Dermatol Ther (Heidelb) (2021) 11:971–982 https://doi.org/10.1007/s13555-021-00534-8 ORIGINAL RESEARCH Itch and Sleep Improvements with Baricitinib in Patients with Atopic Dermatitis: A Post Hoc Analysis of 3 Phase 3 Studies Timo Buhl . David Rosmarin . Esther Serra-Baldrich . Pablo Fernandez-Peñas . Atsuyuki Igarashi . Maria Polina Konstantinou . Sherry Chen . Na Lu . Evangeline Pierce . Marta Casillas Received: March 10, 2021 / Accepted: April 9, 2021 / Published online: April 25, 2021 Ó The Author(s) 2021 ABSTRACT items 1–3 using an electronic daily diary. Data were analyzed by study as least squares mean Introduction: Burdensome symptoms of atopic percent change from baseline in daily scores for dermatitis include itch and sleep disturbance. the randomized patients. Mixed model repeated This post hoc analysis reports the effect of measures analysis was used to analyze change baricitinib on itch and sleep disturbance during from baseline values. the first week of treatment in 3 phase 3 studies. Results: A total of 624, 615, and 329 patients Methods: Patients were randomized 2:1:1:1 to were randomized in BREEZE-AD1, -AD2, and - once-daily placebo or baricitinib 1 mg, 2 mg, or AD7, respectively. Itch severity significantly 4 mg in the BREEZE-AD1 and -AD2 studies and improved with baricitinib 2 mg and 4 mg versus 1:1:1 to once-daily placebo or baricitinib 2 mg placebo starting at day 2 (1 day after first dose) or 4 mg in the BREEZE-AD7 study. Topical cor- in BREEZE-AD1 and -AD7 and at day 1 in ticosteroids were only allowed in BREEZE-AD7. BREEZE-AD2. Patients’ ability to fall asleep Patients completed the itch numerical rating (ADSS item 1) significantly improved with scale and atopic dermatitis sleep scale (ADSS) baricitinib 2 mg and 4 mg versus placebo start- ing at day 2 in all three studies. There were T. Buhl A. Igarashi Department of Dermatology, Venereology and NTT Medical Center, Tokyo, Japan Allergology, University Medical Center Göttingen, Göttingen, Germany M. P. Konstantinou Larrey University Hospital, Toulouse, France D. Rosmarin Department of Dermatology, Tufts Medical Center, S. Chen Boston, MA, USA Tigermed, Somerset, NJ, USA E. Serra-Baldrich N. Lu Dermatology Service, Hospital de la Santa Creu i IQVIA, Morrisville, NC, USA Sant Pau, Barcelona, Spain E. Pierce  M. Casillas (&) P. Fernandez-Peñas Eli Lilly and Company, Lilly Corporate Center, Sydney Medical School, The University of Sydney, Indianapolis, IN 46285, USA Westmead, NSW, Australia e-mail: casillas_marta@lilly.com P. Fernandez-Peñas The Skin Hospital, Darlinghurst, NSW, Australia 972 Dermatol Ther (Heidelb) (2021) 11:971–982 significant improvements in patients waking due to itch (ADSS item 2) with baricitinib 4 mg DIGITAL FEATURES versus placebo starting at day 2 in all three This article is published with digital features, studies. Patients’ ability to return to sleep after including a summary slide, to facilitate under- being woken by itch (ADSS item 3) was signifi- standing of the article. To view digital features cantly improved with baricitinib 4 mg versus for this article go to https://doi.org/10.6084/ placebo starting at day 2 in BREEZE-AD1 and - m9.figshare.14381201. AD2 and at day 4 in BREEZE-AD7. Conclusion: Rapid onset of action, typically 1 day after taking the first dose of baricitinib, INTRODUCTION was observed consistently for the burdensome symptoms of itch and sleep disturbance. Atopic dermatitis is a chronic, relapsing, com- ClinicalTrials.gov identifiers: BREEZE-AD1, plex immune and inflammatory skin condition NCT03334396; BREEZE-AD2, NCT03334422; characterized by various features of atopy. BREEZE-AD7, NCT03733301. Approximately 25% of children and 2–7% of adults are affected by atopic dermatitis world- Keywords: Atopic dermatitis; Baricitinib; Itch; wide [1–3]. Consensus-based European guideli- Patient-reported outcomes; Sleep nes for the treatment of atopic dermatitis in adults currently recommend education, topical agents, wet wrap therapy, ultraviolet (UV) Key Summary Points therapy, psychosomatic counseling, and/or cli- mate therapy for mild-to-moderate disease. For Why carry out this study? severe disease, hospitalization, cyclosporine A, Burdensome symptoms of atopic oral glucocorticosteroids, dupilumab, dermatitis include itch and sleep methotrexate, azathioprine and mycophenolate disturbances. mofetil, psoralen in combination with UVA, and/or alitretinoin are recommended [4]. The phase 3 BREEZE-AD1, -AD2, and -AD7 The primary symptom for atopic dermatitis studies showed that baricitinib, with or is itch (pruritus), which is considered highly without background topical bothersome by patients and can be associated corticosteroids, improved the signs and with a profound negative impact on quality of symptoms of moderate-to-severe atopic life (QoL), manifested as poor overall health and dermatitis compared with placebo. dissatisfaction with life [5]. In a study of 380 This post hoc analysis studies the effect of participants with moderate-to-severe atopic baricitinib on itch and sleep disturbance dermatitis, itch frequency was reported as a during the first week of treatment in problem by 86% of participants, and 42% BREEZE-AD1, -AD2, and -AD7. reported itching C 18 h/day [6]. Very few patients experience an absence of itch for more What was learned from the study? than 1 week at a time [6, 7]. This itching results Baricitinib treatment consistently resulted in scratching, which in turn leads to skin dam- in a rapid onset of action as early as 1 day age, an increased risk of cutaneous infections, after the first dose for the burdensome and even more itching (the vicious itch–scratch symptoms of itch and sleep disturbance. cycle) [8]. The majority of patients with atopic der- These data support the use of baricitinib matitis experience itch during the evening and with or without background topical at night, which causes difficulty in falling asleep corticosteroids for moderate-to-severe in over 80% of patients, as well as frequent atopic dermatitis. nighttime awakenings [7, 9]. This leads to day- time fatigue, irritability, disturbed cognition, Dermatol Ther (Heidelb) (2021) 11:971–982 973 and decreased motor performance [7, 9]. Fur- baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. In thermore, poorer sleep has been shown to be BREEZE-AD7, patients were randomized 1:1:1 to associated with increased disease severity in once-daily placebo or baricitinib at 2 mg or atopic dermatitis [10]. 4 mg for 16 weeks, and the use of low-to-mod- Due to the substantial impact of itch on the erate potency topical corticosteroids was QoL of patients with atopic dermatitis, treat- allowed for active lesions. ments are needed that provide rapid relief as The studies were approved by all local insti- well as durable, long-term control of itch [11]. tutions of the study sites. Details of the insti- Several immunomodulatory agents are under tutions and their ethics committees have been investigation for the treatment of atopic der- previously published [13, 14]. The studies were matitis. Baricitinib, an oral selective Janus performed in accordance with the Declaration kinase (JAK)1/JAK2 inhibitor [12], is indicated of Helsinki 1964 and its later amendments. All in the European Union and is being evaluated subjects provided informed consent to partici- in the USA and other countries for the treat- pate in the study. ment of moderate-to-severe atopic dermatitis in adult patients who are candidates for systemic Patient-reported outcomes therapy. The phase 3, randomized BREEZE-AD1, -AD2, and -AD7 studies investigated oral baric- An electronic daily diary was used to assess itinib as monotherapy (BREEZE-AD1 and -AD2) symptoms in the previous 24 h. Patients com- and in combination with topical corticosteroids pleted multiple items, including the itch (BREEZE-AD7). Baricitinib significantly Numerical Rating Scale (NRS) (measuring the improved the signs and symptoms of moderate- worst itch from 0 = no itch to 10 = worst itch to-severe atopic dermatitis compared with pla- imaginable) [15] and Atopic Dermatitis Sleep cebo at 16 weeks [13, 14]. In all three studies, Scale (ADSS) items 1–3 [16]. The ADSS item 1 baricitinib was found to be well tolerated asks, ‘‘How difficult was it to fall asleep last [13, 14]. night because of your itch?’’; ADSS item 2 asks, Due to the detrimental effects of atopic der- ‘‘How many times did your itch cause you to matitis on QoL, patients require relief of symp- wake up last night?’’; and ADSS item 3 asks, toms as rapidly as possible. Therefore, this post ‘‘Overall, how difficult was it to get back to sleep hoc analysis reports the effect of baricitinib on last night because of your itch?’’