## 4 Discussion  
The APOLO study generated novel real-world (RW) evidence on the burden, treatments patterns, and patient journey of physician-diagnosed M2S-AD. Our results confirm the high burden of both moderate and severe AD on dermatology-specific and generic QoL. AD had at least a moderate effect on QoL based on DLQI in 81% of patients, similar to the 72-84% reported by [PERSON] et al. (2022; referred hereinafter as the Greek study), which reported a similar mean DLQI score (10.1) [17]. This rate was higher than the proportion reported for the EU5 study pooled data (40%) [53]. Notably, the effect of AD was very large in more than 80% of s-AD patients in APOLO. The DLQI scores of m-AD and s-AD were consistent with other European countries (mean: 6.0-10.0 [15; 18] and 12.0-18.9 [18; 28] respectively). In APOLO, EASI and DLQI scores were weakly correlated (rho: 0.25), similarly to the pooled baseline results of duplumab phase 3 trials among M2S-AD patients (rho: 0.29) [54]. However, regression analysis adjusted for baseline factors demonstrated that increased AD severity is associated with a declining QoL, like in other RW studies [15; 17; 55]. Patients with AD suffer from eczema, the presence of which has been associated with an increased risk of depression and anxiety [56], both impacting an individual's HRQoL. The EQ-5D-3L utility index and EQ-VAS findings in APOLO indicate that M2S-AD patients have a lower HRQoL compared with the general Greek population (scores of 0.81 and 74.7, respectively) [43]. A significant proportion of M2S-AD patients reported anxiety/depression (65%), and pain/discomfort (64%), which were equally high in both m-AD and s-AD subpopulations, unlike the respective general Greek norms of 45% and 28% [43]. Regarding the signs and symptoms of AD, a combination of which is necessary for AD severity characterization, multiple outcome measures were utilized in APOLO. In this study, POEM-based moderate eczema severity was more frequently reported than previously reported for M2S-AD in other European countries (\(\sim\)70%) [28]. Consistently, POEM scores were higher than those reported in two M2S-AD RW studies (mean: 10.6-13.1 for overall M2S-AD [18]; 8.8-12.7 for m-AD [15; 18]; 12.2-18.4 for s-AD [18]). APOLO's results indicated that pain intensity was similar to baseline intensity in M2S-AD clinical trials (mean scores: 5.8-6.6 [26]) but higher than that of general AD (any severity) as measured in a US skin-pain NRS validation study (median score: 2.0) [57]. The majority of APOLO patients (80%) experienced pain over the past week, indicating it is a key symptom. Daily pain was reported by 30%, with similar rates between m-AD and s-AD, highlighting that even m-AD patients experience pain frequently. Figure 5: Diagnostic tests performed for AD in the past and/or ordered by the specialized centers at the study visit in the overall M2S-AD population and by EASI-based AD severity. Numbers on top of the bars indicate percentage (%). AD, atopic dermatitis; EASI, Eczema Area and Severity Index; M2S, moderate-to-severe; m-AD, moderate AD; N, number of patients with available data; s-AD, severe/very severe AD. Nearly two-thirds of APOLO patients experienced severe pruritus (PP-NRS \(\geq\) 7; 62%) and daily itching (POEM score 4; 63%), including the majority of m-AD patients. Of note, 40% of m-AD patients were classified as severe (score > 16) per POEM. Furthermore, 96% of patients experienced a median of 3.0 flare-ups in the last year. The mean PP-NRS in APOLO was consistent with that of general AD (any severity) across European countries in a pruritus intensity scale validation study (mean: 6.7) [58] and with baseline levels in M2S-AD clinical trials (mean: 6.5-7.2) [26]. Notably, more APOLO patients experienced sleep disturbance compared with other European studies (54-69%) [17; 19; 53]. Self-reported PP-NRS, pain intensity, and sleep disturbance were positively correlated and significantly associated with DLQI in APOLO.