Journal of Dermatological Treatment ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: https://www.tandfonline.com/loi/ijdt20 Dupilumab improves patient-reported symptoms of atopic dermatitis, symptoms of anxiety and depression, and health-related quality of life in moderate-to-severe atopic dermatitis: analysis of pooled data from the randomized trials SOLO 1 and SOLO 2 Michael J. Cork, Laurent Eckert, Eric L. Simpson, April Armstrong, Sébastien Barbarot, Luis Puig, Giampiero Girolomoni, Marjolein de Bruin-Weller, Andreas Wollenberg, Yoko Kataoka, Anita Remitz, Stefan Beissert, Vera Mastey, Marius Ardeleanu, Zhen Chen, Abhijit Gadkari & Jingdong Chao To cite this article: Michael J. Cork, Laurent Eckert, Eric L. Simpson, April Armstrong, Sébastien Barbarot, Luis Puig, Giampiero Girolomoni, Marjolein de Bruin-Weller, Andreas Wollenberg, Yoko Kataoka, Anita Remitz, Stefan Beissert, Vera Mastey, Marius Ardeleanu, Zhen Chen, Abhijit Gadkari & Jingdong Chao (2020) Dupilumab improves patient-reported symptoms of atopic dermatitis, symptoms of anxiety and depression, and health-related quality of life in moderate-to-severe atopic dermatitis: analysis of pooled data from the randomized trials SOLO 1 and SOLO 2, Journal of Dermatological Treatment, 31:6, 606-614, DOI: 10.1080/09546634.2019.1612836 To link to this article: https://doi.org/10.1080/09546634.2019.1612836 © 2019 The Author(s). Published with Published online: 09 Jun 2019. license by Taylor & Francis Group, LLC Submit your article to this journal Article views: 9149 View related articles View Crossmark data Citing articles: 47 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ijdt20 JOURNAL OF DERMATOLOGICAL TREATMENT 2020, VOL. 31, NO. 6, 606–614 https://doi.org/10.1080/09546634.2019.1612836 ORIGINAL ARTICLE Dupilumab improves patient-reported symptoms of atopic dermatitis, symptoms of anxiety and depression, and health-related quality of life in moderate-to-severe atopic dermatitis: analysis of pooled data from the randomized trials SOLO 1 and SOLO 2 Michael J. Corka, Laurent Eckertb, Eric L. Simpsonc, April Armstrongd, Sebastien Barbarote , Luis Puigf , Giampiero Girolomonig, Marjolein de Bruin-Wellerh, Andreas Wollenbergi, Yoko Kataokaj, Anita Remitzk, Stefan Beissertl, Vera Masteym, Marius Ardeleanum, Zhen Chenm, Abhijit Gadkarim and Jingdong Chaom a Sheffield Dermatology Research, Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill, Sheffield, UK; b Sanofi, Chilly-Mazarin, France; cDepartment of Dermatology, Oregon Health & Science University, Portland, OR, USA; dDepartment of Dermatology, Keck School of Medicine at USC, University of Southern California, Los Angeles, CA, USA; eDepartment of Dermatology, CHU H^otel-Dieu, Nantes, France; fDepartment of Dermatology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; gDepartment of Medicine, Section of Dermatology and Venereology, University of Verona, Verona, Italy; hUniversity Medical Center Utrecht, Utrecht, The Netherlands; iKlinikum der Universit€at M€ unchen, Klinik und Poliklinik f€ur Dermatologie und Allergologie, Munich, Germany; jDepartment of Dermatology, Osaka Habikino Medical Center, Habikino City, Osaka, Japan; kHelsinki University Central Hospital, Helsinki, Finland; lDepartment of Dermatology, Technische Universit€at Dresden, Dresden, Germany; mRegeneron Pharmaceuticals Inc., Tarrytown, NY, USA ABSTRACT ARTICLE HISTORY Background: Atopic dermatitis (AD) profoundly affects quality of life (QoL). Dupilumab significantly Received 15 March 2019 improves clinical outcomes, is well tolerated, and approved to treat inadequately controlled moderate-to- Accepted 23 April 2019 severe AD in adults; however, its effect on patient-reported outcomes (PROs) is not fully characterized. KEYWORDS Objective: To evaluate the impact of dupilumab on patient-reported AD symptoms and QoL. Atopic dermatitis; Methods: Pooled data were analyzed from two identically designed phase 3 studies, LIBERTY AD SOLO 1 dupilumab; patient-reported (NCT02277743) and SOLO 2 (NCT02277769), assessing the following PROs: Peak Pruritus Numerical Rating outcomes; quality of life Scale (NRS), Pruritus Categorical Scale, SCORing AD (SCORAD), Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), five-dimension EuroQoL questionnaire (EQ-5D), and patient-assessed disease status and treatment effectiveness. Results: Dupilumab rapidly improved (vs. placebo) Peak Pruritus NRS scores by day 2 (p < .05), anxiety and depression (HADS), and QoL (DLQI) by week 2, and maintained through week 16 (p < .0001). At week 16, more dupilumab-treated than placebo-treated patients reported improvement in SCORAD itch and sleep, and no pain/discomfort (EQ-5D) (p < .0001). Limitations: Cultural differences of translated PROs. Conclusion: Dupilumab had a significant, positive impact on AD symptoms, including itch, sleep, pain, anxiety and depression, and QoL in adults with moderate-to-severe AD. Introduction in patients with AD than in control populations (16–18), and Atopic dermatitis (AD) is a complex, chronic, systemic, inflamma- patients with AD report higher rates of pain, fatigue, insomnia, tory skin disease characterized by erythematous, eczematous and daytime sleepiness (9,19,20). lesions, and intense pruritus (1–4). Innate and adaptive immune Moderate-to-severe AD in adults can be challenging to treat responses, and environmental factors, contribute to the clinical because of the risk/benefit profiles of systemic therapies (21,22). presentation