. Only those itch and sleep disturbance during the first week who responded C 1 for ADSS item 2 were of treatment in the BREEZE-AD1, -AD2, and - allowed to respond to ADSS item 3. Patients AD7 studies. rated ADSS items 1 and 3 using a 5-point Likert- type scale with response options ranging from METHODS 0 = not at all to 4 = very difficult. Patients rated ADSS item 2 by selecting the number of times Study design they woke up each night due to itch, ranging from 0 to 29 times. The overall severity of a patient’s itching was indicated by selecting the The study designs, patients, assessments, ran- number that best described the worst level of domization and masking methods, procedures, itching in the past 24 h. The ADSS was com- and outcomes for BREEZE-AD1, -AD2, and -AD7 pleted each day for patients’ sleep the previous have been published previously [13, 14]. In night. Each item was scored individually. brief, all three studies included patients with Patients were recommended to take the study moderate-to-severe atopic dermatitis who had medication at approximately the same time an inadequate response to existing topical every day, usually at the start of the day. As therapies; BREEZE-AD1 and -AD2 also allowed patient diaries were used to assess symptoms in patients who were intolerant to topical thera- the previous 24 h, patients could report changes pies. In BREEZE-AD1 and -AD2, patients were randomized 2:1:1:1 to once-daily placebo or 974 Dermatol Ther (Heidelb) (2021) 11:971–982 in symptoms as early as the first day of through day 7, except for baricitinib 2 mg at day treatment. 3 in BREEZE-AD7. Statistically significant improvements in itch NRS compared with pla- Statistical analysis cebo were also observed during the first week of treatment with baricitinib 1 mg in BREEZE-AD1 In this post hoc analysis, the changes from and -AD2. At day 7, the greatest improvements baseline in itch NRS and ADSS items 1–3 were in itch NRS in BREEZE-AD1, -AD2, and -AD7 analyzed for all patients randomized from day 1 were - 25.7, - 18.4, and - 37.8%, respectively, to day 7 in the intention-to-treat population by each with baricitinib 4 mg (Fig. 1). study. Data after any rescue therapy or discon- tinuation were excluded from the analysis. A Rapid improvement in ability to fall mixed model repeated measures analysis was asleep applied to the change from baseline and inclu- ded treatment, region, baseline disease severity, In BREEZE-AD1, -AD2, and -AD7, baricitinib and visit. The treatment-by-visit-interactions 2 mg and 4 mg resulted in statistically signifi- were fixed as categorical effects, and the base- cant improvements in least squares mean per- line and baseline-by-visit-interactions were cent change from baseline in ADSS item 1 fixed as continuous effects with the baseline compared with placebo starting at day 2 and value designated as the mean of the seven daily continuing through day 7. Statistically signifi- assessments prior to the date of first study drug cant improvements in ADSS item 1 compared dose. The treatment comparisons were reported with placebo were also observed during the first as least squares mean percent change from week of treatment with baricitinib 1 mg in baseline and derived as follows: [least squares BREEZE-AD1 and -AD2. At day 7, the greatest mean change from baseline obtained from the improvements in ADSS item 1 in BREEZE-AD1, - mixed model repeated measures analysis/over- AD2, and -AD7 were - 33.5, - 24.5, and all mean at baseline] 9 100. P values for treat- - 52.6%, respectively, each with baricitinib ment comparisons were not controlled by 4 mg (Fig. 2). multiplicity. All data were analyzed with SAS version 9.4 (SAS Institute, Cary, NC, USA). Rapid reduction in nightly awakenings RESULTS In BREEZE-AD1, -AD2, and -AD7, baricitinib 4 mg resulted in a statistically significant Patients improvement in least squares mean percent change from baseline in ADSS item 2 compared with placebo starting at day 2 and continuing A total of 624, 615, and 329 patients were ran- through day 7. Statistically significant domized in BREEZE-AD1, -AD2, and -AD7, improvements in ADSS item 2 compared with respectively. The baseline demographics and placebo were also observed during the first week disease characteristics were balanced among of treatment with baricitinib 1 mg and 2 mg in treatment groups in all three studies (Table 1). BREEZE-AD1 and -AD2 and baricitinib 2 mg in BREEZE-AD7. At day 7, the greatest improve- Rapid improvement in itch ments in ADSS item 2 in BREEZE-AD1, -AD2, and -AD7 were - 41.9, - 45.1, and - 67.8%, In BREEZE-AD1, -AD2, and -AD7, treatment respectively, each with baricitinib 4 mg (Fig. 3). with baricitinib 2 mg and 4 mg resulted in sta- tistically significant improvements in least Rapid improvement in returning to sleep squares mean percentage change from baseline in itch NRS compared with placebo starting at In BREEZE-AD1 and -AD2, baricitinib 4 mg day 2 (1 day after first dose) and continuing resulted in a