DOI: 10.1111/jdv.16003 JEADV ORIGINAL ARTICLE The patient-reported disease burden in adults with atopic dermatitis: a cross-sectional study in Europe and Canada M. de Bruin-Weller,1 A. Gadkari,2 S. Auziere,3 E.L. Simpson,4 L. Puig,5 S. Barbarot,6 G. Girolomoni,7 K. Papp,8 A.E. Pink,9 G. Saba,3 T. Werfel,10 L. Eckert11,* 1 University Medical Center Utrecht, Utrecht, The Netherlands 2 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA 3 Kantar – Health Division, Paris, France 4 Oregon Health and Science University, Portland, OR, USA 5 noma de Barcelona, Barcelona, Spain Hospital de la Santa Creu i Sant Pau, Universitat Auto 6 Centre Hospitalier Universitaire de Nantes, Nantes, France 7 Universita di Verona, Verona, Italy 8 Probity Medical Research, Waterloo, ON, Canada 9 St. John’s Institute of Dermatology, Guy’s and St. Thomas’ NHS Foundation Trust and Kings College London, London, UK 10 Hannover Medical University, Hannover, Germany 11 Sanofi, Chilly-Mazarin, France *Correspondence: L. Eckert. E-mail: Laurent.Eckert@sanofi.com Abstract Background Cross-sectional data on patient burden in adults with atopic dermatitis (AD) from real-world clinical prac- tice are limited. Objective This study compared patient-reported burden associated with adult AD across severity levels from clinical practices in Canada and Europe. Methods This study included adults (18–65 years) diagnosed with AD by dermatologists, general practitioners or aller- gists. Participants categorized as mild (n = 547; 37.3%), moderate (n = 520; 35.4%) or severe (n = 400; 27.3%) based on Investigator’s Global Assessment completed a questionnaire that included pruritus and pain numerical rating scales, Patient-Oriented-Scoring of Atopic Dermatitis (PO-SCORAD) itch and sleep visual analogue scales, Dermatology Life Quality Index (DLQI), and the Hospital Anxiety and Depression Scale (HADS). Participants were also stratified by inade- quate efficacy/intolerance/contraindication to cyclosporine [Cyclo; n = 62 (4 mild, 18 moderate, 40 severe)] and any sys- temic immunomodulatory agent [IMM; n = 104 (13 mild, 31 moderate, 60 severe)] and compared with the severe group excluding participants identified as Cyclo/IMM. Results Age was similar across severity groups; the proportion of women was higher in the mild group relative to sev- ere (61.2% vs. 50.5%; P < 0.001). Compared with moderate and mild, participants with severe AD had more comorbidi- ties, higher itch and pain severity, worse sleep and higher levels of anxiety and depression (all P < 0.001). Mean  SD DLQI score among participants with severe AD (16.2  6.9) showed a large effect on quality of life that was higher than those with moderate (10.2  6.3) and mild (5.5  4.9) (both P < 0.001). The burden among Cyclo and IMM subgroups was generally similar to that of participants with severe AD. Conclusions Adults with AD reported a substantial burden across multiple domains that was significantly higher in those with severe disease. The burden among participants in the Cyclo/IMM subgroups was similar to those with severe AD. Received: 27 March 2019; Accepted: 20 September 2019. Conflicts of interest S. Barbarot has received honoraria for invited talks or scientific advice; research grants from Pierre Fabre Laboratory, Fondation pour la dermatite atopique, Bioderma, Sanofi-Genzyme, Novalac, AbbVie, Novartis, Janssen and Celgene; and non-financial support from AbbVie, Novartis and Janssen. A. Gadkari is an employee of and stockholder in Regeneron Pharmaceuticals, Inc. S. Auziere and G. Saba are employees of Kantar Health Division, who received funding from Sanofi to conduct the study. M. de Bruin-Weller is a consultant for Regeneron Pharmaceuticals, Inc., Sanofi Genzyme; an advisory board member for AbbVie, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, Pfizer, UCB, Eli Lilly; and principal investigator for AbbVie, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, Pfizer. A. Pink has given talks or consulted for Sanofi, Novartis, Almirall, JEADV 2020, 34, 1026–1036 © 2019 Sanofi. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Patient-reported burden of atopic dermatitis 1027 Leo Pharma, Eli Lilly, AbbVie and La Roche Posay. G. Girolomoni has been principal investigator in clinical trials sponsored by and/or and has received personal fees from AbbVie, Abiogen, Almirall, Amgen, Bayer, Biogen, Celgene, Eli Lilly, Galderma, Hospira, Janssen, Leo Pharma, Merck, MSD, Mundipharma, Novartis, Pfizer, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Samsung, Sandoz, Sanofi and Sun Pharma. Kim Papp reports grants and personal fees from AbbVie, Amgen, Anacor, Baxalta, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermira, Dow Pharma, Galderma, Janssen, Kyowa Hakko Kirin, Leo Pharma, Merck (MSD), Merck Serono, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Sanofi, Takeda, UCB and Valeant, and personal fees from Akros, AstraZeneca, Baxter, Cipher, Eli Lilly, Forward Pharma, Meiji Seika Pharma, Mitsubishi Pharma and Mylan. L. Puig has received consultancy honoraria from and participated in clinical trials sponsored by Regeneron Pharmaceuticals, Inc. and Sanofi. T. Werfel has received honoraria for invited talks