INTRODUCTION
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease marked by intense itch that can significantly impact quality of life (QOL). While topical corticosteroids (TCS) are the mainstay of treatment, systemic therapies are recommended for patients who have a high composite score (e.g., SCORAD > 50), failed to respond to topical therapy or are unable to participate in normal daily activities while following an adequate treatment regimen. Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, is approved in several countries for the treatment of moderate-to-severe AD and is recommended in adults who are candidates for systemic therapy. The approved starting dose for most patients is 4 mg/day, with possible reduction to 2 mg/day depending on treatment response.
In the BREEZE-AD7 phase 3 trial of baricitinib in combination with TCS, a regimen that reflects standard of care, baricitinib 4 mg plus TCS improved signs and symptoms of moderate-to-severe AD in patients with prior inadequate response to TCS therapy. The trial included many patients who previously failed, inadequately responded to or were intolerant of systemic therapies, a population that may have more severe, treatment-resistant disease. To better understand the impact of prior systemic use on outcomes with baricitinib, this analysis assesses the efficacy of baricitinib 4 mg in adults with moderate-to-severe AD with and without previous systemic therapy.
METHODS
Trial design
BREEZE-AD7 (NCT03733301) was a double-blind, placebo-controlled, parallel-group, 16-week, phase 3 randomized trial performed in 10 countries across Asia, Australia, Europe, and South America. Trial details and primary outcomes were reported previously. Patients were ≥18 years and had a diagnosis of AD, as defined by the American Academy of Dermatology, ≥12 months before screening and a documented history of inadequate response to topical therapies within 6 months before screening. Patients had a vIGA-AD® score ≥3, an Eczema area and severity index (EASI) score ≥16, and ≥10% body surface area affected. Patients with prior use of systemic therapy, defined as treatment of AD with oral corticosteroids, immunosuppressants or biologics, were permitted to be enroled. Patients discontinued topical therapy 2 weeks and systemic therapy 4 weeks before randomization.
Patients were randomized 1:1:1 to receive once-daily oral placebo, 2 mg baricitinib or 4 mg baricitinib. Patients received moderate- and/or low-potency TCS (such as 0.1% triamcinolone cream and 2.5% hydrocortisone ointment, respectively) for active lesions; topical calcineurin inhibitors and/or crisaborole could be used instead of TCS on areas considered inadvisable for TCS.
The study was conducted in accordance with ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. All investigation sites received approval from the appropriate authorized institutional review board or ethics committee. All patients provided written informed consent.
Outcomes
Week-16 endpoints included the proportions of patients achieving a vIGA-AD score 0 (clear) or 1 (almost clear) with a ≥2-point improvement from baseline, a 75% improvement in EASI score (EASI75), a ≥4-point improvement on the Itch numeric rating scale (NRS) among patients with baseline scores ≥4 and ≥4-point improvement in the dermatology life quality index (DLQI) among patients with baseline scores ≥4. Itch NRS was recorded in a daily diary; weekly mean scores were calculated using non-missing scores of the previous 7 days. Other measures were collected at scheduled clinic visits. As prespecified in the statistical analysis plan, outcomes were compared in patients with and without prior systemic therapy use; the proportion of patients achieving DLQI ≥ 4-point improvement by subgroup was a post hoc analysis.
Statistical analysis
Outcomes were analysed in all randomized patients. This report focuses on patients with and without prior systemic therapy treated with placebo versus baricitinib 4 mg, the recommended starting dose for most patients. Due to small sample sizes across subgroups, comparisons were descriptive. Logistic regression was used to evaluate consistent treatment effects across subgroups, with factors for baseline disease severity, treatment, prior systemic therapy use (yes or no) and the interaction of treatment and systemic therapy use. Insignificant treatment-by-subgroup interactions indicated homogenous treatment effects. Data were censored after rescue treatment or study discontinuation, with nonresponder imputation applied to missing data.
RESULTS
Baseline characteristics of patients treated with baricitinib 4 mg with and without previous systemic therapy use (N = 68, N = 43) versus placebo (N = 75, N = 34) are summarized in Table . Patients with prior systemic therapy use had more severe disease and worse itch and DLQI scores compared to patients without previous systemic use. Systemic therapy use varied geographically, with most patients in Japan being naïve to systemics. Among patients with prior systemic therapy, 74.1% used systemic corticosteroids, 55.9% used immunosuppressants including ciclosporin A and 9.1% used biologics.
