Work ability and quality of working life in atopic dermatitis patients treated with dupilumab

Abstract Atopic dermatitis is associated with work productivity loss. Little is known about how patients perceive their work ability and quality of working life, and how this is affected by treatment. Our primary objective was to investigate work ability and quality of working life at baseline and during treatment in the long term. A registry‐embedded prospective observational cohort study was conducted consisting of patients with atopic dermatitis starting dupilumab in routine clinical care. The instruments used were the Work Ability Index (WAI; questions 1, 2, and 3) and the Quality of Working Life Questionnaire (QWLQ). Ninety‐three patients were included of whom 72 were (self‐)employed (77%). From baseline to 48 weeks, the mean WAI‐1 score (general work ability, range 0–10) improved from 6.8 (±2.0) to 7.9 (±1.3), WAI‐2 (physical work ability, range 1–5) from 3.7 (±0.9) to 4.3 (±0.7), and WAI‐3 (mental/emotional work ability, range 1–5) from 3.4 (±0.9) to 3.9 (±0.8) (p = 0.001, p = 0.005, p < 0.001, respectively). The mean QWLQ total score improved from 74.0 (±9.1) to 77.5 (±9.6) and subscale “Problems due to health situation” improved from 37.4 (±22.3) to 61.5 (±23.1) (range 0–100; p = 0.032, p < 0.001, respectively). In conclusion, patients with moderate‐to‐severe atopic dermatitis starting dupilumab report decreased work ability and quality of working life, mainly due to health‐related problems. Significant improvement of work ability and quality of working life is observed with dupilumab treatment.


K E Y W O R D S
atopic dermatitis, dupilumab, occupation, routine clinical care, work has shown that moderate-to-severe AD has a substantial adverse economic impact with a mean productivity loss of almost 10%. 6 Patients with AD using systemic treatment are found to incur considerable direct costs as well as indirect costs resulting from productivity loss. 7 Little is known about how AD patients perceive their work ability and quality of working life (QWL). The Work Ability Index (WAI) was developed to investigate how long people are able to work and to what extent they are able to work depending on work content and demands.
The WAI is considered reliable and valid, and has become a common tool to investigate work ability in research worldwide. 8,9 QWL is defined by the experiences and perceptions in the work situation. 10 The Quality of Working Life Questionnaire (QWLQ) was developed to assess subjective work outcomes in employed cancer patients. 10,11 In contrast to other questionnaires it was not developed for healthy employees or particular occupations. 12 Adequate internal consistency, construct validity and reproducibility, as well as sufficient responsiveness and interpretability were found in cancer survivors. 12,13 To date, WAI or QWLQ have never been used in the AD population.
The aim of this study was to generate new knowledge on workrelated outcomes in AD, focusing on work ability and QWL in particular. The primary objective was to investigate the work ability and QWL of AD patients at baseline and during dupilumab treatment using WAI and QWLQ scores. The secondary objectives were to explore associations between change in QWLQ (from baseline to 48 weeks) and baseline characteristics, and to explore the convergent validity of the QWLQ.

| Study design and patient population
We conducted a registry-embedded prospective observational study in patients with AD based on the UK Working Party criteria. 14 Patients of the Department of Dermatology of Amsterdam UMC starting treatment with dupilumab in context of routine clinical care, indicating moderate-to-severe disease, were included from November 2017 to February 2020. Six patients refrained from participation and informed consent was obtained from all participants.
Apart from the requirement for informed consent, there were no exclusion criteria. A subset of TREAT NL registry data was used. 15 Patients starting treatment with other systemic immunomodulating therapies or phototherapies, which are also included in the TREAT NL registry, were not included in this study as the numbers were low. At baseline and every 24 weeks thereafter, outcome data was collected (see "Study outcomes"). The study was exempted from evaluation by our local medical research ethics committee (W18_097#18.123).
The study was carried out in accordance with the provisions of the Declaration of Helsinki.
All patients met the national criteria for dupilumab as determined by the Dutch Society of Dermatology which stipulate a failed treatment episode (ineffectiveness or adverse events) with one or more conventional systemic therapy(ies) prior to starting dupilumab. 16 In two patients, dupilumab was prescribed off-label at the time, as they were 17 years old. All other patients were adults. Patients started with an initial loading dose of 600 mg, followed by 300 mg dupilumab injections every 2 weeks. In our analyses we included patients while receiving dupilumab, regardless of dosing interval deviations and follow-up duration. In accordance with (daily practice), patients were allowed to continue using conventional systemic treatment in a tapering schedule and to use topical treatments (e.g., corticosteroids and calcineurin inhibitors).