of AD (5,6). AD affects patients worldwide; the preva- There is a substantial unmet need for safe and effective treatments, lence in adults is 4.4% in the European Union, 3.5% in Canada, especially for patients with inadequate response to currently avail- 4.9% in the United States, and 2.1% in Japan (7). able topical medications and systemic immunosuppressants (11,23). AD adversely affects patients’ quality of life (QoL) (8–12). Dupilumab is a fully human monoclonal antibody directed Pruritus, a prominent symptom of AD, can be intense and debili- against interleukin (IL)-4 receptor alpha (IL-4Ra), which inhibits sig- tating (3,4,13) and is associated with reduced health-related QoL naling of IL-4 and IL-13, cytokines that are key drivers of type 2 dis- (HRQoL) and increased incidence of depression and anxiety eases such as AD, asthma, allergic rhinitis, and food allergies, (11,12,14,15). Rates of depression and suicidal ideation are higher diseases often associated as comorbidities (24). Dupilumab is CONTACT Abhijit Gadkari abhijit.gadkari@regeneron.com Health Economics and Outcomes Research, Medical Affairs, Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Rd., Tarrytown, NY 12533, USA These authors are co-last authors. ß 2019 The Author(s). Published with license by Taylor & Francis Group, LLC This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. JOURNAL OF DERMATOLOGICAL TREATMENT 607 approved for treatment of inadequately controlled, moderate-to- dryness or roughness of the skin; flaking of the skin; cracking of the severe AD in adults. In early and phase 3 clinical trials, including skin; tightness of the skin) and impact of AD on sleep (32). The SOLO 1 (NCT02277743) and SOLO 2 (NCT02277769), dupilumab sig- HADS assesses symptoms of anxiety and depression with seven nificantly improved, versus placebo, AD signs and symptoms in questions for each, on a 0–3 scale (36). The DLQI has 10 questions adults with moderate-to-severe AD, and had a favorable safety pro- about the effect of AD on patients’ QoL during the previous week, file (12,25–28). using a scale of (0–3) (39). The PGADS and PGATE are global assess- The burden of moderate-to-severe AD is not fully captured by ments of disease severity and treatment satisfaction, both on a five- clinical outcome measures. To obtain further insight into the effi- point scale. SCORAD visual analog scale (VAS) itch is a patient- cacy of dupilumab, we evaluated its impact on patient-reported reported component of SCORAD. For VAS itch, patients report aver- symptoms of AD, including pruritus and sleep disturbance, anxiety age itch for the past 3 days or nights. Sleep loss is assessed by and depression, HRQoL, and global assessments of disease and SCORAD VAS sleep—average sleep loss for the past 3 days or nights. treatment effect using pooled data from SOLO 1 and 2. The EQ-5D is a standardized instrument for measuring QoL, with one question for each of five dimensions: mobility, self-care, usual activ- ities, pain or discomfort, and anxiety or depression (40). Methods Study design Statistics The design and methodology of SOLO 1 (NCT02277743) and 2 SOLO 1 and 2 data were pooled within each treatment group, (NCT02277769) have already been published (27). Briefly, SOLO 1 therefore all p values  .05 are considered nominally significant. and 2 were randomized, placebo-controlled, double-blind, phase All statistical tests were two-sided. For categorical endpoints, data 3 trials. Eligible patients were aged  18 years and had AD for obtained after rescue medication use and missing data were con-  3 years, an Investigator’s Global Assessment (IGA) score of 3 sidered ‘nonresponder’ data. For continuous endpoints, data (moderate) or 4 (severe), an Eczema Area and Severity Index obtained after use of rescue medication and missing data were (EASI) score  16, and a pruritus Numerical Rating Scale (NRS) accounted for using the last-observation-carried-forward method. average score  3. Patients received subcutaneous dupilumab Statistical analyses were performed using SAS software, version 300 mg once weekly (qw), or every 2 weeks (q2w), or placebo qw, 9.2 (SAS Institute, Inc., Cary, NC, USA). For comparisons of each for 16 weeks (27). Both trials were conducted in accordance with dupilumab dose with placebo according to the pre-specified hier- the Declaration of Helsinki International Conference on archical order, a significance level of 0.025 was used, controlling Harmonization, Good Clinical Practice guidelines, and applicable for the overall type I error rate at 0.05 for primary and secondary regulatory requirements. All patients provided written informed endpoints. All reported p values are nominal, two-sided. Detailed consent. Study oversight was provided by local institutional descriptions of the statistical analyses for the individual studies review boards or ethics committees at each study site and by an are published elsewhere (27). independent data and safety monitoring committee. Results Patient-reported outcomes Patients Patient-reported outcomes (PROs) reported include least squares (LS) mean percentage change from baseline to week 2 and per- In total, 1,379 patients were enrolled in the two studies. 