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Chronic urticaria (CU) is defined as wheals (hives), angioedema, or both lasting more than 6 weeks [1]. CU can be classified as chronic spontaneous urticaria (CSU), previously recognized as chronic idiopathic urticaria, with the spontaneous appearance of hives and angioedema due to unknown cause, and chronic inducible urticaria (CIndU) for which specific eliciting factors are involved [1]. The worldwide prevalence of CSU is reported to vary between 0.02% and 5.0%, with women having a disproportionately higher incidence and a median age of onset in the 50s [2-7]. The prevalence of CSU in the Korean population ranges between 0.16% and 2.3%, at a similar level [2].

According to the joint initiative by the Korean Academy of Asthma, Allergy and Clinical Immunology (KAAACI) and the Korean Dermatological Association (KDA), nonsedating H1-antihistamines are the first-line treatment for CSU [2]. It has been observed that 50% of patients with CSU continue to be symptomatic despite their treatment with approved doses of H1-antihistamines. In case of inadequate response, the dose of antihistamines can be increased up to four times, but this is effective in only 45% to 50% of patients [8-10]. In addition, leukotriene receptor antagonists have been used, either as a single therapy or in combination with H1-antihistamines [1,2]. In patients who are unresponsive to H1-antihistamines, guidelines recommend treatment escalation to omalizumab and immunomodulators such as cyclosporine [1,11].

CSU is a debilitating skin condition, and its impact goes beyond the skin. CSU has a profound impact on quality of life (QoL) due to anxiety, depression, sleep disturbance, and comorbidities, including autoimmune and endocrine disorders [1,12,13]. Along with QoL impairment, patients with CSU pose a considerable economic burden on the healthcare system [14]. Previous studies such as ASsessment of the Economic and Humanistic Burden of Chronic Spontaneous/Idiopathic URticaria PatiEnts (ASSURE-CSU) (2015) and A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation (AWARE) (2017), which evaluated the burden of disease among patients resistant to H1‑antihistamines, highlighted that symptomatic patients with CSU have poor QoL, and inadequate response to treatment poses a significant impairment to health-related quality of life (HRQoL) and leads to extensive healthcare resource utilization (HRU) [14,15]. However, very few patients who were prescribed omalizumab were included since it had not launched or had not come into wide use at the time of conduct of these studies [14].

There have been no studies in Korea assessing the disease burden on symptomatic patients with CSU in terms of patient-reported outcomes (PROs), HRU, and their relationships, particularly after the approval of omalizumab for the treatment of CSU. The present study evaluated the burden of disease, including HRQoL and HRU, in symptomatic patients with CSU in Korea.

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This real-world study evaluated the overall disease burden of symptomatic patients with CSU in a clinical setting, where omalizumab was available as a treatment option. Symptomatic patients with CSU with treatment history during the past 6 months were enrolled, and their current disease activity, HRQoL, and the impact of previous treatment were assessed. PROs were assessed through various measures such as UAS7, CU-QoL, EQ-5D-5L, and DLQI scores, and the association between disease activity (UAS7) and HRQoL was also evaluated. The present study adequately represents the real-world situation of patients with CSU in Korea, as it was conducted in eight tertiary hospitals where CSU treatment is actively performed.

In the present study, 64.2% of patients with CSU were female. This finding is substantiated by a recent meta-analysis of worldwide population‐based studies, in which women were more affected by urticaria than men [26]. In the ASSURE study, around 70% of patients were reported to have moderate-to-severe CSU, with a mean disease duration of 5 years [27]. This was in line with the results of our study, wherein the overall disease duration of CSU was around 4 years, with nearly 50% of patients categorized as having moderate-to‑severe CSU.

In the present study, patients were treated following the recommended guidelines and previously published studies, suggesting that investigators who participated in the study adhered to urticaria treatment guidelines, contributing to a higher quality of patient care [28,29]. However, some notable differences were observed in the treatment pattern in comparison with other real-world studies, such as ASSURE-CSU and AWARE [14,15]. All (100%) patients enrolled in this study were prescribed medications to treat CSU in the past 6 months, whereas 18.1% of patients in ASSURE and 29.9% in AWARE study at baseline did not receive any treatment [14,15]. In the present study, 35% of patients (who were in uncontrolled status on H1-antihistamines) received omalizumab following the KAAACI/KDA recommendations, and the percentage of patients receiving third-line therapy increased as disease activity worsened (proportion of third-line therapy use in each UAS7 disease category: 36.9% for well‑controlled, 37.2% for mild, 43.7% for moderate, and 45.1% for severe) [11]. However, in the ASSURE-CSU study, less than 6% of patients received omalizumab [14]. This difference could be attributed to omalizumab not being approved for CSU at the time of data collection in the ASSURE-CSU study [14]. Additionally, in the AWARE study, it was observed that the proportion of patients receiving both escalated doses of H1‑antihistamines and omalizumab was quite low although impairment in QoL still remained [30]. Furthermore, a small percentage (11% or less) of patients received escalated doses of H1-antihistamines and omalizumab, indicating a lack of proper treatment in patients with uncontrolled disease [30]. As shown in Fig. 2, among patients with moderate-to-severe CSU (UAS7, 16 to 42), 55.8% still remained on first- or second-line therapy while 44.2% received third-line therapy. Among patients who received third-line therapy, 79.7% had well-controlled, mild, or moderate disease activity. Considering that enrolled patients were still symptomatic for more than 6  months and third-line therapy showed effectiveness in decreasing disease activity, an early and appropriate introduction of step-up treatment based on regular assessment of disease activity could effectively lessen disease burden of patients with CSU.