| Study outcomes
Data collection was based on the TREAT core dataset. 15 As part of this study, we implemented the WAI and QWLQ in the Amsterdam UMC dataset (Appendix S1 and S2). 8,12 The first three WAI questions were used (i.e., WAI-1, WAI-2, WAI-3), giving insight into patient-reported general, physical, and mental work ability, respectively. General work ability (WAI-1) was assessed in comparison to best work ability ever, on a scale of 0 (worst) to 10 (best). Five-point Likert scales were applied to assess work ability with respect to physical (WAI-2) and mental/emotional demands of the work (WAI-3). QWLQ is a 23-item questionnaire focusing on five subscales: (i) Meaning of work; (ii) Perception of the work situation; (iii) Atmosphere in the working environment; (iv) Understanding and recognition in the organization; and (v) Problems due to the health situation, which are scored on a 6-point Likert scale. Higher scores correspond with better QWL, ranging 0-100. 12 These subscales are considered to capture the complete scope of QWL and were based on literature and focus group discussions. 12 In cancer survivors, improvement of more than 3.9 of the QWLQ total score after an intervention is considered clinically meaningful. 13 For the WAI, the clinically meaningful change in score is unknown.
When more than 15% of patients achieve the lowest or highest possible score on the QWLQ or its subscales, this is considered a floor or ceiling effect. 25,26

| Statistical analyses
Patient characteristics and scores were summarized using descriptive statistics and paired t-tests as appropriate. A linear mixedeffects model, with patients as random effect, was used to model Patients with missing data on QWLQ at baseline or 48 weeks were excluded in these analyses.

Convergent validity is assessed by means of hypothesis test-
ing: determining whether scores of an instrument correlate with other instruments in a way that one would expect. 28 Hypothesis testing is part of investigating construct validity, as proposed by the COSMIN taxonomy of measurement properties. 29 Our hypothesis was that a correlation (r) > |0.40| exists for EQ-5D-5L health score, POEM, DLQI, PGA, NRS pruritus, VAS pain, and sleep loss, indicating moderate-to-strong correlations (|0.20|-|0.39|: weak; |0.40|-|0.59|: moderate; |0.60|-|0.79|: strong). 25 Spearman correlations were used to assess the correlation between QWLQ total score, subscale "Problems due to the health situation" and these constructs.
Analyses were performed using SPSS 25.0 (IBM) and R version 4.0.2 (Foundation For Statistical Computing). In all analyses, results were considered statistically significant at p < 0.05.

| RE SULTS
This study included 93 patients with baseline characteristics shown in Table 1. The majority of patients was male (58%) and white (76%).

| Quality of working life
Quality of Working Life Questionnaire scores are shown in Figure 2.
The subscale "Problems due to health situation" was found to have the lowest mean of 37.4 ± 22.3, showing an increase followed by a slight decrease over time. The subscale with the highest baseline score was "Meaning of work" with a mean score of 85.2 ± 13.3, which remained stable over time. The subscale "Understanding and recognition in the organization" showed a decrease from a baseline score of 78.9 ± 14.9. Both the subscale "Perception of the work situation" and "Atmosphere in the working environment" showed a decrease in mean score from baseline (81.3 ± 12.9 and 82.3 ± 11.5, respectively), followed by an increase. The mean QWLQ total score was 74.0 ± 9.1 at baseline, 78.5 ± 9.8 at 24 weeks, 77.5 ± 9.6 at 48 weeks, 72.9 ± 13.1 at 72 weeks, and 76.4 ± 13.2 at 96 weeks. When comparing the means at baseline with 48 weeks, we only found significant improvement for total score and subscale "Problems due to the health situation" (4.1 points with p = 0.032 and 23.3 points with p < 0.001, respectively). Work-related characteristics 3.3 | Characteristics associated with change in QWLQ from baseline to 48 weeks Table 2 shows the baseline characteristics significantly associated with change in score from baseline to 48 weeks (complete results shown in Table S1). We found that females reported more improve- Other h 4 (6) Patients that reported days lost from usual activities (e.g., work, study), n (%) i 54 (58) Average number of days lost from usual activities per month, median (IQR) 5j 4 (1-7)

TA B L E 1 Patient characteristics at baseline
Working patients that reported days lost from usual activities, n (%) k 43 (60) Average number of days lost from usual activities per month in working patients, median (IQR) 6 3.5 (1)(2)(3)(4)(5) Not working patients that reported days lost from usual activities, n (%) l 11 (52) Average number of days lost from usual activities per month in not working patients, median (IQR) 7

Retired 6 (29)
Incapacitated for work because of experienced limitations due to atopic dermatitis 3 (14) Incapacitated for work because of other reasons 3 (14) Incapacitated for work because of a combination of atopic dermatitis and other reasons 1 (5)
Abbreviations: IQR, interquartile range; SD, standard deviation. a Creole and Dutch (n = 1), Chinese and Creole (n = 1), Indonesian and Dutch (n = 2). b Physician diagnosis. c Positive patch test: remaining patients were never tested, unknown or tested negative.