Table 1 Baseline demographics and clinical characteristics in patients with atopic dermatitis with and without a history of prior systemic therapy.
Characteristic | Prior systemic therapy | No prior systemic therapy | ||
Placebo plus TCS (N = 75) | Baricitinib 4 mg plus TCS (N = 68) | Placebo plus TCS (N = 34) | Baricitinib 4 mg plus TCS (N = 43) | |
Age in years, mean (SD) | 35.3 (13.4) | 34.3 (11.5) | 30.2 (12.2) | 33.4 (11.2) |
Female, n (%) | 28 (37.3) | 22 (32.4) | 10 (29.4) | 14 (32.6) |
Race, n (%) | ||||
Asian | 39 (52.0) | 32 (47.1) | 18 (52.9) | 22 (51.2) |
White | 34 (45.3) | 35 (51.5) | 12 (35.3) | 19 (44.2) |
Other | 2 (2.7) | 1 (1.5) | 4 (11.8) | 2 (4.7) |
Years since AD diagnosis, mean (SD) | 21.7 (12.4) | 26.9 (13.4) | 22.8 (12.0) | 23.3 (12.7) |
Geographic region | ||||
Europe | 26 (34.7) | 20 (29.4) | 12 (35.3) | 19 (44.2) |
Japan | 6 (8.0) | 6 (8.8) | 15 (44.1) | 16 (37.2) |
Other | 43 (57.3) | 42 (61.8) | 7 (20.6) | 8 (18.6) |
vIGA-AD® score of 4 at screening, n (%) | 29 (38.7) | 27 (39.7) | 9 (26.5) | 13 (30.2) |
vIGA-AD® score of 4 at baseline, n (%) | 36 (48.6) | 35 (51.5) | 12 (35.3) | 15 (34.9) |
EASI score, mean (SD) | 28.2 (12.3) | 32.2 (13.1) | 29.3 (12.3) | 28.9 (11.7) |
Itch NRS score, mean (SD) | 7.6 (1.6) | 7.2 (1.9) | 7.0 (1.7) | 6.6 (2.2) |
DLQI score, mean (SD) | 16.1 (8.3) | 16.2 (8.0) | 12.6 (6.5) | 12.3 (7.3) |
Body surface area affected, mean (SD) | 46.6 (24.8) | 53.7 (22.8) | 51.4 (23.5) | 49.5 (24.2) |
Prior topical corticosteroids therapy, n (%) | 73 (97.3) | 66 (97.1) | 34 (100) | 42 (97.7) |
Prior topical calcineurin use, n (%) | 42 (56.0) | 41 (60.3) | 21 (61.8) | 23 (53.5) |
Prior systemic therapy, n (%) | 75 (100) | 68 (100) | - | - |
Corticosteroid use | 59 (78.7) | 47 (69.1) | - | - |
Immunosuppressant use | 43 (57.3) | 37 (54.4) | - | - |
Ciclosporin use | 39 (52.0) | 33 (48.5) | - | - |
Biologic use, n (%) | 6 (8.0) | 7 (10.3) | - | - |
At Week 16, higher proportions of patients achieved efficacy outcomes with baricitinib 4 mg versus placebo (Table ). Among patients with and without prior systemic use treated with baricitinib 4 mg versus placebo, respectively, vIGA-AD (0, 1) was achieved in 27.9% and 34.9% versus 13.3% and 17.6% (treatment-by-subgroup interaction p = 0.967). EASI75 was met in 47.1% and 48.8% versus 22.7% and 23.5% (p = 0.603), Itch NRS ≥ 4-point improvement was observed in 44.4% and 43.2% versus 14.1% and 33.3% (p = 0.085) and DLQI ≥ 4-point improvement was seen in 75.8% and 69.2% versus 52.1% and 54.8% (p = 0.735). Consistent treatment effects were observed between patients with or without prior use of systemics (treatment-by-subgroup interactions p = 0.085 for Itch NRS, p > 0.1 for all others).
Table 2 Efficacy outcomes at Week 16 in patients with atopic dermatitis with and without a history of prior systemic therapy.