or scientific advice and research grants from AbbVie, Allmiral, ALK Scherax, Astellas, Janssen/JNJ, Leo, Eli Lilly, Meda, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc./Sanofi, Roche, Stallergen, Takeda and Ziarco. E.L. Simpson has received grant/research support from AbbVie, Eli Lilly Co., Galderma, Kyowa Hakko Kirin, Leo Pharmaceutical Co., Merck, Pfizer, Regeneron Pharmaceuticals, Inc. and a consulting fee from AbbVie Inc., Boehringer-Ingelheim, Dermavant, Eli Lilly, Forte Bio, Incyte, Leo Pharmaceutical Co., Menlo Therapeutics, Pfizer, Pierre Fabre Dermo Cosmetique, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme and Valeant. L. Eckert is an employee of and stockholder in Sanofi. Funding source This study was funded by Regeneron Pharmaceuticals, Inc. and Sanofi. Introduction in Canada, France, Germany, Italy, Spain and the United King- Atopic dermatitis (AD) is a chronic, often relapsing inflamma- dom. Investigators were eligible if they personally initiate medi- tory skin disease with a pathology characterized by skin barrier cal treatment for adult patients with AD and managed and dysfunction and immune dysregulation1; clinical presentation treated a minimum number of these patients over the past includes pruritus (itch), xerosis (abnormally dry skin) and month (≥10 for dermatologists, of which a minimum of 3 were eczematous lesions. The presence of comorbid conditions and moderate or severe, and ≥5 for general practitioners and aller- serum biomarkers supports AD as a systemic, inflammatory dis- gists). Patient participants were required to provide written order.2–4 informed consent prior to participation. The study was For many patients, AD is a lifelong condition, and for all approved at country level by the appropriate ethics committees. patients, it is associated with substantial effects on their daily The study population consisted of adults (18–65 years, inclu- lives. These effects, which appear to increase with greater AD sive) diagnosed with AD by dermatologists (all countries), gen- severity, include persistent itch, sleep disturbances, impaired eral practitioners (France and the United Kingdom) or allergists mental health, reductions in function, productivity and health- (France). Participants were excluded if they participated in any related quality of life (HRQoL), and an impact on life randomized controlled trial for treatment of AD within the past decisions.5–9 Despite characterization of the multidimensional 12 months. Participants were stratified by AD severity as mild, burden, cross-sectional data on the patient-reported burden in moderate or severe based on the Investigator’s Global Assess- adults with AD from real-world clinical practice are limited. ment (IGA). Investigators were requested to evenly include Given the need for real-world data, this study compared the patients across severity levels during enrolment to enable suffi- patient-reported burden associated with adult AD across severity cient sample sizes, as severe AD has the lowest prevalence among levels from clinical practices in Canada and Europe. The burden severity levels regardless of method of severity assessment.10 To was also characterized in a subpopulation of participants in further characterize the burden among those who may be con- whom cyclosporine and other systemic IMM agents do not rep- sidered more difficult to treat in a real-world clinical setting, resent adequate therapeutic options. participants were additionally stratified based on investigator opinion of whether they previously demonstrated inadequate Methods efficacy for or had contraindications or intolerance to systemic immunomodulatory agents (subpopulation abbreviated as Study design and populations IMM, which included methotrexate, azathioprine, cyclosporine This was an international, cross-sectional, observational study of and mycophenolate mofetil). This stratification was regardless of adults with AD seen by investigators in routine clinical practice their AD severity, that is using a population-level approach. As JEADV 2020, 34, 1026–1036 © 2019 Sanofi. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. 1028 de Bruin-Weller et al. Table 1 Demographic and clinical characteristics Variable Value Total population Mild Moderate Severe Number of participants (%) 547 (37.3) 520 (35.4) 400 (27.3) Women, n (%) 335 (61.2)* 274 (52.7) 202 (50.5) Age, years, mean (SD) 38.2 (13.2) 38.0 (12.8) 38.4 (12.8) Age at diagnosis, n (%) <2 years 66 (12.1)* 85 (16.3)† 86 (21.5) 2–4 years 49 (9.0)† 58 (11.2) 58 (14.5) 5–8 years 52 (9.5)† 40 (7.7) 24 (6.0) 9–12 years 38 (6.9) 34 (6.5) 24 (6.0) 13–18 years 44 (8.0) 40 (7.7) 30 (7.5) >18 years 290 (53.0)* 252 (48.5)† 166 (41.5) Missing 8 (1.5) 11 (2.1) 12 (3.0) SCORAD score, mean (SD) 29.2 (14.6)* 49.2 (16.0)* 68.4 (14.9) EASI score, mean (SD) 2.6 (3.6)* 9.5 (8.0)* 22.7 (13.9) Variable Value Subpopulations Cyclo Severe excluding Cyclo IMM Severe excluding IMM (n = 62) (n = 360) (n = 104) (n = 340) Women, n (%) 23 (37.1)‡ 187 (51.9) 43 (41.3) 175 (51.5) Age, years, mean (SD) 40.6 (12.6) 38.1 (12.7) 40.6 (13.4) 38.0 (12.6) Age at diagnosis, n (%) <2 years 21 (33.9) 73 (20.3) 35 (33.7)‡ 65 (19.1) 2–4 years 13 (21.0) 49 (13.6) 