| QWLQ convergent validity
Spearman correlations for the total QWLQ are shown in Table 3, with corresponding scatter plots in Figure S1A and S1B. For all PROMs, no correlations were found (p>0.05) and correlation coefficients did not exceed |0.40|. Only a borderline significant weak correlation was found for DLQI (r = −0.24, p = 0.058). Table 4 shows Spearman correlations of QWLQ subscale 5 "Problems due to the health situation" (scatter plots: Figure S2A and S2B). We found a moderate positive correlation for EQ-5D-5L health state (r = 0.43, p < 0.001) and a strong negative correlation for DLQI (r = −0.65, p < 0.001). In addition, weak negative correlations were found for VAS peak pain and mean sleep loss (r = −0.26, p = 0.035 and r = −0.28, p = 0.023, respectively).

| Floor and ceiling effects
There were no patients in whom the lowest possible QWLQ total score (0) was observed. The highest possible QWLQ total score was found once in one patient (1/201 observations). A ceiling effect was observed only for subscale "Meaning of work" where in 41 out of 201 observations (20%) the highest score (100) was observed. Days lost from usual activities −13.0 ± 6.0 0.060 a Notes: The reference standard was characteristic "not present" or "White" in case of "Asian", "Male" in case of "Female", "Unknown" in case of patch test/contact dermatitis, and "ISCED 0-1" in all ISCED variables.
Abbreviation: SE, standard error. a Borderline significant. Results are based on our multivariate models.

TA B L E 2
Characteristics significantly associated with change in Quality of Working Life Questionnaire (QWLQ) (sub)scores from baseline to 48 weeks of follow-up

| DISCUSS ION
In this study we analyzed work-related patient characteristics of 93 AD patients treated with dupilumab in daily practice. We primarily aimed to describe the longitudinal work ability and QWL of this population. Our patients reported a decreased work ability and QWL at baseline, mainly due to health-related problems. Significant improvement of work ability and QWL was observed with treatment after 48 weeks. Furthermore, we assessed associations between patient characteristics and change in QWLQ and the convergent validity of the QWLQ.
The majority of working patients reported problems at work. In most cases, a combination of problems was reported, including pruritus, fatigue, pain, and psychological complaints. In earlier research, fatigue was found the main reason for work productivity loss in inflammatory bowel disease (IBD). 30 In half of the employed IBD population, disease activity and disease burden was found to cause work productivity loss, driving indirect costs. 30 It has been shown that the majority of moderate-to-severe AD patients miss at least 1 day of work per year. 31 We found that more than half of our working patients reported days lost from usual activities (3.5 median days/month), indicating potential work productivity loss. Another study in AD patients showed a mean of 9.6-19 h/week work productivity loss. 32 Regarding WAI, we found a decreased mean general work ability of 6.8 (0-10) and a mean physical and mental/emotional work ability of 3.7 and 3.4 (1-5) at baseline, respectively, with significant improvement at 48 weeks. In other studies, a mean general work ability of 5.1 was found in cancer survivors and of 5.4 in cancer patients at the time of diagnosis. 33,34 In contrast, a mean general work ability ranging 7.8-8.2 was found in nurses. 35 In other chronic diseases, common prognostic factors for work disability were health complaints, limitation in daily physical activities caused by the disease, heavy manual work, and female sex. 36 At baseline, we observed a mean QWLQ total score of 74.0, together with a mean score of 37.4 for subscale 5 "Problems due to the health situation". In cancer survivors, a mean QWLQ total score of 75 and subscale 5 of 57 has been demonstrated, in contrast to a mean QWLQ total score of 79 and subscale 5 of 81 in employed people without cancer. 12 In IBD patients, a mean QWLQ total score of 78 and subscale 5 of 54 was found. 37 The results for the other subscales were similar between our AD, and cancer survivor and IBD populations. 12,37 The remarkably lower score for subscale 5 in our population shows that patients with AD experience a relatively high QWL burden regarding their health situation. The overall decrease in QWL is shown to be mainly driven by this subscale. We found significant and clinically meaningful improvement of the scores at 48 weeks. 13 Greater improvement was observed in females compared to males. tional nature of the study. We did not focus on strict label use of dupilumab, and patients that used comedication or continued treatment in an alternative dosing schedule due to ineffectiveness or side-effects were included in our analyses.

| Implications for research and clinical practice
Further investigation of work ability and QWL using WAI and QWLQ in a larger population and comparing different treatments would be of interest. In the future, QWLQ could be used at a group level as effect measurement of interventions in research, as well as on individual patient level to monitor different aspects of QWL and to intervene with supportive care if appropriate. The latter strategy may facilitate to identify patients that benefit from tailored interventions. A need exists for development of programs that can support this demand. Furthermore, investigating the impact on work productivity specifically can contribute to determining the cost-effectiveness of treatments.

| Conclusion
In conclusion, the majority of AD patients starting with dupilumab, indicating moderate-to-severe disease, experience days lost from work and other usual activities, demonstrating potential work productivity loss. Most working patients report problems at work, often a combination of pruritus, fatigue, pain, and psychological complaints. Patients report a decreased work ability and experience a high burden regarding QWL, in particular due to health-related problems. There seems to be significant improvement of work ability and QWL with dupilumab treatment over time.