457 centage of patients with  3-point reduction from baseline patients received dupilumab 300 mg q2w, 462 received dupilu- through week 16 in daily Peak Pruritus NRS score (29,30), (a pre- mab 300 mg qw, and 460 received placebo. In this pooled ana- specified secondary endpoint); percentage of patients reporting lysis, treatment groups had similar baseline demographics and ‘absence of’/‘mild’ pruritus as well as ‘severe’ pruritus from base- disease characteristics (Table 1). line through week 16 in Pruritus Categorical Scale (PCS) score (31); LS mean change from baseline at week 2 and percentage of Pruritus patients at week 16 reporting absence of symptoms in the past week in each Patient-Oriented Eczema Measure (POEM) item Compared with placebo, dupilumab improved Peak Pruritus NRS (32,33); LS mean change from baseline at week 16 for patient- scores as early as day 2, regardless of dose regimen, with 4.5% LS reported Scoring AD (SCORAD) itch and sleep (34,35); LS mean mean percentage change from baseline for dupilumab q2w, change from baseline at week 2 and week 16 in Hospital Anxiety p ¼ .0033 vs. placebo; 4.0% for dupilumab qw, p ¼ .0110 vs. pla- and Depression Scale (HADS) score (36,37); LS mean change from cebo, and 0.6% for placebo; (Figure 1). More patients in the dupilu- baseline at week 2 and the percentage of patients reporting ‘not mab q2w and dupilumab qw groups had a  3-point improvement at all’ at week 16 in Dermatology Life Quality Index (DLQI) score in Peak Pruritus NRS score by day 4, compared with patients in the (38,39); percentage of patients reporting ‘good,’ ‘very good,’ or placebo group (7.4% and 8.0%, respectively, vs. 3.3%; p ¼ .0044 and ‘excellent’ through week 16 in Patient Global Assessment of p ¼ .0019, respectively, vs. placebo) and at weeks 2 and 16 (at week Disease Status (PGADS) and Patient Global Assessment of 2: 17.1% and 20.2%, respectively, vs. 5.1%; week 16: 48.8% and Treatment Effect (PGATE); and on the five-dimension, three-level 50.3%, respectively, vs. 15.0% of placebo recipients; p < .0001 vs. pla- EuroQoL questionnaire (EQ-5D) (40), the percentage of patients cebo, either regimen at both time points; Table 2, Figure 1). reporting no pain or discomfort at week 16. Dupilumab also rapidly improved itch severity as assessed on Peak Pruritus NRS measures the intensity of worst itch in the pre- the PCS. At week 2, more patients in the dupilumab q2w and vious 24 hours on a scale of 0–10; higher scores indicate more severe dupilumab qw groups reported ‘absent or mild’ pruritus, com- pruritus. PCS measures intensity of itching, scratching, and/or discom- pared with patients in the placebo group (29.1% and 30.7%, fort due to pruritus in the previous 24 hours on a four-point scale respectively, vs. 13.9%; p < .0001 vs. placebo for either dose regi- (30). POEM assesses frequency of AD symptoms (itching, soreness, or men; Table 2). At week 16, more dupilumab-treated patients pain; redness of the skin, bleeding, weeping, or oozing of the skin; reported ‘absent or mild’ pruritus, compared with placebo (51.9% 608 M. J. CORK ET AL. Table 1. Baseline demographics and disease characteristics of patients in SOLO 1 and SOLO 2 (pooled data). Characteristic Placebo (n ¼ 460) Dupilumab 300 mg q2w (n ¼ 457) Dupilumab 300 mg qw (n ¼ 462) Mean age, years (SD) 38.4 (14.0) 38.3 (14.4) 38.2 (14.5) Male, n (%) 250 (54.3) 267 (58.4) 281 (60.8) Race, n (%) White 302 (65.7) 320 (70.0) 317 (68.6) Black or African American 36 (7.8) 23 (5.0) 35 (7.6) Asian 106 (23) 98 (21.4) 96 (20.8) Other 8 (1.7) 8 (1.8) 8 (1.7) AD duration, years (%) 28.8 (14.4) 27.9 (15.2) 27.6 (15.4) BSA (%), mean (SD) 55.8 (23.3) 53.7 (22.2) 54.1 (22.3) EASI total score, mean (SD) 34.0 (14.4) 32.4 (13.3) 32.5 (13.3) IGA = 4, n (%) 225 (48.9) 223 (48.8) 218 (47.2) Peak weekly averaged pruritus NRS score, mean (SD) 7.4 (1.8) 7.4 (1.8) 7.3 (1.9) PCS score n (%) ‘absence of’/‘mild’ pruritus 40 (8.7) 32 (7.0) 37 (8.4) ‘moderate’ pruritus 197 (42.8) 218 (47.7) 193 (41.8) ‘severe’ pruritus 222 (48.3) 206 (45.1) 227 (49.1) SCORAD total score, mean (SD) 68.8 (14.5) 67.1 (13.7) 67.5 (13.3) POEM score, mean (SD) 20.6 (5.9) 20.3 (6.0) 20.7 (5.9) DLQI score, mean (SD) 15.1 (7.5) 14.7 (7.3) 15.1 (7.5) HADS total score, mean (SD) 13.2 (8.3) 13.0 (7.4) 13.7 (8.2) GISS total score, mean (SD) 9.1 (1.8) 9.0 (1.8) 8.9 (1.7) AD: atopic dermatitis; BSA: body surface area; DLQI: Dermatology Life Quality Index; EASI: Eczema Area and Severity Index; GISS: Global Individual Signs Score; HADS: Hospital Anxiety and Depression Scale; IGA: Investigator’s Global Assessment; NRS: Numerical Rating Scale; PCS: Pruritus Categorical Scale; POEM: Patient-Oriented Eczema Measure; qw: weekly; q2w: every 2 weeks; SCORAD: SCORing Atopic Dermatitis; SD: standard deviation. Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 –3.4% * † LS mean percentage change from baseline –20 –22.5%‡ in Peak Pruritus NRS scores ± SE –24.7% ‡ –40 –60 –80 * p = .0110 dupilumab 300 mg qw vs. placebo (day 2) † p = .0033 dupilumab 300 mg q2w vs. placebo (day 2) ‡ p < .0001 dupilumab 300 mg qw and dupilumab 300 mg q2w vs. placebo (day 3–15) –100 Figure 1. LS mean percentage change from baseline to week 2 in daily Peak Pruritus NRS score. Placebo, n ¼ 460; dupilumab 300 mg q2w, n ¼ 457; dupilumab 300 mg qw, n ¼ 462. LS: least squares; NRS: Numerical Rating Scale; qw: weekly; q2w: every 2 weeks; SE: standard error. and 53.7%, respectively, vs. 19.3%; p < .0001 vs. placebo for either patients reported ‘no pain/discomfort’ at week 16 (45.7% for dupi- dose regimen; Table 2). In addition, fewer dupilumab-treated lumab q2w, 43.2% for dupilumab qw, and 13.5% for placebo; patients reported ‘severe pruritus’ at week 16, compared with pla- p < .0001 vs. placebo, either dose regimen; Table 