22 (21.2)‡ 44 (12.9) 5–8 years 3 (4.8) 23 (6.4) 5 (4.8) 22 (6.5) 9–12 years 3 (4.8) 21 (5.8) 6 (5.8) 21 (6.2) 13–18 years 0 30 (8.3) 1 (1.0)‡ 29 (8.5) >18 years 21 (33.9) 153 (42.5) 34 (32.7) 148 (43.5) SCORAD score, mean (SD) 60.1 (17.2)§ 68.7 (15.0) 60.6 (17.1)§ 68.7 (14.9) EASI score, mean (SD) 19.4 (13.4) 22.5 (14.0) 18.0 (13.2)‡ 22.5 (14.0) *P < 0.001 and †P ≤ 0.05 vs. IGA severe; ‡P < 0.05 and §P < 0.001 for Cyclo or IMM groups vs. severe groups excluding Cyclo/IMM participants, respec- tively. Cyclo, participants with inadequate efficacy for or contraindications or intolerance to cyclosporine; EASI, Eczema Area and Severity Index; IGA, Investigator’s Global Assessment; IMM, participants with inadequate efficacy for or contraindications or intolerance to any systemic immunomodulatory agent (including Cyclo participants); SCORAD, Scoring of Atopic Dermatitis; SD, standard deviation. cyclosporine is the only approved systemic immunomodulatory pen-and-paper questionnaire that consisted of translations in therapy, a separate subpopulation was created consisting only of their native language of validated measures and stand-alone study participants who had previously demonstrated inadequate questions that assessed diverse domains affected by AD. The efficacy for or had contraindications or intolerance to cyclospor- Pruritus Numerical Rating Scale (NRS; 0 = no itch to ine (subpopulation abbreviated Cyclo). Neither participants 10 = worst itch imaginable)14 measured average overall itch who had refused any systemic treatment nor those who were within the past 24 h and the Patient-Oriented SCORAD (PO- treated with systemic corticosteroids were included in these sub- SCORAD) visual analogue scale (VAS; 0 = no itching, populations, as systemic corticosteroids are not recommended 10 = unbearable itching)15 assessed itch intensity over the past for chronic administration.11 3 days. Worst pain within the past 24 h was evaluated using a pain NRS (0 = no pain, 10 = worst imaginable pain). Sleep Outcomes quantity and quality were assessed using the PO-SCORAD The presence of atopic and non-atopic comorbidities was sleep VAS (0 = no trouble sleeping to 10 = unable to sleep abstracted from the medical records of the study participants over the past 3 days).15 As stand-alone questions, item 2 from by the investigator. Two clinical measures were included, the the Patient-Oriented Eczema Measure (POEM) was used to Eczema Area and Severity Index (EASI)12 and the Scoring of determine the frequency of sleep disturbances over the past Atopic Dermatitis (SCORAD) scale.13 Participants completed a week,16 and question 4 modified from the Pittsburgh Sleep JEADV 2020, 34, 1026–1036 © 2019 Sanofi. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. Patient-reported burden of atopic dermatitis 1029 Quality Index17 was used to determine the number of hours with mild (12.1%; P < 0.001) and moderate AD, (16.3%; of sleep per night over the past week. P < 0.05), and conversely, lower proportions of participants The Hospital Anxiety and Depression Scale (HADS)18 evalu- with severe AD were diagnosed as adults (Table 1). ated mental health based on two subscales with score ranges of Eczema Area and Severity Index and SCORAD scores 0–21 that determine the extent of anxiety and depression; scores increased with greater AD severity; participants with severe dis- ≥8 indicate the presence of anxiety or depression symptoms and ease had significantly higher scores than those with mild and scores ≥11 are suggestive of clinical anxiety or depression. The moderate AD (all P < 0.001; Table 1). Dermatology Life Quality Index (DLQI)19 assessed the impact of In the subpopulations compared with those who had severe AD on HRQoL over the past week (score range 0–30, higher AD, the Cyclo group had a lower proportion of women (37.1% scores indicate greater impact). Stand-alone questions assessed vs. 51.9%; P < 0.05), and higher proportions of IMM partici- productivity as days missed from work or study during the past pants were diagnosed at earlier ages (Table 1). The scores on 4 weeks. EASI and SCORAD were significantly higher among participants Statistical analysis Outcomes were compared between participants with IGA- rated severe AD and those with mild and moderate disease. (a) Severity Additionally, the IMM and Cyclo groups, regardless of IGA severity, were compared with IGA severe after excluding the 100 Mild patients who were IGA severe and part of the IMM and Moderate Cyclo groups, respectively; that is all statistical comparisons 80 Severe 64.5% (n = 40) are made between groups that did not have overlapping 57.7% Subjects (%) (n = 60) 60 populations. To explore the robustness of this comparison, a post hoc sensitivity analysis was conducted for the IMM 40 29.0% 29.8% (n = 18) (n = 31) subpopulation with severe AD vs. the IGA group excluding 12.5% these IMM patients. Comparisons were conducted using 20 6.5% (n = 13) (n = 4) bivariate analyses with Z-tests for categorical variables and paired-sample t-tests for continuous variables; comparisons 0 Cyclo (n = 62) IMM (n = 104) were based on observed values. Analyses were conducted using DAISIE version 2.4.25 (ADN, Paris, France); nominal (b) Contraindications Inadequate response P-values are reported as there was no correction for multiple Intolerance/toxicity comparisons. Reason for Cyclo/IMM categorization* Results 100 37.1% 38.5% Demographic and clinical characteristics 80 (n = 23) (n = 40) The study population consisted of 1467 adults with AD Subjects (%) 60 (Canada, n = 127; France, n = 288; Germany, n = 287; Italy, n = 288; Spain, n = 290; and the United Kingdom, n = 187) 40 50.0% (n = 31) 58.7% (n = 61) who were enroled by 245 clinicians. The stratification criteria resulted in similar proportions of participants across severity 20 19.4% levels (mild, 37.3%; moderate, 35.4% and severe, 27.3%; (n = 12) 11.5% (n = 12) Table 1). While the Cyclo and IMM subpopulations consisted 0 of participants from all severity levels, the majority of these par- Cyclo (n = 62) IMM (n = 104) ticipants had severe AD, 64.5% and 57.7%, respectively (Fig. 1a). Inadequate response was the most frequent catego- Figure 1 Investigator Global Assessment-rated severity (a) and reasons for categorization (b) of the Cyclo and immunomodulatory rization of Cyclo (50.0%) and IMM (58.7%) participants agent (IMM) subpopulations. *Numbers of patients for each reason (Fig. 1b). add up to more than the group number, as some patients were In the total population, severe AD comprised a significantly characterized by multiple reasons. Cyclo, participants with inade- lower proportion of women relative to mild (50.5% vs. 61.2%; quate efficacy for or contraindications or intolerance to cyclospor- P < 0.001; Table 1), and age was similar across severity levels. ine; IMM, participants with inadequate efficacy for or contraindications or intolerance to any systemic immunomodula- However, the proportion of participants with severe AD who tory agent (including Cyclo participants). were diagnosed <2 years old, 21.5%, was higher relative to those JEADV 2020, 34, 1026–1036 © 2019 Sanofi. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. 1030 de Bruin-Weller et al. with severe AD relative to the Cyclo and IMM subgroups vs. 40.3%; P < 0.001). Relative to severe, significantly higher (Table 1). proportions of the Cyclo (77.4% vs. 51.7%; P < 0.001) and The number of atopic comorbidities increased with AD sever- IMM (76.0% vs. 50.3%; P < 0.001) subgroups had ≥1 non-ato- ity and was significantly higher for asthma, food allergies and pic comorbidities, with significantly higher proportions relative atopic keratoconjunctivitis among participants with severe dis- to severe for emotional/mental, cardiac/vascular and urology/re- ease compared with those who had mild and moderate AD nal conditions (Table 2). (Table 2). The proportion of participants with ≥1 comorbid non-atopic condition was higher among those with severe AD Patient-reported burden in total population (54.3%) relative to mild (41.7%; P < 0.001) and moderate Patient-reported scores on measures of itch and pain were con- (46.7%; P < 0.05; Table 2); comorbid emotional or mental con- sistently worse with increasing AD severity, and participants ditions had the highest prevalence across severity levels and with severe AD reported significantly higher scores, indicating showed significance (P < 0.001) for those with severe relative to more severe itch and pain, relative to those with mild and mod- mild and moderate AD. erate AD (all P < 0.001; Fig. 2). Greater effects on sleep quantity The proportions of Cyclo and IMM participants with ≥1 ato- and quality were reported by participants with severe AD relative pic comorbidity were similar to their respective severe compara- to those with moderate and mild disease (P < 0.001; Fig. 3). tor groups (Table 2). Only for the individual atopic comorbidity Participants with severe AD reported significantly higher anx- of asthma was there a significantly higher prevalence relative to iety and depression than those with moderate and mild AD severe for Cyclo (61.3% vs. 41.4%; P < 0.05) and IMM (59.6% (both P < 0.001; Table 3), with anxiety consistently higher than Table 2 Selected comorbid conditions Variable Number (%) of participants Total population Mild Moderate Severe (n = 547) (n = 520) (n = 400) ≥1 atopic comorbidity 322 (58.9)* 388 (74.6)† 322 (80.5) Asthma 111 (20.3)* 165 (31.7)* 174 (43.5) Food allergies 55 (10.1)* 98 (18.8)† 101 (25.3) Seasonal allergies 179 (32.7)* 219 (42.1) 176 (44.0) Atopic keratoconjunctivitis 2 (0.4)* 5 (1.0)† 12 (3.0) ≥1 non-atopic comorbidity 228 (41.7)* 243 (46.7)† 217 (54.3) Emotional or mental conditions 92 (16.8)* 107 (20.6)* 125 (31.3) Cardiac/vascular conditions 46 (8.4) 56 (10.8) 48 (12.0) Musculoskeletal/integument conditions 34 (6.2) 37 (7.1) 35 (8.8) Endocrine/metabolic conditions 41 (7.5) 52 (10.0) 44 (11.0) Urology/renal condition 10 (1.8) 14 (2.7) 9 (2.3) Variable Number (%) of participants Subpopulations Cyclo Severe excluding Cyclo IMM Severe excluding IMM (n = 62) (n = 360) (n = 104) (n = 340) ≥1 atopic comorbidity 53 (85.5) 289 (80.3) 85 (81.7) 272 (80.0) Asthma 38 (61.3)‡ 149 (41.4) 62 (59.6)§ 137 (40.3) Food allergies 20 (32.3) 86 (23.9) 31 (29.8) 81 (23.8) Seasonal allergies 32 (51.6) 156 (43.3) 45 (43.3) 151 (44.4) Atopic keratoconjunctivitis 2 (3.2) 10 (2.8) 4 (3.8) 8 (2.4) ≥1 non-atopic comorbidity 48 (77.4)§ 186 (51.7) 79 (76.0)§ 171 (50.3) Emotional or mental conditions 29 (46.8)‡ 102 (28.3) 45 (43.3)‡ 94 (27.6) Cardiac/vascular conditions 14 (22.6)‡ 37 (10.3) 24 (23.1)§ 32 (9.4) Musculoskeletal/integument conditions 6 (9.7) 31 (8.6) 14 (13.5) 28 (8.2) Endocrine/metabolic conditions 7 (11.3) 38 (10.6) 13 (12.5) 35 (10.3) Urology/renal condition 5 (8.1)§ 5 (1.4) 6 (5.8)‡ 5 (1.5) *P < 0.001 and †P ≤ 0.05 vs. IGA severe; ‡P ≤ 0.05 and §P ≤ 0.001 for Cyclo or IMM groups vs. severe groups excluding Cyclo/IMM participants, respec- tively. Cyclo, participants with inadequate efficacy for or contraindications or intolerance to cyclosporine; IGA, Investigator’s Global Assessment; IMM, participants with inadequate efficacy for or contraindications or intolerance to any systemic immunomodulatory agent (including Cyclo participants). JEADV 2020, 34, 1026–1036 © 2019 Sanofi. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. Patient-reported burden of atopic dermatitis 1031 depression. Among participants with severe AD, 65.8% and Results of the sensitivity were generally similar to that of 56.2% had subscale scores indicative of anxiety and depression the main analysis, with a burden that was comparable between symptoms, respectively (scores ≥8) and 40.3% and 29.9% had the severe IMM subpopulation and the severe group excluding scores suggestive of clinical anxiety and depression (scores ≥11), those in the IMM subpopulation (Table 5). The only excep- respectively; these proportions were higher than the respective tions were slightly, but statistically significant (P < 0.05) proportions of participants who had mild and moderate AD (all higher pain NRS scores and greater anxiety among the IMM P < 0.001; Table 3). severe subpopulation. The mean DLQI score among participants with severe AD, 16.2  6.9, was higher than those with mild (5.5  4.9) Discussion and moderate, 10.2  6.3, respectively (both P < 0.001; This study continues the real-world characterization of the adult Table 3). All individual domain scores of the DLQI burden of AD by complementing a previous study in the United increased with AD severity, and those with severe disease States that described the high burden associated with moderate/ reported higher scores than those having moderate and mild severe AD and showed that inadequate disease control was com- AD (all P < 0.001). mon and exacerbated the disease burden.20 The current analysis Participants with severe AD who were either students or employed at least part time reported greater loss of productivity (P < 0.05) compared with those who had mild and moderate (a) (b) AD (Table 3). PO-SCORAD Question Sleep VAS Scale 4 of the PSQI Mild Hours of sleep per night over the past Patient-reported burden in Cyclo and IMM subpopulations 10 Moderate 10 week, mean (standard deviation) Mean score (standard deviation) Severe The Cyclo and IMM subpopulations reported similar burdens * 5.5 6.8 6.3 across all outcomes relative to their severe comparator groups 8 8 * 5.6 (Table 4), except for a lower mean score on the pruritus NRS in 3.6 6 6 the IMM subpopulation relative to those with severe AD (7.0 vs. 2.0 6.5; P < 0.05). 4 4 2 2 0 0 3 1 5 8 5 5 (a) (b) (c) 53 51 39 52 50 38 Pruritus PO-SCORAD Pain = = = = = = n n n n n n NRS Scale Itch VAS Scale NRS Scale (c) POEM Item 2 * (Sleep Disturbance in Past Week) 10 * 7.1 7.3 No nights 1–2 nights 3–4 nights 5–6 nights Every night Mean score (standard deviation) 5.6 100 6.0% 8 5.3 * 3.4% 18.9% 4.5 2.6% 11.3% 7.5% 7.6% 26.8% 40.7%* 44.3% 3.8 80 3.5 6 30.8% 18.1% Subjects (%)a 3.0 13.9% 77.2% 60 90.8%* 1.7 4 40.2% 27.6% 40 55.2% 2 20 22.5% 22.6% 8.4% 0 Mild Moderate Severe (n = 536) (n = 513) (n = 395) re = ) = 1) 1) re = ) = 1) 5) re = 4) = 0) 1) ve (n 533 ve (n 534 (n 51 39 (n 51 39 ve (n 53 (n 51 39 Se ate = Se ate = Se ate = er (n er (n er (n od ild od ild od ild M M M Figure 3 Impact of atopic dermatitis on patient-reported sleep M M M problems. *P < 0.001 vs. mild and moderate. aPercentages sum to <100% as data were missing from seven subjects (three mild, one Figure 2 Impact of atopic dermatitis on patient-reported itch and moderate and three severe). POEM, Patient-Oriented Eczema pain. *P < 0.001 vs. mild and moderate. NRS, numerical rating Measure; PO-SCORAD, Patient-Oriented Scoring of Atopic Der- scale; PO-SCORAD, Patient-Oriented Scoring of Atopic Dermatitis matitis scale; PSQI, Pittsburgh Sleep Quality Index; VAS, visual scale; VAS, visual analogue scale. analogue scale. JEADV 2020, 34, 1026–1036 © 2019 Sanofi. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. 