI, 1.12-2.42]) and concomitant autoimmune disease (HR, 1.60 [95% CI, 1.08-2.36]) was associated with a higher chance of discontinuation, while presence of spontaneous wheals (HR, 0.62 [95% CI, 0.41-0.93]) was associated with a lower chance of discontinuation. Of the protocol aspects, the availability of self-administration (HR 1.53 [95% CI, 1.07-2.19]) was associated with a higher chance of discontinuation, whereas access to higher than standard-dose omalizumab treatment (HR, 0.40 [95% CI, 0.27-0.58]) was associated with a lower chance of discontinuation due to ineffectiveness (Figure 2B).
A small proportion of patients (n = 44) discontinued omalizumab due to adverse effects. Multivariate Cox regression analysis showed that disease duration of more than 2 years (HR, 2.08 [95% CI, 1.10-3.94]) was associated with a higher chance, whereas fast response (HR, 0.29 [95% CI, 0.14-0.62]) was associated with a lower chance of discontinuation due to adverse effects (Figure 2C). The most commonly reported adverse effects leading to discontinuation were arthralgia in 8 patients, headache in 6 patients, and fatigue in 4 patients. Anaphylaxis led to discontinuation of omalizumab in 2 patients.
Discussion
This international multicenter cohort study investigated the performance of omalizumab in patients with chronic urticaria in clinical settings using drug survival analysis to assess time to discontinuation and factors associated with discontinuation. In contrast to randomized clinical trial methods, drug survival analysis is especially useful to assess how treatment is received and handled by patients and physicians in clinical practice, allowing for the evaluation of the long-term performance of treatment, which was more than 10 years in this study. This study primarily confirms the effectiveness of omalizumab in chronic urticaria by demonstrating that omalizumab discontinuation occurs gradually over years with decreasing overall survival rates from 76% to 39% across 7 years, mostly driven by one reason: well-controlled disease. Reassuringly, discontinuation due to ineffectiveness or adverse effects was rare and occurred mostly within the first treatment year. The current study expands on data from 4 earlier smaller single-country omalizumab survival studies,11,12,14 showing comparable survival rates over a much shorter period of 1.5 and 3 years with limited power for differentiation between reasons for discontinuation and predictors.12
The large decrease in the omalizumab survival rate associated with well-controlled disease demonstrates that many patients achieved a response enabling them to stop over time. In daily practice, this process might be delayed due to fear of relapse while being symptom free. This calls for the identification of biomarkers that monitor chronic urticaria disease activity and indicate remission in patients with complete control with omalizumab treatment.
Because omalizumab is considered non–disease modifying,3 we speculate that the presented omalizumab survival rates for well-controlled disease may provide information on the disease duration in patients with moderate to severe chronic urticaria. With an average of 2 years of chronic urticaria before omalizumab treatment and an average omalizumab survival of 7 years in patients with well-controlled disease, these patients had 9 years of total chronic urticaria duration. However, our finding might be an overestimation as patients may have gone into spontaneous remission earlier while still continuing omalizumab treatment. Most cohort studies investigating patients with moderate to severe chronic urticaria in secondary and tertiary centers report an average total chronic urticaria duration of 1 to 2 years.22,23,24,25,26 Only 2 older questionnaire-based studies reported a longer median disease duration of 2 to 4 years27 and even more than 10 years,28 indicating that our estimated long chronic urticaria duration has rarely been observed before.
Interestingly, patients with predominantly chronic spontaneous urticaria had a shorter overall omalizumab survival compared to patients with predominantly chronic inducible urticaria, reflecting a longer estimated treatment duration in patients with chronic inducible urticaria, contradictory to a previous omalizumab drug survival study.13 We also observed that the presence of chronic inducible urticaria was associated with a longer time to discontinuation due to well-controlled disease and was not associated with a shorter time to discontinuation due to ineffectiveness. This suggests that omalizumab is effective in patients with chronic inducible urticaria, despite the need for longer treatment, possibly reflecting longer disease duration than in chronic spontaneous urticaria.29,30
We found that a fast response was associated with a shorter time to omalizumab discontinuation due to well-controlled disease, which could be explained by early interval prolongation with subsequent discontinuation.20 Pathomechanistically, fast and good omalizumab response is associated with autoallergic chronic spontaneous urticaria (presence of immunoglobulin E autoantibodies), whereas slow and insufficient response is associated with the autoimmune subtype IIb.31,32 Accordingly, we identified that concomitant autoimmune disease was associated with the ineffectiveness of omalizumab. Also, we found that a longer time to omalizumab discontinuation due to well-controlled disease was associated with a long disease duration before starting omalizumab. Longer disease and treatment duration may be linked to the development of autoimmune chronic spontaneous urticaria.33 Thus, we hypothesized that early effective treatment of chronic urticaria with complete disease control may shorten disease duration by preventing the transition to autoimmune chronic spontaneous urticaria. A previous study on the coexistence of autoallergic and autoimmune chronic spontaneous urticaria demonstrated that almost all patients with autoimmune chronic spontaneous urticaria also have autoallergic chronic spontaneous urticaria, but not vice versa. This suggests that patients with autoallergic chronic spontaneous urticaria develop autoimmune chronic spontaneous urticaria over time,33 which supports our hypothesis and should be investigated in future studies.