statistically significant Table 1 Baseline patient demographics and disease characteristics Baseline study characteristics BREEZE-AD1 BREEZE-AD2 BREEZE-AD7 Placebo. Baricitinib Baricitinib Baricitinib Placebo Baricitinib Baricitinib Baricitinib Placebo 1 TCS Baricitinib Baricitinib N = 249 1 mg 2 mg 4 mg N = 244 1 mg 2 mg 4 mg N = 109 2 mg 1 TCS 4 mg 1 TCS N = 127 N = 123 N = 125 N = 125 N = 123 N = 123 N = 109 N = 111 Age (years) 35 (12.6) 36 (12.4) 35 (13.7) 37 (12.9) 35 (13.0) 33 (10.0) 36 (13.2) 34 (14.1) 34 (13.2) 34 (12.8) 34 (11.4) Female, n (%) 101 (40.6) 49 (38.6) 41 (33.3) 42 (33.6) 90 (36.9) 45 (36.0) 58 (47.2) 41 (33.3) 38 (34.9) 39 (35.8) 36 (32.4) Race, n (%) Caucasian 147 (59.5) 74 (58.3) 75 (61.0) 70 (56.5) 169 (69.3) 85 (68.0) 85 (69.1) 82 (66.7) 46 (42.2) 50 (45.9) 54 (48.6) Asian 73 (29.6) 40 (31.5) 35 (28.5) 41 (33.1) 72 (29.5) 36 (28.8) 37 (30.1) 38 (30.9) 57 (52.3) 57 (52.3) 54 (48.6) Duration since AD 26 (15.5) 27 (14.9) 25 (14.6) 25 (14.9) 25 (13.9) 24 (12.7) 24 (13.8) 23 (14.8) 22.0 (12.2) 24.6 (14.8) 25.5 (13.2) diagnosis (years) Dermatol Ther (Heidelb) (2021) 11:971–982 Weight (kg) 73 (15.7) 74 (17.2) 75 (17.7) 74 (17.2) 72 (15.5) 75 (16.6) 72 (14.7) 73 (14.9) 73 (15.8) 72 (15.5) 73 (17.8) Body mass index (kg/m) 25 (4.5) 25 (4.6) 25 (5.1) 25 (4.3) 25 (4.3) 26 (5.2) 25 (5.0) 25 (4.2) 26 (4.6) 25 (4.7) 25 (5.1) Geographic region, n (%) Europea 135 (54.2) 67 (52.8) 67 (54.5) 68 (54.4) 111 (45.5) 57 (45.6) 56 (45.5) 56 (45.5) 38 (34.9) 38 (34.9) 39 (35.1) Japan 45 (18.1) 23 (18.1) 21 (17.1) 22 (17.6) 45 (18.4) 22 (17.6) 22 (17.9) 23 (18.7) 21 (19.3) 20 (18.3) 22 (19.8) Otherb 69 (27.7) 37 (29.1) 35 (28.5) 35 (28.0) 88 (36.1) 46 (36.8) 45 (36.6) 44 (35.8) 50 (45.9) 51 (46.8) 50 (45.0) vIGA-ADc score of 4, n (%) 105 (42.2) 53 (41.7) 52 (42.3) 51 (40.8) 121 (49.6) 63 (50.8) 62 (50.4) 63 (51.2) 48 (44.4) 50 (45.9) 50 (45.0) d EASI 32 (13.0) 29 (11.8) 31 (11.7) 32 (12.7) 33 (12.8) 33 (12.7) 35 (16.0) 33 (12.7) 29 (12.3) 29 (11.9) 31 (12.6) SCORADe 68 (14.0) 66 (14.4) 68 (13.0) 68 (12.9) 68 (12.7) 67 (12.9) 69 (13.3) 68 (13.6) 66.6 (13.8) 66.8 (14.0) 68.3 (13.2) Body surface area affected 53 (23.1) 47 (21.2) 50 (22.1) 52 (21.8) 52 (21.7) 55 (21.9) 55 (26.1) 54 (21.5) 48.1 (24.4) 50.6 (21.6) 52.1 (23.3) Itch NRSf 6.7 (2.0) 6.1 (2.1) 6.4 (2.2) 6.5 (2.0) 6.8 (2.2) 6.4 (2.2) 6.6 (2.2) 6.6 (2.2) 7.4 (1.7) 7.0 (2.1) 7.0 (2.0) g Skin pain NRS 6.1 (2.5) 5.5 (2.4) 5.7 (2.6) 5.7 (2.4) 6.2 (2.5) 5.7 (2.7) 6.2 (2.5) 6.0 (2.6) 6.8 (2.3) 6.3 (2.5) 6.0 (2.5) ADSS item 1h 2.0 (1.1) 1.8 (1.0) 1.9 (1.1) 1.9 (1.0) 1.9 (1.2) 1.8 (1.1) 1.9 (1.1) 1.9 (1.1) 2.3 (1.1) 2.1 (1.1) 2.1 (1.0) ADSS item 2i 3.4 (5.2) 2.5 (3.4) 2.3 (4.1) 3.3 (5.2) 1.8 (2.1) 1.6 (1.8) 2.1 (2.9) 1.9 (2.5) 1.8 (2.0) 1.9 (2.3) 1.8 (2.3) ADSS item 3j 2.2 (1.0) 2.1 (0.9) 2.3 (1.0) 2.2 (0.9) 2.2 (1.0) 2.2 (1.0) 2.2 (1.0) 2.3 (0.9) 2.5 (0.9) 2.4 (1.0) 2.4 (0.8) k POEM 21 (5.6) 20 (5.6) 21 (5.6) 21 (5.6) 21 (6.3) 20 (6.5) 21 (6.0) 20 (6.3) 20.9 (6.7) 21.0 (6.3) 21.4 (6.0) 975 Table 1 continued 976 Baseline study BREEZE-AD1 BREEZE-AD2 BREEZE-AD7 characteristics Placebo. Baricitinib Baricitinib Baricitinib Placebo Baricitinib Baricitinib Baricitinib Placebo 1 TCS Baricitinib Baricitinib N = 249 1 mg 2 mg 4 mg N = 244 1 mg 2 mg 4 mg N = 109 2 mg 1 TCS 4 mg 1 TCS N = 127 N = 123 N = 125 N = 125 N = 123 N = 123 N = 109 N = 111 DLQIl 14 (7.4) 13 (6.8) 13 (7.7) 14 (7.1) 15 (8.1) 15 (8.1) 14 (7.7) 14 (8.4) 15.0 (7.9) 15.0 (7.7) 14.7 (7.9) Data are presented as the mean (SD) unless otherwise indicated. Data for race excludes patients who were not Caucasian or Asian AD Atopic dermatitis, ADSS Atopic Dermatitis Sleep Scale, DLQI Dermatology Life Quality Index, EASI Eczema Area and Severity Index, N number of patients, n number of patients in a subgroup, NRS numeric rating scale, POEM Patient Oriented Eczema Measures, SCORAD SCORing Atopic Dermatitis, SD standard deviation, TCS topical corticosteroids, viGA-AD Validated Investigator Global Assessment for Atopic Dermatitis a Europe: BREEZE-AD1: Czech Republic, Denmark, France, Germany, and Italy; BREEZE-AD2: Austria, Hungary, Poland, Spain, and Switzerland; BREEZE-AD7: Austria, Germany, Italy, Poland, and Spain b Other: BREEZE-AD1: India, Mexico, Russia, and Taiwan; BREEZE-AD2: Argentina, Australia, Israel, and South Korea; BREEZE-AD7: Argentina, Australia, Japan, South Korea, and Taiwan c vIGA-AD measures the investigator’s global assessment of disease severity based on a static 5-point scale from 0 (clear skin) to 4 (severe disease) d EASI scores range from 0 to 72, with higher scores indicating greater severity