2). Overall, by cebo (20.8% and 21.9%, respectively, vs. 36.7%; p < .0001 vs. pla- week 16, 62.0–62.2% of dupilumab-treated patients reported ‘no cebo for either dose regimen; Table 2). pain/discomfort,’ vs. 39.2% of placebo-treated patients, and For SCORAD VAS itch score, dupilumab-treated patients had a 37.8–37.9% of dupilumab-treated patients reported ‘some/extreme higher LS mean change from baseline at week 16 than placebo- pain/discomfort,’ in contrast to 60.8% of placebo-treated patients. treated patients (4.00 for dupilumab q2w, 4.06 for dupilumab qw, and 1.26 for placebo; p < .0001, either regimen vs. placebo) Sleep (Table 2). Dupilumab-treated patients (either regimen) had greater LS mean change from baseline at week 16 in SCORAD sleep than placebo- Pain treated patients (3.3 for dupilumab q2w, 3.4 for dupilumab Among patients reporting at least ‘some pain/discomfort’ on the qw, and 0.82 for placebo; p < .0001, either dose regimen vs. pla- EQ-5D at baseline, more dupilumab- than placebo-treated cebo; Table 2). At week 16 more dupilumab- than placebo-treated JOURNAL OF DERMATOLOGICAL TREATMENT 609 Table 2. Patient-reported outcomes in SOLO 1 and SOLO 2 (pooled data). Placebo (n ¼ 460) Dupilumab 300 mg q2w (n ¼ 457) Dupilumab 300 mg qw (n ¼ 462) Peak Pruritus NRS: improvement, n/ N (%)a  3 points from baseline at day 4 15/447 (3.3) 34/451 (7.4)b 37/445 (8.0)c  3 points from baseline at week 2 23/447 (5.1) 77/451 (17.1)d 90/445 (20.2)d  3 points from baseline at week 16 67/447 (15.0) 220/451 (48.8)d 224/445 (50.3)d PCS score: n (%)e Week 2 ‘absence of’ or ‘mild’ pruritus 64 (13.9) 133 (29.1)d 142 (30.7)d ‘moderate’ pruritus 184 (40.0) 211 (46.2)f 200 (43.3) ‘severe’ pruritus 169 (36.7) 95 (20.8)d 101 (21.9)d Week 16 ‘absence of’ or ‘mild’ pruritus 89 (19.3) 237 (51.9)d 248 (53.7)d ‘moderate’ pruritus 74 (16.1) 102 (22.3) 78 (16.9) ‘severe’ pruritus 39 (8.5) 26 (5.7) 18 (3.9)g POEM score: LS mean change from base- 1.6 (0.27) 5.8 (0.27)d 6.2 (0.26)d line at week 2 (SE) DLQI score: LS mean change from base- 1.9 (0.25) 5.6 (0.25)d 5.7 (0.25)d line at week 2 (SE) HADS score: LS mean change from base- 0.8 (0.23) 2.9 (0.23)d 3.0 (0.23)d line at week 2 (SE) HADS score: LS mean change from base- 1.0 (0.28) 4.7 (0.28)d 5.0 (0.28)d line at week 16 (SE) SCORAD VAS itch score: LS mean change 1.26 (0.14) 4.00 (0.14)d 4.06 (0.14)d from baseline at week 16 (SE)h SCORAD VAS sleep score: LS mean 0.82 (0.14) 3.30 (0.14)d 3.40 (0.14)d change from baseline at week 16 (SE)i EQ-5D: patients reporting no pain or dis- 49/362 (13.5) 169/370 (45.7)d 163/377 (43.2)d comfort at week 16, n/N (%)j PGADS: patients reporting their status as 60 (13.0) 98 (21.4)k 102 (22.1)l ‘good’ at week 16 n (%) PGADS: patients reporting their status as 53 (11.5) 174 (38.1)d 169 (36.6)d ‘very good’ or ‘excellent’ at week 16 n (%) PGATE: patients reporting their status as 52 (11.3) 98 (21.4)d 85 (18.4)m ‘good’ at week 16 n (%) PGATE: patients reporting their status as 45 (9.8) 199 (43.5)d 204 (44.2)d ‘very good’ or ‘excellent’ at week 16 n (%) DLQI: Dermatology Life Quality Index; EQ-5D: 5-dimension 3-level EuroQoL; HADS: Hospital Anxiety and Depression Scale; LS: least squares; n/N: number of patients with outcome/total number of patients in this treatment group; NRS: Numerical Rating Scale; PCS: Pruritus Categorical Scale; PGADS: Patient Global Assessment of Disease Status; PGATE: Patient Global Assessment of Treatment Effect; POEM: Patient- Oriented Eczema Measure; qw: weekly; q2w: every 2 weeks; SCORAD: SCORing Atopic Dermatitis; SE: standard error; VAS: visual analog scale. a Analyses for patients with Peak Pruritus NRS score  3 were conducted on the subset of patients with baseline Peak Pruritus NRS  3. b p ¼ .0044 vs. placebo. c p ¼ .0019 vs. placebo. d p < .0001 vs. placebo. e Values after first rescue treatment were set to missing (censoring). f p ¼ .0166 vs. placebo. g p ¼ .0035 vs. placebo. h Analysis for SCORAD itch was performed in patients from whom baseline data were collected: placebo, n ¼ 440; dupilumab 300 mg q2w, n ¼ 444; dupilumab 300 mg qw, n ¼ 449. i Analysis for SCORAD sleep was performed in patients from whom baseline data were collected: placebo, n ¼ 440; dupilumab 300 mg q2w, n ¼ 445; dupilumab 300 mg qw, n ¼ 449. j Among the subset of patients who reported at least some pain or discomfort on the EQ-5D at baseline (placebo, n ¼ 362; dupilumab 300 mg q2w, n ¼ 370; dupilumab 300 mg qw, n ¼ 377). k p ¼ .0003 vs. placebo. l p ¼ .0007 vs. placebo. m p ¼ .0026 vs. placebo. patients reported absence of sleep disturbance as assessed by either dose regimen vs. placebo; Table 2). For all POEM items, at POEM (51.2%, 43.5%, and 17.6% for dupilumab q2w, dupilumab week 16 a greater proportion of patients treated with dupilumab, qw, and placebo, respectively; p < .0001, either dose regimen vs. vs. placebo, reported having no symptoms during the past week placebo; Figure 2). (p < .0001, either dupilumab dose regimen vs. placebo; Figure 2). Patient-reported symptoms of AD Symptoms of anxiety and depression Compared with placebo, dupilumab rapidly improved AD symp- toms as assessed by POEM. Significant improvement in POEM Both dupilumab dose regimens improved symptoms of anxiety scores was observed in dupilumab-treated patients as early as and depression as early as week 2, as assessed by HADS, com- week 2, with an LS mean change from baseline of –5.8 for dupilu- pared with placebo. Improvement was maintained through week mab q2w, –6.2 for dupilumab qw, and –1.6 for placebo (p < .0001 16 (p < .0001 both regimens vs. placebo; Table 2). 