Sleep Disturbance Mediates the Association Between Disease Activity and Work Productivity Impairments in Chronic Urticaria

To the Editor,

Chronic urticaria (CU) is a condition where hives, with or without angioedema, persist for over 6 weeks. In recent years, leveraging various disease‐specific patient‐reported outcome measures (PROMs), such as the Weekly Urticaria Activity Score (UAS7) and Chronic Urticaria Quality of Life Questionnaire (CU‐Q2oL), there is a growing focus on the psychosocial burden of CU, including its impact on quality of life, sleep quality, and work productivity [1, 2]. In this report, we presented a causal mediation analysis, a statistical approach that quantifies the mediating effect of a given factor in a causal relationship, to better characterize their interrelationships [3].

Adult patients with newly diagnosed CU were enrolled from the Hong Kong West Cluster (HKWC), an Urticaria Centre of Reference and Excellence, between July 2022 and October 2024. All patients fulfilled the diagnostic criteria in the 2021 international EAACI/GA [2] LEN/EuroGuiDerm/APAAACI guideline as verified by an attending physician. They completed the validated Traditional Chinese UAS7, CU‐Q2oL, and Work Productivity and Activity Impairment Questionnaire: General Health, version 2.0 (WPAI) [1, 2]. We also retrieved their demographic and clinical characteristics, including sex, age, presence of concomitant angioedema, self‐reported potential urticarial trigger, autoimmune disorders, suspected food or drug allergy, and regular antihistamine use before clinic visit. Patients with incomplete data were excluded. This study was approved by the Institutional Review Board of The University of Hong Kong/Hospital Authority HKWC. All patients offered informed consent.

We first calculated the Spearman correlations between PROMs on IBM SPSS Statistics version 28 (IBM, Armonk, NY), with p‐values adjusted by the Bonferroni method. Based on this, we performed a mediation analysis bootstrapped with 5000 simulations on R version 4.3.1 (R Foundation, Vienna, Austria) via the mediation package [3]. UAS7, CU‐Q2oL Sleep & Concentration, and three WPAI domains (Presenteeism, Work productivity loss and Activity impairment) were respectively inputted as disease exposure, mediator, and outcomes. Patients' clinicodemographic characteristics were considered covariates. Besides, p < 0.05 denotes statistical significance.

Data from a total of 246 CU patients were analyzed. Of whom, 196 (79.7%) were female and the mean age was 49 ± 15 years. Concomitant angioedema and potential urticarial triggers were reported by 143 (58.1%) and 48 (19.5%) of them, respectively. As shown in Table S1, their mean ± standard deviation scores were 13.2 ± 12.3 for UAS7, 32.7 ± 31.3 for CU‐Q2oL Sleep & Concentration, 2.1 ± 12.4 for WPAI Absenteeism, 23.6 ± 28.9 for WPAI Presenteeism, 23.3 ± 28.5 for WPAI Work productivity loss, and 29.5 ± 30.3 for WPAI Activity impairment, with almost all of them significantly correlated to one another (all p < 0.05 except WPAI Absenteeism; Table S2).

In our mediation analysis, disease activity was significantly associated with work productivity and activity impairments in all three constructed models (all p < 0.05; Table 1 and Figure 1). Of which, sleep quality was a significant mediator (all p < 0.05), with the mediated effect ranging from 30.5% of the total effect in WPAI Activity impairment to 48.2% and 49.8% in WPAI Work productivity loss and WPAI Presenteeism, respectively. These associations were further confirmed in the bootstrapping analysis (Figure S1).

TABLE 1.

Causal mediation analysis with UAS7 as exposure and CU‐Q2oL sleep and concentration as mediator.

Outcome	Total effect (95% CI)	p‐value	Direct effect (95% CI)	p‐value	Indirect effect (95% CI)	p‐value	% mediated (95% CI)	p‐value
WPAI Presenteeism	1.254 (0.88 to 1.61)	< 0.0001	0.630 (0.19 to 1.08)	0.0052	0.624 (0.33 to 0.94)	< 0.0001	49.8% (25% to 82%)	< 0.0001
WPAI Work productivity loss	1.265 (0.88 to 1.63)	< 0.0001	0.655 (0.21 to 1.09)	0.0044	0.610 (0.33 to 0.92)	< 0.0001	48.2% (26% to 80%)	< 0.0001
WPAI Activity impairment	1.565 (1.31 to 1.82)	< 0.0001	1.087 (0.74 to 1.41)	< 0.0001	0.477 (0.26 to 0.73)	< 0.0001	30.5% (16% to 48%)	< 0.0001

Note: Adjusted covariates: Sex, age, presence of concomitant angioedema, potential urticarial trigger, autoimmune disorders, suspected food allergy, suspected drug allergy, regular antihistamine use prior to clinic visit.

Abbreviations: CI, confidence interval; CU‐Q2oL, Chronic Urticaria Quality of Life Questionnaire; UAS7, Weekly Urticaria Activity Score; WPAI, Work Productivity and Activity Impairment Questionnaire. Bold text denotes reaching statistical significance.

FIGURE 1.

Causal mediation models. *Denotes statistical significance; solid line represents significant correlations whereas dotted line represents insignificant correlations. CU‐Q2oL, Chronic Urticaria Quality of Life Questionnaire; UAS7, Weekly Urticaria Activity Score; WPAI, Work Productivity and Activity Impairment Questionnaire.

To our knowledge, we are the first to report the mediating role of sleep disturbances between active urticaria and impaired work productivity. Our findings demonstrate how active disease is translated, via sleep interference, into functional impairments and affects patients' daily activities. This phenomenon might be multifactorial. Intuitively, pruritic sensations can cause difficulty initiating or maintaining sleep. Previous reports also suggest an association between CU and obstructive sleep apnea, which may affect sleep quality [4]. At the cellular level, CU is a mast cell‐mediated condition involving histamine, which has a wake‐promoting property.

Since almost half of the productivity impairments in CU were attributed to sleep disturbances, it is vital to have interventions targeting this unmet problem. At writing, there is limited data on the efficacy of existing CU treatments for sleep dysfunction. Fortunately, trials for CU have been increasingly incorporating sleep‐related outcomes as endpoints, which show promising outcomes with various biologics [5]. In addition, given the poorer treatment response of type IIb spontaneous CU, future studies are warranted to explore the differences in the extent of sleep disturbances and treatment effectiveness between the two spontaneous CU endotypes [6]. This study is limited by its single‐center nature. Sleep quality was only assessed by a CU‐Q2oL domain instead of standalone measures. No provocation tests were performed to confirm inducible CU. Some confounders such as patients' occupation were not included in this study.

To conclude, there is a significant association between disease activity and work productivity and activity impairments in CU, with sleep disturbance being a significant mediator. Further efforts are warranted to explore and address this unmet need in CU.

Authors' Contribution

H.W.F.M. researched the data and drafted the manuscript. E.L. and J.C.Y.W. researched the data. P.H.L. conceptualized and supervised the study. All authors contributed to and approved the final version of the manuscript before submission.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.