It has been observed that HRQoL deteriorates significantly in patients with CSU, owing to its unpredictable symptoms [31]. ED is thought to cause CSU and is a common comorbidity among patients with CSU [13]. In the present study, patient’s ED and stigma were evaluated in the subdomains of CU-QoL; however, the presence of anxiety, depression, or other psychiatric illness as comorbidities was not assessed. The poor QoL results of patients with CSU enrolled in this study were consistent with those of previous studies [14,15,32]. It suggests that despite better treatment compliance with treatment guidelines, patients with CSU still have unmet needs and there remains room for improvement in care. In line with previous studies, it was observed that patients with severe disease had worse QoL [31-34]. For all three HRQoL measurements (i.e., CU-QoL, EQ-5D-5L, and DLQI), the mean scores among the four UAS7 activity states differed significantly. Multivariate regression analysis showed that UAS7 continued to be a significant variable in CU-QoL and had a relatively larger coefficient value than other variables. These findings suggest that it may be possible to predict QoL among patients with CSU by assessing disease activity.

Factors that were negatively associated with QoL included female sex and disease activity. In addition to these factors, third-line therapy was also associated with poor QoL. This can be interpreted that as disease activity worsened, patients could not be controlled on first- or second-line treatment and thus presumably had lower QoL, requiring treatment with third-line agents such as omalizumab.

Atopic dermatitis (5.6%) and angioedema (11.0%) were negatively associated with CU-QoL, but the results were not statistically significant in the multivariate analysis. This may be attributed to the high proportion of women with comorbidities affecting QoL in the total population. Autoimmune diseases, atopic dermatitis, and angioedema were observed in 4.0%, 6.5%, and 12.1% of females, respectively, at higher proportions than those in males (1.7%, 3.9%, and 8.9%, respectively). Additionally, angioedema is often underdiagnosed and under-reported in patients with CSU despite being associated with significant CSU activity, poor HRQoL, and productivity impairment [27].

Almost all patients visited the outpatient department in the past 6 months. The results correspond with those from a previously published real-world study, in which 72.1% of patients had at least one visit to a healthcare professional for their CSU in the past 12 months [14]. In our study, as disease activity worsened, the number of outpatient department visits tended to increase. However, ER visits or hospitalization did not increase significantly with an increase in disease activity. This may be because hospitalization and emergency department admission provide more intensive treatment focused on acute symptoms than outpatient departments where the focus is on long‑term disease control. The proportion of patients with ER visits or hospitalization in the past 6 months was higher in severe (9.9%) and well-controlled (7.2%) disease activity states. The high rate reported in well-controlled patients could infer that they previously had severe disease activity requiring hospitalization and ER visits and have now been effectively transitioned to the well-controlled state. The average cost per patient for CSU management was estimated to be $86.3 in the present study, with no correlation with disease activity.

The present study had a few limitations that need to be highlighted. First, the study collected medical information retrospectively, and cross-sectional questionnaires had different recall periods, which may have caused difficulties in interpreting causality and effects. Second, since only patient responses were captured to determine their QoL and disease activity, there could be a discrepancy between subjective disease activity reported by the patient and objective judgment of the physicians for treatment. This could have led to overestimation or underestimation of patient responses and subsequent interpretation of the study results. Third, as the dosage of antihistamine used was not collected, the line of H1-antihistamine therapy (approved dose or increased dose to four-folds) could not be differentiated. Lastly, owing to the coronavirus disease 2019 (COVID-19) pandemic, HRU could have been underestimated due to patients minimizing hospital visits in fear of infection risks during travel or at the hospital.

In conclusion, this study demonstrates that almost half of the symptomatic patients with CSU have moderate-to-severe disease activity despite standard care, and more than half of them remain on first- or second-line therapy. Symptomatic patients with CSU have considerable burden on HRQoL and HRU; disease activity affects the burden of disease. CSU management requires a comprehensive approach that considers the line of therapy, QoL, disease activity, HRU, and PROs.

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