1032 de Bruin-Weller et al. expands on those results by presenting data from Canada and The comorbidity burden, which increased with AD severity, the EU that represent a community-based (office and hospital was consistent with the recognized association between AD and practices) population rather than academic medical centres as in other atopic conditions, including those that are considered the U.S. study. components of the atopic march.1,26,27 Among the non-atopic The proportion of women was highest among the mild AD comorbidities, emotional or mental conditions had the highest severity group and was statistically significant compared with prevalence regardless of severity, followed by cardiovascular severe. Although the clinical relevance of this observation is comorbidities. The presence of the former is not surprising, unclear, it is possible that women may make clinical visits given that a substantial proportion of participants reported more frequently than men even when their AD is mild, as HADS scores that are considered indicative of clinical anxiety women engage in healthcare-seeking behaviour more fre- and depression. The burden of cardiac and vascular conditions quently than men.21,22 Almost half of the participants (48.3%) is consistent with Silverberg et al.28 and further supports an reported being diagnosed after 18 years of age, consistent with association between cardiovascular disease and AD severity. other studies in which 37–59% of individuals reported diag- The patient-reported burden also appeared to increase with nosis during adulthood.6,20 However, diagnosis does not nec- greater disease severity and was significantly higher for those essarily equate with onset, and the time of AD onset remains with severe AD vs. both mild and moderate disease across all unknown. Adult-onset AD has been suggested to represent, at outcomes. This association between AD severity and burden was least in some cases, individuals who may have forgotten their generally consistent with the U.S. study,20 and the current strati- childhood disease,23 most likely a result of recall bias, as par- fication across 3 severity levels rather than combined moderate/ ticipants with more severe childhood AD may remember their severe enabled a more granular assessment, albeit statistical com- disease better than those with less severe childhood AD. parison of mild with moderate was not performed. Despite the uncertainty regarding onset, the proportion of Within each AD severity level, itch intensity scores were simi- participants who reported being diagnosed <2 years old lar on the NRS and SCORAD VAS despite the fact that the recall increased with severity, providing support for the concept that periods are 24 h for the former and 3 days for the latter, suggest- earlier onset may be associated with persistent and more sev- ing that itch intensity is generally maintained over at least short ere disease in adulthood.24,25 periods of time and likely correlates with AD severity. Given that Table 3 Impact of atopic dermatitis severity on patient-reported mental health, health-related quality of life and productivity Outcome Mild Moderate Severe HADS, n 536 513 395 Total score, mean (SD) 9.2 (7.0)* 12.8 (7.4)* 17.6 (7.9)‡ HADS-A score, mean (SD) 5.5 (4.0)* 7.3 (4.2)* 9.4 (4.1)‡ HADS-D score, mean (SD) 3.8 (3.7)* 5.5 (3.9)* 8.2 (4.4)‡ HADS-A ≥8, n (%) 135 (25.2)* 228 (44.4)* 260 (65.8) HADS-A ≥11, n (%) 59 (11.0)* 118 (23.0)* 159 (40.3) HADS-D ≥8, n (%) 92 (17.2)* 157 (30.6)* 222 (56.2) HADS-D ≥11, n (%) 33 (6.2)* 60 (11.7)* 118 (29.9) DLQI, n 533 511 387 Total score, mean (SD) 5.5 (4.9)* 10.2 (6.3)* 16.2 (6.9) Symptoms and feelings, mean (SD) 2.0 (1.3)* 3.1 (1.5)* 4.3 (1.3) Daily activities, mean (SD) 1.1 (1.3)* 2.2 (1.6)* 3.4 (1.7) Leisure, mean (SD) 0.9 (1.4)* 1.8 (1.6)* 3.1 (1.9) Work and school, mean (SD) 0.4 (0.8)* 1.0 (1.1)* 1.5 (1.2) Personal relationships, mean (SD) 0.6 (1.0)* 1.3 (1.5)* 2.5 (1.9) Treatment, mean (SD) 0.5 (0.7)* 0.9 (0.8)* 1.4 (0.9) Productivity in past 4 weeks among part-/full-time employees or students, n 466 445 321 At least 1 day missed, n (%) 155 (33.3)* 233 (52.4)† 202 (62.9) Total number of days missed related to atopic dermatitis, mean (SD) 0.9  2.6* 2.0  4.1*,§ 3.7  5.9¶ *P < 0.001 and †P ≤ 0.05 vs. IGA severe. ‡n = 394. §n = 439; 6 participants who indicated a total number of days exceeding 4 weeks were excluded. ¶n = 307; 14 participants who indicated a total number of days exceeding 4 weeks were excluded. DLQI, Dermatology Quality of Life Index; HADS, Hospital Anxiety and Depression Scale; HADS-A, HADS anxiety subscale; HADS-D, HADS depression sub- scale; SD, standard deviation. JEADV 2020, 34, 1026–1036 © 2019 Sanofi. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. Patient-reported burden of atopic dermatitis 1033 Table 4 Patient-reported burden in the Cyclo and IMM populations Outcome Cyclo Severe excluding Cyclo IMM Severe excluding IMM Itch, n 62 355 102 336 NRS, mean (SD) 6.6 (2.2) 7.0 (2.2) 6.5 (2.3)* 7.0 (2.2) PO-SCORAD VAS, mean (SD) 7.0 (2.2) 7.2 (2.1) 6.9 (2.3) 7.2 (2.1) Pain NRS, mean (SD) 4.6 (2.5) 4.5 (2.7) 4.7 (2.7) 4.4 (2.7) Sleep PO-SCORAD VAS, mean (SD) [n] 5.0 (2.9) [62] 5.5 (2.8) [355] 4.9 (2.9) [102] 5.5 (2.8) [336] Sleep disturbed every night over 15 (24.2) 94 (26.5) 25 (24.5) 88 (26.2) past week (POEM item 2), n (%) Sleep disturbance frequency (POEM item 2), n (%) No nights 6 (9.7) 32 (9.0) 10 (9.8) 30 (8.9) 1–2 nights 10 (16.1) 83 (23.4) 25 (24.5) 79 (23.5) 3–4 nights 20 (32.3) 95 (26.8) 28 (27.5) 89 (26.5) 5–6 nights 10 (16.1) 49 (13.8) 12 (11.8) 48 (14.3) Every night 15 (24.2) 94 (26.5) 25 (24.5) 88 (26.2) Hours of sleep per night over the 6.0 (1.5) [60] 5.6 (1.6) [347] 5.9 (1.4) [99] 5.6 (1.6) [328] past week, mean (SD) [n] HADS, n 62 355 102 336 Total score, mean (SD) 