610 M. J. CORK ET AL. Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw 1.7 ltch 8.3 11.5 17.6 Sleep disturbance 51.2 43.5 15.9 Bleeding 51.4 50.4 POEM 20.7 Oozing 58.6 53.5 9.3 Cracking 38.1 32.9 8.3 Flaking 26.9 25.3 3.9 Dry/rough 12.9 16.2 22.6 Problems caused by skin treatments 50.5 46.8 31.7 Sexual difficulties caused by skin problems 68.5 60.6 27.0 Skin creating problems with partner, friends or family 64.3 56.9 21.1 Skin preventing work or study 52.5 50.0 27.6 Skin causing difficulties doing sports 60.2 DLQI 53.5 23.0 Skin affecting social and leisure activities 58.9 51.5 17.2 Skin influence on clothing 47.0 42.4 24.3 Trouble shopping or looking after home or yard 62.8 56.9 13.9 Embarrassed or self-conscious 40.3 36.4 3.7 p < .0001 for both dose regimens Itchy, sore, painful, stinging skin 13.6 vs. placebo for all items 15.8 0 10 20 30 40 50 60 70 80 90 100 Percentage of patients at week 16 reporting absence of symptoms in the past week Figure 2. Patient-reported symptoms and Qol: percentage of patients reporting absence of symptoms in the past week in each POEM item at week 16 in SOLO 1 and 2 (pooled data), placebo, n ¼ 460; dupilumab 300 mg q2w, n ¼ 457; dupilumab 300 mg qw, n ¼ 462; and percentage of patients reporting ‘not at all’ on individ- ual DLQI items at week 16 in SOLO 1 and 2 (pooled data), placebo, n ¼ 460; dupilumab 300 mg q2w, n ¼ 457; dupilumab 300 mg qw, n ¼ 462. DLQI: Dermatology Life Quality Index; POEM, Patient-Oriented Eczema Measure; qw: weekly; q2w: every 2 weeks; QoL: quality of life. Health-related quality of life 2, vs. 17.7% of placebo recipients, as did 54.4% and 54.2%, respect- ively, at week 16, versus 17.4% of placebo recipients (p < .0001 vs. Improvement in HRQoL, as assessed by the DLQI, versus placebo placebo, either dose regimen; Figure 3). In addition, more dupilu- occurred as early as week 2, with 5.6 LS mean change from base- mab-treated patients reported a ‘good,’ ‘very good,’ or ‘excellent’ line for dupilumab q2w, 5.7 for dupilumab qw, and 1.9 for pla- global treatment effect at each visit, as assessed by PGATE; 57.3% cebo (p < .0001 vs. placebo, either dose regimen; Table 2). At week and 58.0%, respectively, vs. 24.3% of placebo recipients at week 2, 16, more dupilumab- than placebo-treated patients responded ‘not to more than 70% of dupilumab-treated patients at week 6, and at all’ to each item of the DLQI, indicating minimal impact on QoL with sustained improvement though week 16 (p < .0001 vs. placebo, (p < .0001 vs. placebo, either dose regimen; Figure 2). either dose regimen; Figure 3). Global assessment of disease status and treatment effect Safety Patients’ impressions of their disease status, as measured by PGADS, Safety data from the individual studies have been previously pub- improved over time, with more patients in the dupilumab q2w and lished (27). Briefly, the incidence of adverse events was similar in qw groups reporting ‘very good or excellent’ status at week 16, the dupilumab and placebo groups (27). compared with placebo (38.1% and 36.6%, respectively, vs. 11.5%; p < .0001 vs. placebo, either dose regimen; Table 2). Patients whose Discussion baseline PGADS rating was ‘poor/fair’ showed rapid improvement, with 43.9% and 45.3% of patients receiving dupilumab q2w, dupilu- In this pooled analysis of data from SOLO 1 and 2, dupilumab mab qw reporting ‘good,’ ‘very good,’ or ‘excellent’ status by week treatment resulted in rapid improvement of multiple outcomes JOURNAL OF DERMATOLOGICAL TREATMENT 611 PGADS: Placebo PGATE: Placebo Dupilumab 300 mg q2w Dupilumab 300 mg q2w Dupilumab 300 mg qw Dupilumab 300 mg qw 100 or ‘excellent’ on PGADS and PGATE (%) p < .0001 dupilumab vs. placebo for all time points Patients reporting ‘good’, ‘very good’, 80 65.0% 60 62.6% 54.4% 54.2% 40 20 21.1% 17.4% 0 0 2 4 6 8 12 16 Week Figure 3. Percentage of patients reporting ‘good’, ‘very good’, or ‘excellent’ on the PGADS and PGATE through week 16 after reporting ‘poor’ or ‘fair’ at baseline in SOLO 1 and 2 (pooled data). p < .0001 for both dupilumab regimens vs. placebo at all time points. Placebo, n ¼ 460; dupilumab 300 mg q2w, n ¼ 457; dupilumab 300 mg qw, n ¼ 462. PGADS data is for patients reporting ‘poor’ or ‘fair’ at baseline. PGADS: Patient Global Assessment of Disease Status; PGATE: Patient Global Assessment of Treatment Effect; qw: weekly; q2w: every 2 weeks. important to patients, including pruritus, sleep disturbance, pain, QoL, measuring the percentage of patients with the absence of symptoms of anxiety and depression, and HRQoL. symptoms in POEM and DLQI categories. The results presented here are noteworthy because patients Dupilumab treatment has been reported to reduce pain and entering SOLO 1 and 2 had a substantial disease burden not con- discomfort (41). Pain has rarely been evaluated systematically in trolled by topical treatments. Before enrollment, 32.9% of patients AD studies, an important gap in characterizing the burden of AD in SOLO 1 and 33.0% in SOLO 2 had received systemic glucocorti- (9). Recent reports highlight pain as an important symptom in coids, and 25.9% and 31.4%, respectively, had received systemic patients with moderate-to-severe AD and support pain as a rele- immunosuppressants (27). These pooled analyses confirm findings vant outcome in determining AD-related treatment response (47). from previous studies of dupilumab (25–28,41). Future clinical