Outcome, n (%) | Prior systemic therapy | No prior systemic therapy | ||
Placebo plus TCS (N = 75) | Baricitinib 4 mg plus TCS (N = 68) | Placebo plus TCS (N = 34) | Baricitinib 4 mg plus TCS (N = 43) | |
vIGA-AD® score 0 or 1 | 10 (13.3) | 19 (27.9) | 6 (17.6) | 15 (34.9) |
EASI75 | 17 (22.7) | 32 (47.1) | 8 (23.5) | 21 (48.8) |
≥4-point improvement in Itch NRS score | 10 (14.1) | 28 (44.4) | 11 (33.3) | 16 (43.2) |
≥4-point improvement in DLQI score | 37 (52.1) | 50 (75.8) | 17 (54.8) | 27 (69.2) |
Consistent with the overall study population, the proportions of patients achieving vIGA-AD (0, 1), EASI75 and ≥4-point improvement in the Itch NRS and DLQI increased over time and were consistently higher in patients treated with baricitinib 4 mg versus placebo, regardless of prior systemic therapy use (Figures and ). The separation of curves between baricitinib and placebo for both patients with and without prior systemic therapy was evident by Week 2 for EASI75 and Itch NRS and by Week 4 for vIGA-AD and DLQI.
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DISCUSSION
In this analysis of adults with moderate-to-severe AD, baricitinib 4 mg plus TCS significantly reduced disease activity compared to placebo plus TCS, regardless of prior systemic therapy use. Improvements were consistently seen earlier with baricitinib plus TCS compared to TCS alone, and outcomes were similar between baricitinib-treated patients with and without a history of systemic therapy.
Itch is a highly burdensome symptom of AD with substantial effects on QOL. In the overall population, itch relief was observed as early as 2 days after treatment, with 44% of baricitinib-4-mg-treated patients achieving a clinically meaningful ≥4-point improvement in the Itch NRS by Week 16. Among placebo-treated patients in the current study, patients with prior systemic therapy had lower itch response rates at Week 16 than patients naïve to systemics (14.1% vs. 33.3%), suggesting that spontaneous itch relief is difficult to achieve in patients with prior systemic therapy. However, baricitinib-treated patients had rapid itch relief regardless of having prior systemic use or not (44.4% vs. 43.2%). Additionally, clinically meaningful improvements in skin inflammation, QOL and overall disease severity were observed in both groups with baricitinib, indicating that baricitinib may be effective for patients naïve to systemic therapy and for patients with previous systemic therapy use.
These results are consistent with findings from BREEZE-AD4, in which baricitinib 4 mg plus TCS was superior to placebo plus TCS in improving symptoms in patients with moderate-to-severe AD who had an inadequate response, intolerance or contraindication to ciclosporin A. Patients previously treated with systemic agents, including ciclosporin A, may be more difficult to treat due to the chronic and refractory nature of their disease. However, in both BREEZE-AD4 and the current subgroup analysis of BREEZE-AD7, patients who previously failed or inadequately responded to systemic therapies experienced rapid and significant improvements in signs and symptoms of AD with baricitinib. Moreover, though patients with prior systemic use had more severe baseline disease, baricitinib response rates through Week 16 were similar to those in patients naïve to systemic therapy. This analysis supports findings from BREEZE-AD4 and expands on the comparative effects of baricitinib in patients with and without previous use of systemic therapy, namely that prior systemic therapy does not impact efficacy of baricitinib for treatment of moderate-to-severe AD.
It is not known if patients with prior systemic therapy failed or did not tolerate treatment, nor how long they were on treatment. However, patients previously treated with systemics in this study had longer disease duration and more severe baseline disease than patients naïve to systemics, suggesting these patients represent a refractory population. As dupilumab and other biologics were not yet or had only recently been approved for AD at the time of BREEZE-AD7, few patients had prior experience with biologics. Efficacy of baricitinib in patients with inadequate response to biologics may be investigated in future studies.
CONCLUSIONS
Patients who previously failed or inadequately responded to systemic therapies experienced rapid and significant improvements in signs and symptoms of AD with baricitinib treatment. Response rates were similar in patients naïve to systemic therapy. These findings suggest that prior systemic therapy use does not impact the efficacy of baricitinib for treatment of moderate-to-severe AD. Baricitinib may be an effective treatment option for patients new to systemic therapy and for patients with previous systemic use.