e SCORAD is a combined score of investigator-reported disease severity and affected body surface area and patient-reported symptoms of itch and sleep dysfunction; scores range from 0–103 f Itch NRS, ranging from 0 (no itch) to 10 (worst itch imaginable) g Skin Pain NRS, ranging from 0 (no pain) to 10 (worst pain) h ADSS item 1 assesses how difficult it was to fall asleep the previous night due to itch using a 5-point Likert-type scale with response options ranging from 0 = not at all to 4 = very difficult i ADSS item 2 assesses the frequency of nighttime awakenings due to itch the previous night on a scale of 0–29 j ADSS item 3 assesses how difficult it was to get back to sleep the previous night due to itch using a 5-point Likert-type scale with response options ranging from 0 = not at all to 4 = very difficult k POEM is a composite measure of patient-reported symptoms, including the effect of symptoms on sleep and evaluates the frequency of symptoms (including itch) and the effect of atopic dermatitis on sleep on a scale of 0–28 l DLQI evaluates health-related quality of life on a scale of 0–30 Dermatol Ther (Heidelb) (2021) 11:971–982 Dermatol Ther (Heidelb) (2021) 11:971–982 977 Fig. 1 Least squares mean percent change from baseline in Fig. 2 Least squares mean percent change from baseline in itch NRS during the first week of treatment in BREEZE- ADSS item 1 during the first week of treatment in AD1 (a), BREEZE-AD2 (b), and BREEZE-AD7 (c). The BREEZE-AD1 (a), BREEZE-AD2 (b), and BREEZE- number of patients assessed at each time point ranged from AD7 (c). The number of patients assessed at each time 215–240 for placebo, 111–125 for baricitinib 1 mg, point ranged from 215–240 for placebo, 111–125 for 113–117 for baricitinib 2 mg, and 115–121 for baricitinib baricitinib 1 mg, 113–117 for baricitinib 2 mg, and 4 mg in BREEZE-AD1; 208–232 for placebo, 101–115 115–121 for baricitinib 4 mg in BREEZE-AD1; for baricitinib 1 mg, 112–116 for baricitinib 2 mg, and 208–232 for placebo, 101–115 for baricitinib 1 mg, 113–120 for baricitinib 4 mg in BREEZE-AD2; and 112–116 for baricitinib 2 mg, and 113–120 for baricitinib 104–105 for placebo, 104–107 for baricitinib 2 mg, and 4 mg in BREEZE-AD2; and 104–105 for placebo, 103–107 for baricitinib 4 mg in BREEZE-AD7. Asterisks 104–107 for baricitinib 2 mg, and 103–107 for baricitinib indicate significant difference compared to placebo at: 4 mg in BREEZE-AD7. Asterisks indicate significant *P B 0.05, **P B 0.01, and ***P \ 0.001. LS least squares, difference compared to placebo at: *P B 0.05, **P B NRS numeric rating scale, TCS topical corticosteroids 0.01, and ***P \ 0.001. LS least squares, TCS topical corticosteroids 978 Dermatol Ther (Heidelb) (2021) 11:971–982 improvement in least squares mean percent change from baseline in ADSS item 3 compared with placebo starting at day 2 and continuing through day 7. In BREEZE-AD7, baricitinib 4 mg resulted in a statistically significant improve- ment in ADSS item 3 compared with placebo on days 4, 5, and 7. Statistically significant improvements in ADSS item 3 compared with placebo were also observed during the first week of treatment with baricitinib 2 mg in all three studies. At day 7, the greatest improvements in ADSS item 3 in BREEZE-AD1, -AD2, and -AD7 were - 25.1, - 17.2, and - 39.3%, respectively, each with baricitinib 4 mg (Fig. 4). DISCUSSION The phase 3 BREEZE-AD1, -AD2, and -AD7 studies showed that baricitinib, with or without topical corticosteroids, significantly improved the signs and symptoms of moderate-to-severe atopic dermatitis compared with placebo at 16 weeks [13, 14]. This post hoc analysis adds to the previously reported findings for BREEZE- AD1, -AD2, and -AD7 and shows that the onset of baricitinib is rapid with improvements in the burdensome symptoms of itch and sleep dis- turbance, typically reported as early as 1 day after the first dose (i.e., day 2). As discussed above, many patients experi- ence itch in the evening and at night, which causes sleep difficulties and substantially Fig. 3 Least squares mean percent change from baseline in impacts QoL [7, 9, 17]. Consequently, it is crit- ADSS item 2 during the first week of treatment in ical for patients’ wellbeing and QoL that treat- BREEZE-AD1 (a), BREEZE-AD2 (b), and BREEZE- ments for atopic dermatitis provide relief of AD7 (c). The number of patients assessed at each time symptoms as quickly as possible. This analysis point ranged from 215–240 for placebo, 111–125 for demonstrates that daily assessment of patient- baricitinib 1 mg, 113–117 for baricitinib 