trials in moderate-to-severe AD should administer Pruritus has a considerable negative effect on patients’ HRQoL appropriate PRO scales to characterize the burden of AD-related and sleep (11,14,42,43). In a recent study, nearly 70% of patients pain and enable evaluation of treatment efficacy in different with moderate-to-severe AD reported pruritus caused sleep distur- dimensions of pain. bances including delay falling asleep or waking at night (11). The improvement in anxiety and depression measured by the Sleep deprivation negatively affects HRQoL and daily productivity HADS anxiety and depression subscales reported for the individ- ual SOLO trials (27), in addition to the improvement in overall (42,43). Stronger itch intensity has been linked to increased stress HADS scores reported here, suggests dupilumab reduces anxiety levels and depression (14). and depression, symptoms prevalent among patients with AD The rapid improvement in itch observed in this study may that increase the disease burden in patients with more severe dis- have a downstream effect on other aspects of disease burden, as ease (8). AD-related depression may be not only a secondary indicated by early responses assessed by POEM, DLQI, and HADS, comorbidity but also a symptom caused directly by inflammatory and previous reports that improvement in itch is positively corre- cytokines, as suggested by recent evidence for the contribution of lated with QoL improvement, as measured by DLQI (44). inflammatory cytokines to the development of depression in gen- Improvements in itch and sleep have been demonstrated by eral medicine (48). Improving anxiety and depression in patients other drugs for treatment of moderate-to-severe AD (45). with AD may potentially reduce their risk of suicidal ideation. Significant improvement with dupilumab was seen not only in Global assessments provide a ‘real-world’ assessment of dis- composite measures but also in the individual components of the ease status and treatment effectiveness from the patient’s per- DLQI and POEM, including improvement in itchy, painful, sore or spective, demonstrated by the rapid increase in satisfaction stinging skin, feelings of embarrassment, and reduced sleep dis- among dupilumab-treated patients in this study, reported by the turbance. The observed improvement in itch is also clinically PGATE and PGADS. In this analysis, this self-perceived improve- meaningful, defined as a within-person change of  3–4 points in ment was greater than 70% among dupilumab-treated patients. Peak Pruritus NRS score (46). This pooled analysis is the first to In SOLO 1 and 2, among patients not reaching an IGA score of 0 demonstrate itch improvement as early as day 2 with dupilumab or 1 at week 16, a greater proportion of dupilumab- than pla- treatment. This study also applied stringent criteria to determine cebo-treated patients reported ‘good,’ ‘very good,’ or ‘excellent’ the effectiveness of dupilumab in improving AD symptoms and on the PGATE (49), demonstrating that physician assessments 612 M. J. CORK ET AL. such as IGA might not fully capture disease status and treat- Chao are employees and shareholders of Regeneron ment efficacy. Pharmaceuticals, Inc. A limitation to consider when interpreting these results is this pooled analysis was not pre-specified; therefore, all p values Funding should be considered nominal. In conclusion, dupilumab is not only clinically efficacious in AD Research sponsored by Sanofi and Regeneron Pharmaceuticals, (27), but also demonstrates efficacy in a range of outcomes, with Inc. Medical writing and editorial assistance was provided by Lola significant, early-onset improvements in patient-reported AD MacRae, PhD, and Vicki Schwartz, PhD, of Excerpta Medica, symptoms including itch, pain, sleep disturbance, anxiety and funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. depression, HRQoL, and patients’ assessment of disease status and treatment effect versus placebo in moderate-to-severe AD. ORCID These data expand upon previous reports by showing that dupilu- mab improves AD in multiple dimensions important to the Sebastien Barbarot http://orcid.org/0000-0002-6629-9100 patient and highlight the importance of PROs in assessing the Luis Puig http://orcid.org/0000-0001-6083-0952 efficacy of treatments for AD. References Disclosure statement 1. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of Dr. Cork is an investigator and consultant for AbbVie, Astellas crisaborole ointment, a novel, nonsteroidal phosphodiester- Pharma, Boots Pharmaceuticals, Dermavant, Galapagos NV, ase 4 (PDE4) inhibitor for the topical treatment of atopic Galderma, Hyphens Pharma, Johnson & Johnson, Leo Pharma, dermatitis (AD) in children and adults. J Am Acad Dermatol. L’Oreal, Menlo Therapeutics, Inc., Novartis, Oxagen Limited, Pfizer, 2016;75:494–503.e6. Procter & Gamble, Regeneron Pharmaceuticals, Inc., Reckitt 2. Bieber T. Atopic dermatitis. N Engl J Med. 2008;358: Benckiser, and Sanofi Genzyme. Dr. Eckert is an employee of and 1483–1494. may hold stock and/or stock options in Sanofi. Dr. Simpson has 3. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care received research funding from AbbVie, Amgen, Celgene, Chugai, for the management of atopic dermatitis: section 1. Dermira, Galderma, Genentech, Lilly, Menlo Therapeutics, Diagnosis and assessment of atopic dermatitis. J Am Acad Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme, and has Dermatol. 