17.0 (8.1)† 17.5 (7.8) 16.6 (8.1)‡ 17.3 (7.8) HADS-A score, mean (SD) 9.2 (4.2)† 9.3 (4.1) 9.1 (4.2)‡ 9.3 (4.1) HADS-D score, mean (SD) 7.8 (4.6)† 8.1 (4.3) 7.5 (4.6)‡ 8.1 (4.3) HADS-A ≥8, n (%) 41 (66.1) 229 (64.5) 67 (65.7) 214 (63.7) HADS-A ≥11, n (%) 21 (33.9) 140 (39.4) 35 (34.3) 132 (39.3) HADS-D ≥8, n (%) 31 (50.0) 199 (56.1) 51 (50.0) 187 (55.7) HADS-D ≥11, n (%) 18 (29.0) 104 (29.3) 29 (28.4) 95 (28.3) DLQI, n 59 350 98 331 Total score, mean (SD) 15.2 (6.8) 16.0 (6.9) 14.9 (6.9) 16.0 (6.9) Symptoms and feelings, mean (SD) 4.0 (1.4) 4.3 (1.3) 4.0 (1.5) 4.2 (1.3) Daily activities, mean (SD) 3.2 (1.7) 3.4 (1.6) 3.1 (1.7) 3.4 (1.7) Leisure, mean (SD) 2.9 (1.8) 3.1 (1.9) 2.7 (1.9) 3.1 (1.9) Work and school, mean (SD) 1.5 (1.2) 1.5 (1.2) 1.4 (1.2) 1.5 (1.2) Personal relationships, mean (SD) 2.2 (1.7) 2.4 (1.9) 2.2 (1.8) 2.4 (1.9) Treatment, mean (SD) 1.5 (0.8) 1.4 (1.0) 1.5 (0.9) 1.4 (0.9) Productivity in past 4 weeks among 47 294 75 282 part-/full-time employees or students, n At least 1 day missed, n (%) 34 (72.3) 183 (62.2) 51 (68.0) 175 (62.1) Total number of days missed related to atopic dermatitis, mean (SD) [n] 3.8 (5.8) [44] 3.7 (5.8) [283] 3.2 (4.9) [71] 3.7 (5.9) [271] *P < 0.05 vs. for IMM vs. severe group excluding IMM participants. †n = 61. ‡n = 101. DLQI, Dermatology Quality of Life Index; HADS, Hospital Anxiety and Depression Scale; HADS-A, HADS anxiety subscale; HADS-D, HADS depression sub- scale; NRS, numerical rating scale; POEM, Patient-Oriented Eczema Measure; PO-SCORAD, Patient-Oriented Scoring of Atopic Dermatitis; SD, standard deviation; VAS, visual analogue scale. itch is a cardinal symptom of AD and is the primary patient the most important item rated by patients for judging treatment complaint, it was not surprising that itch was significantly response.30 While lack of knowledge of the presence and impact greater among those with severe AD relative to mild and moder- of pain in AD has been identified as an important gap in the ate disease. Pain severity also appeared to increase with AD clinical presentation of AD,31 a recent study has emphasized the severity, and this relationship expands the recognition of pain as contribution of pain to the burden of AD and suggested that having a tangible and measurable presence in AD that is also pain correlates with other clinical and patient-reported out- related to disease severity. This relationship may be especially comes.32 relevant as pain and itch appear to have overlapping mecha- Reductions in quality and quantity of sleep are consistent with nisms,29 and pain has previously been suggested to be, after itch, the observed relationship between itch and sleep33,34 and the JEADV 2020, 34, 1026–1036 © 2019 Sanofi. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. 1034 de Bruin-Weller et al. Table 5 Sensitivity analysis comparing patient-reported burden in Table 5 Continued the severe IMM population compared with the severe population excluding the IMM participants Outcome Severe with Severe IMM excluding Outcome Severe with Severe IMM IMM excluding Productivity in past 4 39 282 IMM weeks among part-/full- Itch, n 59 336 time employees or NRS, mean (SD) [n] 7.2 (2.1) [58] 7.0 (2.2) students, n [333] At least 1 day missed, n (%) 27 (69.2) 175 (62.1) PO-SCORAD VAS, 7.5 (1.9) 7.2 (2.1) Total number of days 3.8 (5.4) [36] 3.7 (5.9) [271] mean (SD) missed related to atopic Pain NRS, 5.3 (2.7) [58]* 4.4 (2.7) [334] dermatitis, mean (SD) [n] mean (SD) [n] *P ≤ 0.05 vs. for severe IMM vs. severe group excluding IMM participants. Sleep, n 59 336 DLQI, Dermatology Quality of Life Index; HADS, Hospital Anxiety and PO-SCORAD VAS, 5.8 (2.9) 5.5 (2.8) Depression Scale; HADS-A, HADS anxiety subscale; HADS-D, HADS mean (SD) depression subscale; NRS, numerical rating scale; POEM, Patient-Oriented Sleep disturbed 18 (30.5) 88 (26.2) Eczema Measure; PO-SCORAD, Patient-Oriented Scoring of Atopic Der- every night matitis; SD, standard deviation; VAS, visual analogue scale. over past week (POEM item 2), n (%) contribution of sleep disturbance to poorer health, reduced work Sleep disturbance frequency (POEM item 2), n (%) productivity and increased healthcare resource use.35 While No nights 3 (5.1) 30 (8.9) results of previous studies have been inconsistent with regard to 1–2 nights 10 (16.9) 79 (23.5) the relationship between sleep disturbance and AD severity,36 3–4 nights 20 (33.9) 89 (26.5) the decremental effects on quality and quantity of sleep with 5–6 nights 7 (11.9) 48 (14.3) increasing AD severity shown in the current analysis support Every night 18 (30.5) 88 (26.2) such a relationship. Hours of sleep per night 5.8 (1.4) [57] 5.6 (1.6) [328] over the past week, HADS scores showed a substantial presence of anxiety and mean (SD) [n] depression symptoms, even among participants with mild and HADS, n 59 336 moderate AD, and also suggested the presence of clinical anxiety Total score, 19.4 (8.1) [58] 17.3 (7.8) [336] and/or depression. As reported in other studies, anxiety was mean (SD) [n] more common than depression.6,7,20 The proportions of partici- HADS-A score, 10.4 (4.3) [58]* 9.3 (4.1) [336] pants with moderate and severe AD who had scores indicative of mean (SD) [n] clinical