The high drug survival rates associated with ineffectiveness and adverse effects show that omalizumab is effective and well tolerated in the long-term in clinical settings, as very few patients discontinued for these reasons. However, these favorable omalizumab survival rates might be partially influenced by the current absence of effective and safe alternative treatment options, probably leading to acceptance of some discomfort or suboptimal effectiveness in some patients. Therefore, observations of how upcoming chronic urticaria treatment might alter current omalizumab survival rates would be of interest in future studies.
The presence of spontaneous wheals (vs angioedema or chronic inducible urticaria) was associated with a longer omalizumab treatment duration due to ineffectiveness, indicating that these patients have a lower risk of stopping because of ineffectiveness. A shorter time to discontinuation due to ineffectiveness was associated with immunosuppressive cotreatment at the start of omalizumab. Possibly, as immunosuppressive drugs at baseline are prescribed in patients with severe and refractory disease, this may be a proxy for severe disease rather than being causally related to ineffectiveness. This knowledge might guide physicians in daily practice to start early treatment escalation (eg, omalizumab up-dosing) in cases of insufficient response in patients who used immunosuppressive drugs at start of omalizumab treatment.
A similar trend in well-controlled disease as major contributor of omalizumab survival was seen in all participating centers, although survival rates differed between them. Protocol-specific aspects were identified as independent determinants of omalizumab survival. Access to higher than standard-dose omalizumab treatment was associated with longer time to discontinuation due to ineffectiveness, confirming that omalizumab up-dosing contributes to its effectiveness as it is associated with a lower likelihood of stopping because of insufficient response. Although the influence of protocol aspects on drug survival seems logical, the difference in omalizumab survival between centers is probably also affected by other aspects such as population differences, and preferences of physicians and patients, which were not compared in this study. However, awareness of the influence of these protocol aspects on treatment duration is crucial, and investigating whether treatment algorithms could be optimized to improve cost-effectiveness may be of interest.
Limitations
In this large daily practice cohort study, missing data were inevitable, which could be considered as a limitation. In order to maintain statistical power for predictor analysis, missing data were imputed. However, limited data collection time across centers may have led to data not missing at random and might subsequently have introduced bias. Additionally, a high degree of missingness in UAS7 and UCT values at baseline and the handling of these scores as continuous variables in the multiple imputation method may have been at risk for incorrect estimation. Additionally, omalizumab dosing varied between patients, which could be considered as a limitation of data generalizability, but is also a study outcome.
Conclusions
This multinational cohort study demonstrated overall omalizumab survival rates of 76% to 39% after 1 to 7 years, respectively, differentiated per reason for discontinuation in a large international multicenter chronic urticaria cohort. The high performance of omalizumab in daily practice is confirmed by demonstrating that most patients were able to discontinue omalizumab due to well-controlled disease, while ineffectiveness and adverse effects were reasons for discontinuation in only 18% and 4% of patients, respectively. Fast response, short disease duration, and presence of spontaneous wheals were favorable determinants for discontinuation. Drug survival rates together with the identified determinants provide important daily practice information to support patients and physicians in expectation management around treatment duration and reasons and potential predictors for discontinuation. These findings highlight a future research opportunities for identifying biomarkers of chronic urticaria activity and remission in complete responders to omalizumab treatment.
eTable 1. Participating UCAREs, number of inclusions and center specific data lock date
eTable 2. Omalizumab treatment strategy per center
eMethods. Supplemental methods
eTable 3. Patient and treatment characteristics in total and per center
eTable 4. Drug survival rates
eTable 5. Overall drug survival rates differentiated per subcategory of chronic urticaria
eTable 6. Reasons for omalizumab discontinuation in patients who stopped first treatment episode in total and per center
eFigure. Omalizumab drug survival curves for overall drug survival and differentiated for the reasons for discontinuation per center
Survey in German and in English
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Participating UCAREs, number of inclusions and center specific data lock date
eTable 2. Omalizumab treatment strategy per center
eMethods. Supplemental methods
eTable 3. Patient and treatment characteristics in total and per center
eTable 4. Drug survival rates
eTable 5. Overall drug survival rates differentiated per subcategory of chronic urticaria
eTable 6. Reasons for omalizumab discontinuation in patients who stopped first treatment episode in total and per center
eFigure. Omalizumab drug survival curves for overall drug survival and differentiated for the reasons for discontinuation per center
Survey in German and in English
Data Sharing Statement
