Impact on health‐related quality of life and symptoms of anxiety and depression after 32 weeks of Dupilumab treatment for moderate‐to‐severe atopic dermatitis

Abstract Dupilumab is the first biological agent approved for treatment of moderate‐to‐severe atopic dermatitis (AD). Evidence of Dupilumab effectiveness on psychological outcomes beyond 16 weeks of treatment from real‐life settings is lacking. To evaluate the effectiveness of Dupilumab treatment up to 32 weeks, focusing health‐related quality of life and psychological outcome of patients with moderate‐to‐severe AD. An observational prospective cohort study was conducted in a real‐life setting at an Italian tertiary centre. Assessment of outcome measures was carried out at baseline, after 16 and 32 weeks of treatment. A total of 171 patients were included. EASI‐75 and EASI‐90 were achieved in 85% and 60% of the participants, respectively, after 16 weeks, and in 89.6% and 69.8% after 32 weeks of treatment. Significant improvements (p < 0.001; r = 0.57–0.95) were found after 16 weeks for each outcome considered, including clinician and patient‐reported measures of AD severity and scales of health‐related quality of life and psychological morbidity, and maintained up to 32 weeks. Further analysis revealed that patients' quality of life was more associated with the subjective perception of disease severity rather than objective measures and suggested a possible different response to treatment based on the age of AD onset. Dupilumab was confirmed to be rapid, effective and safe in patients with moderate‐to‐severe AD. Its positive impact on psychological outcomes up to 32 weeks was ascertained here, adding new evidence on the need to consider subjective factors affecting patients' perception of disease severity in evaluating the response to treatment.


| INTRODUCTION
Atopic dermatitis (AD) is a common and chronic immune-mediated inflammatory skin disease characterized by erythematous and eczematous lesions with intense pruritus, affecting 7-10% of adults. 1 AD is associated with debilitating effects on health-related quality of life including pain, sleep disturbances, and psychological morbidity. 2,3 Systemic treatment for moderate-to-severe AD was limited because of the risk/ benefit ratio associated, and a need for safe and effective solutions for those patients who did not respond to topic medications or immunosuppressants was present. 4,5 A significant change has occurred when a fully human monoclonal antibody Dupilumab was approved by US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients with moderate-to-severe AD nonresponsive to cyclosporine or other treatments. 6 Dupilumab targets the interleukin (IL-4) receptor-alpha (IL-4Rα) subunit and inhibits signaling of cytokines IL-4 and IL-13, both driving at least Type 2 inflammation including AD. 7 The effectiveness and safety of Dupilumab were evaluated in placebo-controlled Phase 3 clinical trials in adults with moderateto-severe AD inadequately controlled with topical treatment or intolerant to immunosuppressants or corticosteroids. [8][9][10][11] Results from these clinical trials were robust and consistent in showing that, compared with a placebo, Dupilumab significantly improves objective signs of AD, symptoms related including pruritus, pain, sleep disturbance, anxiety and depression, and multiple areas of patients' healthrelated quality of life.
Despite this evidence, findings resulting from real-life experience reflecting actual conditions encountered in daily practice are limited to date, especially beyond 16 weeks of treatment. This study was precisely conducted to obtain further insight into the effectiveness of long-term Dupilumab treatment and its impact on health-related quality of life and psychological outcome of moderate-to-severe AD patients.

| Participants and procedures
Prospectively collected data from a tertiary referral centre for AD in northern Italy (Dermatology Clinic of the University of Turin) was analyzed in this study. Consecutive patients more than 18 years old with a clinical or histological diagnosis of AD were enrolled between January and September 2019. Patients received Dupilumab for moderate-to-severe AD (EASI ≥ 24 or less in cases with eczema in sensitive areas) due to cyclosporine inefficiency, loss of efficiency, or contraindication.
This study was approved by the local ethical committee of the Turin University Hospital (No. CS2/1359).

| Measures
Extent and severity of AD were evaluated by dermatologists through the Eczema Area and Severity Index (EASI) 12  severe. 14 Improvements of 75% (EASI-75) and 90% (EASI-90) in EASI score from baseline were considered as parameters for minimal clinically important difference (MCID). 15 SCORAD score ranged from 0 to 103, with higher scores indicating more severe AD. A reduction of 8.2 points from baseline score was considered as MCID for SCORAD index. 15 Patients self-reported AD symptoms through the Patient-Reported Eczema Measure (POEM) 16 (scores ranged from 0 to 28) and Numerical Rating Scales (0-10) for pruritus (Itch-NRS) and sleep disorders (Sleep-NRS). A reduction of 3.4 points from baseline score was considered as MCID for POEM. 15