2014;70:338–351. received consultancy honoraria from Anacor, Asubio, Celgene, 4. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care Galderma, Genentech, Medicis, and Merck. Dr. Armstrong is an for the management of atopic dermatitis: section 2. employee of The University of Southern California and has Management and treatment of atopic dermatitis with top- received consultancy honoraria from AbbVie, Amgen, Eli Lilly, ical therapies. J Am Acad Dermatol. 2014;71:116–132. Janssen, Merck, Novartis, and Pfizer; research funding from 5. Boguniewicz M, Leung DY. Atopic dermatitis: a disease of AbbVie, Eli Lilly and Janssen; and speaker honoraria from AbbVie. altered skin barrier and immune dysregulation. Immunol Dr. Barbarot is an investigator and consultant with honorarium for Rev. 2011;242:233–246. Pierre Fabre Laboratories and has received honoraria as a speaker 6. Werfel T, Allam JP, Biedermann T, et al. Cellular and molecu- for Bioderma and for participation on advisory boards for Sanofi lar immunologic mechanisms in patients with atopic derma- titis. J Allergy Clin Immunol. 2016;138:336–349. Genzyme. Dr. Puig has received research funding and consultancy 7. Barbarot S, Auziere S, Gadkari A, et al. Epidemiology of honoraria from Regeneron Pharmaceuticals, Inc. and Sanofi. Dr. atopic dermatitis in adults: results from an international sur- Girolomoni has received consultancy honoraria from and/or is an vey. Allergy. 2018;73:1284–1293. advisory board member for AbbVie, Abiogen, Allmirall, Biogen, 8. Eckert L, Gupta S, Amand C, et al. Impact of atopic derma- Celgene, Eli Lilly, Galderma, Hospira, Leo Pharma, Menlo titis on health-related quality of life and productivity in Therapeutics, Merck, Novartis, Pfizer, Pierre Fabre, Regeneron adults in the United States: an analysis using the National Pharmaceuticals, Inc, Samsung, Sandoz, Sanofi, and Sun Pharma. Health and Wellness Survey. J Am Acad Dermatol. 2017;77: Dr. de Bruin-Weller is principal investigator, advisory board mem- 274–279. ber, and consultant for Regeneron Pharmaceuticals, Inc., and 9. Drucker AM, Wang AR, Qureshi AA. Research gaps in quality Sanofi Genzyme; and principal investigator and advisory board of life and economic burden of atopic dermatitis: the member for AbbVie. Dr. Wollenberg has received lecturer and/or National Eczema Association burden of disease audit. JAMA consultancy honoraria from Almirall, Anacor, Astellas, Beiersdorf, Dermatol. 2016;152:873–874. Bioderma, Celgene, Chugai, Galderma, GSK, Hans Karrer, Leo 10. Sanchez-Perez J, Dauden-Tello E, Mora AM, et al. Impact of Pharma, L’Oreal, MEDA, MedImmune, Merck Sharp & Dohme, atopic dermatitis on health-related quality of life in Spanish Novartis, Pierre Fabre, Pfizer, Regeneron Pharmaceuticals, Inc., and children and adults: the PSEDA study. Actas Dermosifiliogr. Sanofi. Dr. Kataoka has received research funding from Sanofi and 2013;104:44–52. lecturer honoraria from Sysmex. Dr. Remitz has served as primary 11. Simpson EL, Bieber T, Eckert L, et al. Patient burden of mod- investigator, consultant, and lecturer for AbbVie, Eli Lily, Leo erate to severe atopic dermatitis (AD): insights from a phase Pharma, Novartis, Roche, and Regeneron-Sanofi. Dr. Beissert has 2b clinical trial of dupilumab in adults. J Am Acad Dermatol. received speaker honoraria from Abbvie, Actelion, Bristol Myers 2016;74:491–498. Squibb, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, 12. Tsianakas A, Luger TA, Radin A. Dupilumab treatment Novartis, Pfizer, and La Roche-Posay, and is an advisory board improves quality of life in adult patients with moderate-to- member for Actelion, Amgen, Celgene, Galderma, Janssen-Cilag, severe atopic dermatitis: results from a randomized, pla- Leo Pharma, Lilly, Menlo Therapeutics, Merck Sharp & Dohme, cebo-controlled clinical trial. Br J Dermatol. 2018;178: Novartis, and Pfizer. Drs. Mastey, Ardeleanu, Chen, Gadkari, and 406–414. JOURNAL OF DERMATOLOGICAL TREATMENT 613 13. DaVeiga SP. Epidemiology of atopic dermatitis: a review. 30. Yosipovitch G, Reaney M, Mastey V, et al. Validation of the Allergy Asthma Proc. 2012;33:227–234. peak pruritus numerical rating scale: results from clinical 14. Chrostowska-Plak D, Reich A, Szepietowski JC. Relationship studies of dupilumab in adult patients with moderate-to- between itch and psychological status of patients with severe atopic dermatitis. Presented at: American Academy atopic dermatitis. J Eur Acad Dermatol Venereol. 2013;27: of Dermatology Annual Meeting; 2017 March 3–7; Orlando, e239–e242. FL. Abstract 5063. 15. Yaghmaie P, Koudelka CW, Simpson EL. Mental health 31. Kaufmann R, Bieber T, Helgesen AL, et al. Onset of pruritus comorbidity in patients with atopic dermatitis. J Allergy Clin relief with pimecrolimus cream 1% in adult patients with Immunol. 2013;131:428–433. atopic dermatitis: a randomized trial. Allergy. 2006;61: 16. Dieris-Hirche J, Gieler U, Petrak F, et al. Suicidal ideation in 375–381. adult patients with atopic dermatitis: a German cross-sec- 32. Charman CR, Venn AJ, Williams HC. The patient-oriented tional study. Acta Derm Venerol. 2017;97:1189–1195. eczema measure: development and initial validation of a 17. Silverberg JI. Selected comorbidities of atopic dermatitis: new tool for measuring atopic eczema severity from the atopy, neuropsychiatric, and musculoskeletal disorders. Clin patients’ perspective. Arch Dermatol. 2004;140:1513–1519. Dermatol. 2017;35:360–366. 