2 mg, and reported outcomes allows for the detection of 115–121 for baricitinib 4 mg in BREEZE-AD1; early improvements. Itch significantly 208–232 for placebo, 101–115 for baricitinib 1 mg, improved with baricitinib 2 mg and 4 mg versus 112–116 for baricitinib 2 mg, and 113–120 for baricitinib placebo starting at day 2 in BREEZE-AD1 and - 4 mg in BREEZE-AD2; and 104–105 for placebo, AD7 and at day 1 in BREEZE-AD2. In all three 104–107 for baricitinib 2 mg, and 103–107 for baricitinib studies, patients’ ability to fall asleep (ADSS 4 mg in BREEZE-AD7. Asterisks indicate significant item 1) significantly improved with baricitinib difference compared to placebo at: *P B 0.05, **P B 2 mg and 4 mg versus placebo starting at day 2, 0.01, and ***P \ 0.001. LS least squares, TCS topical and there were significant improvements in corticosteroids patients’ waking due to itch (ADSS item 2) with baricitinib 4 mg versus placebo starting at day 2. Furthermore, patients’ ability to return to sleep Dermatol Ther (Heidelb) (2021) 11:971–982 979 after being woken by itch (ADSS item 3) was significantly improved with baricitinib 4 mg versus placebo starting at day 2 in BREEZE-AD1 and -AD2 and at day 4 in BREEZE-AD7. Signifi- cant improvements were observed more con- sistently with the baricitinib 4 mg dose compared with the baricitinib 2 mg dose. These data show that baricitinib provides a rapid onset of efficacy, typically 1 day after taking the first dose, for the burdensome symptoms of itch and sleep disturbance. These findings, which show responses to baricitinib are rapid, complement the primary outcome data, indicating that responses to baricitinib are also durable [13, 14]. Several other JAK inhibitors that are approved or under investigation (both oral and topical formulations) for the treatment of ato- pic dermatitis are also being investigated for rapid onset of action for itch [18–22]. While these studies are not head-to-head and do not allow direct comparison of different agents, collectively they suggest that JAK inhibitors are an efficacious therapeutic option with a rapid onset of action in patients with atopic dermatitis. One limitation of this study was that, unlike full sleep studies or actigraphy, the measures reported by study participants were not objec- tive and may not have been self-assessed or reported consistently. Hence, the data should be interpreted with caution. A strength of this study was the consistency in results across the three separate phase 3 studies. Fig. 4 Least squares mean percent change from baseline in ADSS item 3 during the first week of treatment in BREEZE-AD1 (a), BREEZE-AD2 (b), and BREEZE- CONCLUSIONS AD7 (c). The number of patients assessed at each time point ranged from 158–183 for placebo, 65–81 for Baricitinib treatment consistently resulted in a baricitinib 1 mg, 60–74 for baricitinib 2 mg, and 59–83 rapid onset of action, typically 1 day after the for baricitinib 4 mg in BREEZE-AD1; 124–156 for first dose, in the improvement of the clinically placebo, 52–75 for baricitinib 1 mg, 59–74 for baricitinib burdensome symptoms of itch and sleep dis- 2 mg, and 57–76 for baricitinib 4 mg in BREEZE-AD2; turbance. Together with the primary outcome and 48–70 for placebo, 47–74 for baricitinib 2 mg, and data [13, 14] and safety profile [23], the findings 28–65 for baricitinib 4 mg in BREEZE-AD7. Asterisks from this study support the use of baricitinib, indicate significant difference compared to placebo at: with or without topical corticosteroids, in the *P B 0.05, **P B 0.01, and ***P \ 0.001. ADSS atopic treatment of moderate-to-severe atopic dermatitis sleep scale, LS least squares, TCS topical dermatitis. corticosteroids 980 Dermatol Ther (Heidelb) (2021) 11:971–982 ACKNOWLEDGEMENTS Thermo Fisher. David Rosmarin has received honoraria as a consultant for AbbVie, Celgene, We thank the patients, their families, the study Dermavant, Dermira, Eli Lilly and Company, sites, and the study personnel who participated Incyte, Janssen, Novartis, Pfizer, Regeneron, in the BREEZE-AD1, -AD2, and -AD7 studies. Sanofi, Sun Pharmaceuticals, and VielaBio; research support from AbbVie, Amgen, Bristol Myers-Squibb, Celgene, Dermira, Eli Lilly and Funding. This study was sponsored by Eli Company, Galderma, Incyte, Janssen, Merck, Lilly and Company. The journal’s Rapid Service Novartis, Pfizer, and Regeneron Pharmaceuti- Fee was funded by Eli Lilly and Company. cals Inc; and has served as a paid speaker for Authorship. All named authors meet the AbbVie, Amgen, Celgene, Janssen, Eli Lilly and International