| Statistical analyses
Data were analyzed with SPSS software v. 25.0 for Mac (IBM, Armonk, New York). Two-sided p-value < 0.05 was considered statistically significant.General descriptive statistics were calculated to synthetize data exposition; median and interquartile ranges were used for non-normally distributed variables. One-way repeated measure analyses of variance (ANOVA) with the Bonferroni post hoc test to take account of pairwise comparisons were run to estimate changes in outcomes variables throughout assessment points (i.e., baseline, after 4 months, and after 8 months). The Friedman test was used as nonparametric alternative and Wilcoxon signed-rank tests were run for pairwise comparisons. Effect-size estimate r was calculated to standardize the size of the effects observed. Multiple linear regressions were run to study the effect of outcome variables on a DLQI score at baseline and after 16 weeks; semi-partial correlation coefficients were calculated to estimate the amount of the variance in DLQI accounted by each independent outcome variable individually. Two-way and three-way mixed ANOVAs were performed to determine differences between independent groups (formed by demographic characteristics, clinical features, and combinations of these) in changes of outcome variables over time (baseline>T1). Follow-up tests were performed to explore main effects.

| Descriptive analysis
The sample considered included 171 participants, 91 (53.2%) males and 80 (46.8%) females, with a mean age of 39.3 ± 16.2. Detailed sample characteristics are reported in Table 1

| Longitudinal analysis
Results of one-way repeated measures ANOVAs and Friedman tests are reported in Table 2

| Regression analysis
The model performed with outcome scores at baseline was statisti-    Adjusting for other independent variables, POEM, Itch-NRS and HADS-A singly accounted for 2.5%, 5.2%, and 2.3% of the variance in DLQI, respectively. A more detailed summary of regression analysis is presented in Table 3.

| Mixed-design analysis
Two-way mixed ANOVA revealed a significant two-way interaction between time (baseline > T1) and age of AD onset on SF36 Physical Health summary measure (F = 3.407, p = 0.020, partial η 2 = 0.091) controlling for EASI score. There was a significant difference in physical health between different ages of AD onset after 16 weeks of treatment (F = 3.169, p = 0.027, partial η 2 = 0.081). Physical health was significantly lower in the ≥31 age group compared to the other categories of age of AD onset (p = 0.025).
Three-way mixed ANOVA revealed significant three-way interactions among time (baseline > T1), sex, and age of AD onset on SF36 Mental Health summary measure (F = 2.729, p = 0.044, partial η 2 = 0.077) controlling for EASI score. There was a significant two-way interaction between sex and age of AD onset after 16 weeks of treatment (F = 3.553, p = 0.017, partial η 2 = 0.093). Significant simple main effect of age of AD onset at T1 was observed for females (F = 3.724, p = 0.014, partial η 2 = 0.097). Mental health was lower in females with age of AD onset ≥31 compared to those with age of AD onset < 18 (p = 0.015) and within the first year of age (p = 0.027).

| DISCUSSION
This study showed that Dupilumab treatment of moderate-to-severe  Only three participants (1.7%) in this study did not report any improvement in AD signs and symptoms, less than reported in previous multicentre real-life studies. 25,29 Single-centre studies like this typically ensure greater treatment uniformity and adherence and this should be kept in mind when weighing up the result.
In line with the literature, we reported that blepharitis with or without mild conjunctivitis was the most frequent AE related to Dupilumab treatment, being reported indeed by 19 participants, with only 4 of whom discontinued the therapy due to this AE. These data are lower than that reported in other real-life studies, [24][25][26] higher than reported in a study conducted in Korea, 27 and very similar to previous Italian studies. [21][22][23]28 Dupilumab-induced conjunctivitis seemed to be specific to AD, since it was not reported in clinical trials with other The study of between-group differences across changes in outcome variables from baseline to 16 weeks of treatment suggested that, controlling for changes in EASI scores, the improvement in physical health was lower in patients with AD onset in adulthood (i.e., ≥31 years old) and that the improvement in mental health was lower in females with AD onset in adulthood. The nonsignificant interaction of EASI scores seemed to exclude that these sub-populations were Dupilumab nonresponders. The absence of comparable data in the literature does not allow to argue further these observations. Future investigations will eventually confirm these findings and provide possible explanations.
The main strengths of this real-life study are that the participants were not selected and represented a large sample of the total Italian AD population treated with Dupilumab, to date. Moreover, this study added expected evidences about consolidation beyond 4 months of well-documented rapid improvements in clinician-and patientreported measures in patients with moderate-to-severe AD treated with this drug. The main limitation of this study is the absence of control group and/or comparisons with other systemic therapies.

| CONCLUSION
This study has shown that Dupilumab treatment in a routine clinical setting can lead to rapid and significant improvement in signs and