33. Schram ME, Spuls PI, Leeflang MM, et al. EASI, (objective) 18. Yu SH, Silverberg JI. Association between atopic dermatitis SCORAD and POEM for atopic eczema: responsiveness and and depression in US adults. J Invest Dermatol. 2015;135: minimal clinically important difference. Allergy. 2012;67: 3183–3186. 99–106. 19. Silverberg JI, Garg NK, Paller AS, et al. Sleep disturbances in 34. Kunz B, Oranje AP, Labreze L, et al. Clinical validation and adults with eczema are associated with impaired overall guidelines for the SCORAD index: consensus report of the health: a US population-based study. J Invest Dermatol. European Task Force on Atopic Dermatitis. Dermatology 2015;135:56–66. (Basel). 1997;195:10–19. 20. Sibbald C, Drucker AM. Patient burden of atopic dermatitis. 35. European Task Force on Atopic Dermatitis. Severity scoring Dermatol Clin. 2017;35:303–316. of atopic dermatitis: the SCORAD index. Consensus report 21. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for of the European Task Force on Atopic Dermatitis. the management of atopic dermatitis: section 3. Dermatology. 1993;186:23–31. Management and treatment with phototherapy and sys- 36. Zigmond AS, Snaith RP. The hospital anxiety and depression temic agents. J Am Acad Dermatol. 2014;71:327–349. scale. Acta Psychiatr Scand. 1983;67:361–370. 22. Megna M, Napolitano M, Patruno C, et al. Systemic treat- 37. Bjelland I, Dahl AA, Haug TT, et al. The validity of the Hospital Anxiety and Depression scale. An updated litera- ment of adult atopic dermatitis: a review. Dermatol Ther ture review. J Psychosom Res. 2002;52:69–77. (Heidelb). 2017;7:1–23. 38. Basra MK, Salek MS, Camilleri L, et al. Determining the min- 23. Guttman-Yassky E, Simpson E, Margolis D, et al. 2016. imal clinically important difference and responsiveness of Patient-reported disease burden in adults with atopic the Dermatology Life Quality Index (DLQI): further data. dermatitis: a US cross-sectional study. Poster presented at: Dermatology (Basel). 2015;230:27–33. The 25th European Academy of Dermatology and 39. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)-a Venereology Congress; 2016 September 28–October 2; simple practical measure for routine clinical use. Clin Exp Vienna, Austria. Dermatol. 1994;19:210–216. 24. Gandhi NA, Bennett BL, Graham NM, et al. Targeting key 40. Szende A, Janssen B, Cabases J, editors. Self-reported popu- proximal drivers of type 2 inflammation in disease. Nat Rev lation health: an international perspective based on EQ-5D. Drug Discov. 2016;15:35–50. Dordrecht, Netherlands: Springer; 2014. 25. Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment 41. Simpson EL. Dupilumab improves general health-related in adults with moderate-to-severe atopic dermatitis. N Engl quality-of-life in patients with moderate-to-severe atopic J Med. 2014;371:130–139. dermatitis: pooled results from two randomized, controlled 26. Thaçi D, Simpson EL, Beck LA, et al. Efficacy and safety of phase 3 clinical trials. Dermatol Ther (Heidelb). 2017;7: dupilumab in adults with moderate-to-severe atopic derma- 243–248. titis inadequately controlled by topical treatments: a rando- 42. Murota H, Takahashi A, Nishioka M, et al. Showering reduces mised, placebo-controlled, dose-ranging phase 2b trial. atopic dermatitis in elementary school students. Eur J Lancet. 2016;387:40–52. Dermatol. 2010;20:410–411. 27. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 43. Sutton EL. Psychiatric disorders and sleep issues. Med Clin trials of dupilumab versus placebo in atopic dermatitis. N North Am. 2014;98:1123–1143. Engl J Med. 2016;375:2335–2348. 44. Yosipovitch G, Eckert L, Chen Z, et al. Correlations of itch 28. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long- with quality of life and signs of atopic dermatitis across term management of moderate-to-severe atopic dermatitis dupilumab trials. Ann Allergy Asthma Immunol. 2017;119: with dupilumab and concomitant topical corticosteroids S95. (LIBERTY AD CHRONOS): a 1-year, randomised, double- 45. Ruzicka T, Hanifin JM, Furue M, et al. Anti-interleukin-31 blinded, placebo-controlled, phase 3 trial. Lancet. 2017;389: receptor A antibody for atopic dermatitis. N Engl J Med. 2287–2303. 2017;376:826–835. 29. Phan NQ, Blome C, Fritz F, et al. Assessment of pruritus 46. Simpson E, Beck L, Gadkari A, et al. Defining a responder on intensity: prospective study on validity and reliability of the the Peak Pruritus Numerical Rating Scale (NRS) in patients visual analogue scale, numerical rating scale and verbal rat- with moderate-to-severe atopic dermatitis: detailed analysis ing scale in 471 patients with chronic pruritus. Acta Derm from randomized trials of dupilumab. J Am Acad Dermatol. Venereol. 2012;92:502–507. 2017;76(6 Suppl 1):AB93. 614 M. J. CORK ET AL. 47. Kobyletzki L, Thomas K, Schmitt J, et al. What factors are 49. Simpson E, Silverberg JI, Thaçi D, et al. Atopic dermatitis patients important to patients when assessing treatment response: treated with dupilumab and not achieving Investigator’s Global an international cross-sectional survey. Acta Derm Venerol. Assessment 0 or 1 demonstrated clinically meaningful and sig- 2017;97:86–90. nificant improvements in signs, symptoms, and quality of life: a 48. Felger JC, Lotrich FE. Inflammatory cytokines in depression: post-hoc analysis of the LIBERTY AD SOLO studies. Poster pre- neurobiological mechanisms and therapeutic implications. sented at: The American Academy of Dermatology Annual Neuroscience. 2013;246:199–229. Meeting 2018; February 16–20, 2018; San Diego, CA.