## 4 Discussion
Sleep disturbance has been previously associated with worse HRQoL (EQ-5D) [19], while a positive correlation between pain intensity and DLQI is supported by RW US research [24; 25] and M2S-AD international clinical trials [26; 27]. The above results support the conclusion that M2S-AD patients are burdened by severe pruritus, sleep disturbance, and pain, which affect their QoL; hence, addressing these is an important patient-reported treatment goal [59] and a persistent challenge in AD management. Moreover, APOLO highlighted the impact on productivity. 'Work productivity loss' and 'activity impairment' scores in APOLO were worse than those in non-AD European patients (23.5 and 27.9%, respectively) [53]. APOLO scores were within the range of European RW evidence in the literature for M2S-AD (mean: 20.2-33.1% and 25.4-37.7%) [18; 53] but slightly better than for M2S-AD patients in the Greek study (mean: 31.2-48.5% and 30.6-39.3%) [17]. Interestingly, emerging data suggest that pruritus severity is associated with sleep disturbance, which in turn is associated with work productivity [60]. Most patients (82%) in APOLO were receiving TCIs and/or TCSs, while a considerable proportion received AD-specific ST (39%), mainly systemic steroids and classical immunosuppressive. The absence of targeted small molecules like (JAKis) and the low utilization of biologics likely reflects the limited period of availability and reimbursement status of these agents in Greece at the time of data collection. This is also supported by the doubling in prescription rates of biologics post-study (14% versus past/current rate of 7%). These data may serve as a benchmark for the future uptake of newly approved therapies, including injectable biologics and oral JAKis, which have shown important improvements in QoL, anxiety/depression, and sleep disturbance in M2S-AD patients [27; 61; 62; 63; 64; 65]. With regard to selection of systemic treatment, our study offers insights on specific comorbidities that may affect the selection of JAK inhibitors, such as history of venous thromboembolism or cancer. Lastly, despite the growing body of evidence on HCRU in Europe [2], Greek data are scarce [4; 17]. Considering the intercountry differences in healthcare accessibility, local data remain necessary to capture the impact of AD in specific healthcare settings. APOLO provides insights into the patient journey before resorting to expert centers, given that the participants were suffering from AD symptoms for a median of 12 years before the study visit. In the last year, 91% of patients had performed a mean of 6.2 AD-related HCP visits (excluding pharmacists), higher than the 2.6-2.9 range reported for the last year in the Greek study [17]. This difference may be partly attributed to the fact that the APOLO population comprised physician-diagnosed AD patients, in contrast to the self-reported AD population of the Greek study [4; 17]. Although s-AD patients had higher rates of hospitalization and ER visits (10% and 38% versus 4% and 22% in m-AD), both m-AD and s-AD patients attended a similar number of HCP visits and hospital/specialized center consultations in the last year, demonstrating the high HCRU by m-AD patients as well. Altogether, the above findings join the published literature showing a significant humanistic burden among M2S-AD patients. The comparisons described above should be cautiously interpreted. The differences in study designs (telephone or web-based surveys [15; 17; 19; 28; 53]), AD severity rating methods (Patient-Oriented SCORing Atopic Dermatitis/PO-SCORAD-based [15]; POEM-based [17]; physician-reported [18]; DLQI-based [19]; self-reported [28; 53]), distribution between moderate and severe cases (m-ADproportion: 75% [15]; 78-84% [18]; 59% [19]; 79% [28]; 87% [53]; not available [17]), and healthcare settings (referral expert centers versus physician practices) should be considered. The limitations of this study include selection bias, confounding, and information/ misclassification bias.