Committee of Medical Journal Company, Novartis, Pfizer, Regeneron Pharma- Editors (ICMJE) criteria for authorship for this ceuticals Inc, and Sanofi. Esther Serra-Baldrich article, take responsibility for the integrity of has served on advisory boards or acted as a the work as a whole, and have given their speaker for Abbvie, Eli Lilly and Company, approval for this version to be published. Galderma, Novartis, Pfizer, and Sanofi. Pablo Fernández-Peñas has served on advisory boards Authors’ contributions. Evangeline Pierce for AbbVie, Celgene, Eli Lilly and Company, and Marta Casillas conceived and designed the Roche, MSD, Janssen, Novartis, and MEDA; study. Timo Buhl, David Rosmarin, Esther Serra- received grants/research support from AbbVie, Baldrich, Pablo Fernandez-Peñas, Atsuyuki Amgen, Eli Lilly and Company, Janssen, Igarashi, and Maria Polina Konstantinou were Novartis, Pfizer, Regeneron, and Roche; and investigators and collected the data. Sherry received honoraria or consultation fees from Chen and Na Lu conducted the statistical AbbVie, Amgen, Eli Lilly and Company, Gal- analyses. All the authors had full access to all derma, Janssen, La Roc, Merck-Serono, MSD, the data reported in the study and were Novartis, Roche, and Schering Plough. Atsuyuki involved in critically revising the manuscript Igarashi has received honoraria or fees for serv- for important intellectual content. ing on advisory boards, as a speaker and as a consultant, and grants, as an investigator, from Medical writing, editorial, and other assis- AbbVie, Amgen, Eli Lilly and Company, Japan tance. Medical writing support was provided by Tobacco Inc., Leo Pharma, Maruho, Novartis, Andrew Sakko, PhD, CMPP, and editorial sup- Otsuka Pharmaceutical, Pfizer, Sanofi, and Torii port was provided by Cynthia Rae Abbott of Pharmaceutical. Maria Polina Konstantinou has Syneos Health and funded by Eli Lilly and been a principal and subinvestigator for Abbvie, Company in accordance with Good Publication Boehringer Ingelheim, Leo Pharma, Pfizer, and Practice (GPP3) guidelines (http://www.ismpp. Sanofi and a speaker and consultant for Abbvie, org/gpp3). Janssen, and Leo Pharma. Sherry Chen is a full- time employee of Tigermed. Na Lu is a full-time Prior presentation. These data were previ- employee of IQVIA. Evangeline Pierce and ously presented, in part, at the European Acad- Marta Casillas are full-time employees of and emy of Dermatology and Venereology own stock in Eli Lilly and Company. Congress, Vienna, Austria (virtual event), 28 October–1 November 2020 (Buhl T, et al. EADV Compliance with ethics guidelines. The 2020. Virtual Meeting. P0231). studies were approved by all institutions. Details of the institutions and their ethics Disclosures. Timo Buhl has received hono- committees have been previously published raria for lectures and advisory boards from [13, 14]. The studies were performed in accor- AstraZeneca, ALK Abello, Eli Lilly and Com- dance with the Declaration of Helsinki 1964 pany, Janssen, MEDA, Sanofi, and Novartis and and its later amendments. All subjects provided research grants from Kiniksa, Philips, and informed consent to participate in the study. Dermatol Ther (Heidelb) (2021) 11:971–982 981 Data availability. Eli Lilly provides access to 2. Silverberg JI, Gelfand JM, Margolis DJ, et al. Atopic all individual participant data collected during dermatitis in US adults: from population to health care utilization. J Allergy Clin Immunol Pract. the trial, after anonymization, with the excep- 2019;7:1524–32. tion of pharmacokinetic or genetic data. Data are available to request 6 months after the 3. Boguniewicz M, Fonacier L, Guttman-Yassky E, indication studied has been approved in the et al. Atopic dermatitis yardstick: practical recom- mendations for an evolving therapeutic landscape. USA and EU and after primary publication Ann Allergy Asthma Immunol. 2018;120:10-22e2. acceptance, whichever is later. No expiration date of data requests is currently set once data 4. Wollenberg A, Barbarot S, Bieber T, et al. Consen- are made available. Access is provided after a sus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and proposal has been approved by an independent children: part I. J Eur Acad Dermatol Venereol. review committee identified for this purpose 2018;32:657–82. and after receipt of a signed data sharing agreement. Data and documents, including the 5. Silverberg JI, Gelfand JM, Margolis DJ, et al. Patient burden and quality of life in atopic dermatitis in US study protocol, statistical analysis plan, clinical adults: a population-based cross-sectional study. study report, and blank or annotated case report Ann Allergy Asthma Immunol. 