anxiety and/or depression were lower than the propor- HADS-D score, 9.0 (4.6) [58] 8.1 (4.3) [336] mean (SD) [n] tions who had emotional or mental comorbidities recorded in HADS-A ≥8, n (%) 46 (78.0)* 214 (63.7) their clinical history, suggesting that at least in some of these HADS-A ≥11, n (%) 27 (45.8) 132 (39.3) participants, these conditions may not be recognized. These HADS-D ≥8, n (%) 35 (59.3) 187 (55.7) results emphasize the need for mental health assessment and HADS-D ≥11, n (%) 23 (39.0) 95 (28.3) support as part of AD management, as meta-analyses consis- DLQI, n 56 331 tently have shown an increased risk of depression and suicidal- Total score, 17.5 (6.8) 16.0 (6.9) ity.37–39 mean (SD) The DLQI indicates the extent of effects on participants’ daily Symptoms and 4.6 (1.3) 4.2 (1.3) feelings, mean (SD) lives; symptoms/feelings followed by daily activities were the Daily activities, 3.6 (1.7) 3.4 (1.7) domains most affected across severity levels. Higher AD severity mean (SD) resulted in a greater impact as indicated by higher scores on the Leisure, mean 3.2 (1.9) 3.1 (1.9) total DLQI as well as on individual domains. The total score (SD) among those with severe AD (16.2) was consistent with a very Work and school, 1.6 (1.2) 1.5 (1.2) large impact of AD on HRQoL, and the score among partici- mean (SD) pants with moderate AD (10.2) was borderline between what is Personal relationships, 2.8 (1.8) 2.4 (1.9) mean (SD) considered moderate (6–10) and large effects (11–20).40 These Treatment, mean 1.6 (0.9) 1.4 (0.9) effects on participants’ daily lives were also reflected by lost pro- (SD) ductivity among those who were employed at least part time. Even among participants with mild AD, approximately one- third reported missing at least 1 day of work due to AD in the JEADV 2020, 34, 1026–1036 © 2019 Sanofi. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. Patient-reported burden of atopic dermatitis 1035 past 4 weeks, increasing to half and almost two-thirds of partici- severity that is uniformly used in clinical practice, and thus eval- pants with moderate and severe AD, respectively, with up to 3.7 uation of severity in the clinical setting remains challenging.47,48 missed days of work among the participants with severe disease. Sleep and productivity were evaluated using stand-alone ques- While previous studies have also documented substantial work tions, and their lack of validation may represent another limita- and activity impairment associated with AD and their economic tion. Last, data from all countries were evaluated together, and implications,41–44 costs were not estimated in the current study, while the survey questionnaire with all measures was adminis- and only absenteeism was evaluated; presenteeism has been tered in the language appropriate for each country, it is possible reported to be the primary driver of lost productivity in AD.42,44 that there may be country-specific or cultural differences in the The Cyclo and IMM subpopulations consisted of partici- interpretation of questions and/or perceptions of AD and its pants across all AD severity levels, reflecting clinically rele- impact. vant groups that may be expected to encompass a range of In conclusion, this study from real-world clinical practice disease severity. Notably, despite mild/moderate AD in 35% confirmed the substantial multidimensional burden reported by and 42% of the Cyclo and IMM populations, respectively, adults with AD includes disease-related symptoms (itch), pain, the patient-reported burden in these subpopulations was sim- sleep disturbance, mental health and HRQoL. Participants with ilar to those with severe AD after excluding those partici- severe AD reported the highest burden, which was significant pants identified as Cyclo and IMM, respectively. The relative to those with less severe disease. Participants for whom observation that inadequate efficacy and intolerance were the cyclosporine or other systemic immunomodulators do not rep- primary reasons for categorization of these participants resent a therapeutic option had a disease burden similar to those emphasizes the lack of effective options for AD control, with severe disease. These results highlight the need for addi- regardless of severity. Although there was no difference in tional and more effective therapeutic options. Furthermore, the mean age, significantly higher proportions of these subpopu- high patient-reported burden associated with AD demonstrates lations were diagnosed at an earlier age, possibly denoting the need for AD assessment that goes beyond clinical measures that longer disease duration may be associated with a higher of disease activity and takes into account the patient perspective. likelihood of receiving and failing immunosuppressant ther- apy. The results of the post hoc sensitivity analysis, with two Acknowledgements exceptions, were comparable to the main analysis in showing Medical writing support was provided by E. Jay Bienen, PhD, similar burdens between the severe IMM subpopulation and and funded by Sanofi and Regeneron Pharmaceuticals, Inc. the severe group excluding the IMM participants. 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