2018;121:340–7. forms, will be provided in a secure data sharing environment. For details on submitting a 6. Simpson EL, Bieber T, Eckert L, et al. Patient burden of moderate to severe atopic dermatitis (AD): request, see the instructions provided at http:// insights from a phase 2b clinical trial of dupilumab www.vivli.org. in adults. J Am Acad Dermatol. 2016;74:491–8. Open Access. This article is licensed under a 7. Chrostowska-Plak D, Salomon J, Reich A, Szepi- etowski JC. Clinical aspects of itch in adult atopic Creative Commons Attribution-Non- dermatitis patients. Acta Derm Venereol. 2009;89: Commercial 4.0 International License, which 379–83. permits any non-commercial use, sharing, adaptation, distribution and reproduction in 8. Langan SM, Irvine AD, Weidinger S. Atopic der- any medium or format, as long as you give matitis. Lancet. 2020;396:345–60. appropriate credit to the original author(s) and 9. Yu SH, Attarian H, Zee P, Silverberg JI. Burden of the source, provide a link to the Creative sleep and fatigue in US adults with atopic der- Commons licence, and indicate if changes were matitis. Dermatitis. 2016;27:50–8. made. The images or other third party material 10. Bender BG, Ballard R, Canono B, Murphy JR, Leung in this article are included in the article’s DYM. Disease severity, scratching, and sleep quality Creative Commons licence, unless indicated in patients with atopic dermatitis. J Am Acad Der- otherwise in a credit line to the material. If matol. 2008;58:415–20. material is not included in the article’s Creative 11. Pavlis J, Yosipovitch G. Management of itch in Commons licence and your intended use is not atopic dermatitis. Am J Clin Dermatol. 2018;19: permitted by statutory regulation or exceeds the 319–32. permitted use, you will need to obtain permis- sion directly from the copyright holder. To view 12. Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent a copy of this licence, visit http:// models of arthritis: preclinical characterization of creativecommons.org/licenses/by-nc/4.0/. INCB028050. J Immunol. 2010;184:5298–307. 13. Simpson EL, Lacour JP, Spelman L, et al. Baricitinib in patients with moderate-to-severe atopic der- matitis and inadequate response to topical corti- REFERENCES costeroids: results from two randomized monotherapy phase III trials. Br J Dermatol. 1. Barbarot S, Auziere S, Gadkari A, et al. Epidemiology 2020;183:242–55. of atopic dermatitis in adults: results from an international survey. Allergy. 2018;73:1284–93. 14. Reich K, Kabashima K, Peris K, et al. Efficacy and safety of baricitinib combined with topical corti- costeroids for treatment of moderate to severe 982 Dermatol Ther (Heidelb) (2021) 11:971–982 atopic dermatitis: a randomized clinical trial. JAMA atopic dermatitis. Immunotargets Ther. 2020;9: Dermatol. 2020;156:1333–43. 255–72. 15. Newton L, DeLozier AM, Griffiths PC, et al. 20. Nakagawa H, Nemoto O, Igarashi A, et al. Delgoci- Exploring content and psychometric validity of tinib ointment, a topical Janus kinase inhibitor, in newly developed assessment tools for itch and skin adult patients with moderate to severe atopic der- pain in atopic dermatitis. J Patient Rep Outcomes. matitis: a phase 3, randomized, double-blind, 2019;3:42. vehicle-controlled study and an open-label, long- term extension study. J Am Acad Dermatol. 16. Lee JY, Kim M, Yang HK, et al. Reliability and 2020;82:823–31. validity of the Atopic Dermatitis Symptom Score (ADSS). Pediatr Allergy Immunol. 2018;29:290–5. 21. Bissonnette R, Papp KA, Poulin Y, et al. Topical tofacitinib for atopic dermatitis: a phase IIa ran- 17. Chang YS, Chiang BL. Sleep disorders and atopic domized trial. Br J Dermatol. 2016;175:902–11. dermatitis: a 2-way street? J Allergy Clin Immunol. 2018;142:1033–40. 22. Silverberg JI, Simpson EL, Thyssen JP, et al. Efficacy and safety of abrocitinib in patients with moderate- 18. Nezamololama N, Fieldhouse K, Metzger K, Good- to-severe atopic dermatitis: a randomized clinical erham M. Emerging systemic JAK inhibitors in the trial. JAMA Dermatol. 2020;156:863–73. treatment of atopic dermatitis: a review of abroci- tinib, baricitinib, and upadacitinib. Drugs Context. 23. Bieber T, Thyssen JP, Reich K, et al. Pooled safety 2020;9:2020-8-5. analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J Eur 19. Singh R, Heron CE, Ghamrawi RI, et al. Emerging Acad Dermatol Venereol. 2021;35(2):476–85. role of Janus kinase inhibitors for the treatment of