AUTHOR CONTRIBUTIONS
Each author has met the authorship criteria established by the International Committee of Medical Journal Editors. All authors (Antonio Costanzo, Akio Tanaka, Tiago Torres, Bibiana Pérez-García, Bibiana Pérez-García, Yun-Fei Chen, Fan Emily Yang, Jill Kolodsick, Hitoe Torisu-Itakura and Najwa Somani) contributed to the study design and data interpretation. Statistical analysis was performed by Yun-Fei Chen and Fan Emily Yang. All authors contributed to writing and reviewing the manuscript, and all authors approved the final manuscript.
ACKNOWLEDGEMENTS
Medical writing and editorial support were provided by Amy K. Ellinwood, MPH, PhD, of Eli Lilly and Company. This study was funded by Eli Lilly and Company.
CONFLICTS OF INTEREST STATEMENT
A. C. has received research grants from Janssen-Cilag, Novartis, Abbvie and speakers honoraria fom Amgen, Almirall, Abbvie, Boehringer Ingelheim, Celgene, Galderma, Novartis, Lilly, Janssen-Cilag, Sanofi, UCB. A. T. has received research grant from Maruho, consulting fees from Maruho, Torii Pharma, Sanofi and Otsuka Pharma, honorarium from Maruho, Torii Pharma, Sanofi, Otsuka Pharma, Eli Lilly, Pfizer and Abbvie. T. T.: AbbVie, Almirall, Amgen, Arena Pharmaceuticals, Biocad, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Fresenius Kabi, Janssen, LEO Pharma, Eli Lilly, MSD, Mylan, Novartis, Pfizer, Samsung-Bioepis, Sanofi-Genzyme, Sandoz and UCB. B. P. G. has received honoraria as speaker and/or advisor as well as funding to attend conferences for Sanofi, Abbvie, Boheringer Ingelheim, Lilly, Galderma, Leo Pharma, Pierre Fabre, Meda Pharma, FAES Pharma. A. S., Y. C., F. Y., J. K., H. T. I. and N. S. are employees and shareholders of Eli Lilly and Company.
DATA AVAILABILITY STATEMENT
Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at .
ETHICS STATEMENT
The study was conducted in accordance with ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. All investigation sites received approval from the appropriate authorized institutional review board or ethics committee. All patients in this manuscript have given written informed consent for participation in the study and the use of their deidentified, anonymized, aggregated data and their case details (including photographs) for publication.
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Abstract
Background
The Janus kinase (JAK)1/JAK2 inhibitor baricitinib in combination with topical corticosteroids (TCS) improved moderate‐to‐severe atopic dermatitis (AD) in the phase 3 BREEZE‐AD7 trial. Patients with previous systemic therapy may have more severe, treatment‐resistant disease.
Objectives
To assess the efficacy of baricitinib 4 mg in adults with moderate‐to‐severe AD with and without previous use of systemic therapy.
Methods
Patients were randomized 1:1:1 to TCS plus once‐daily oral placebo, 2 mg baricitinib or 4 mg baricitinib for 16 weeks. Outcomes were assessed in patients treated with baricitinib 4 mg with and without previous use of systemic therapy (N = 68, N = 43) versus placebo (N = 75, N = 34). Prior use of systemic therapy was defined as treatment of AD with oral corticosteroids, immunosuppressants or biologics. Endpoints included the proportions of patients achieving a vIGA‐AD® score 0 or 1 with >2‐point improvement from baseline, 75% improvement in the Eczema area and severity index score (EASI75), ≥4‐point improvement on the Itch numeric rating scale (NRS) and ≥4‐point improvement in the dermatology life quality index (DLQI). Logistic regression was used to evaluate consistent treatment effects across subgroups.
Results
At Week 16, among patients with and without previous use of systemics treated with baricitinib 4 mg versus placebo, respectively, vIGA‐AD score (0, 1) was achieved in 27.9% and 34.9% versus 13.3% and 17.6%, EASI75 was met in 47.1% and 48.8% versus 22.7% and 23.5%, Itch NRS ≥ 4‐point improvement was observed in 44.4% and 43.2% versus 14.1% and 33.3% and DLQI ≥ 4‐point improvement was seen in 75.8% and 69.2% versus 52.1% and 54.8%. Consistent treatment effects were observed between patients with or without prior use of systemics (treatment‐by‐subgroup interactions p = 0.085 for Itch NRS, p > 0.1 for all others).
Conclusions
Baricitinib 4 mg significantly reduced disease severity in AD compared to placebo regardless of prior systemic therapy.
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Details

1 Dermatology IRCSS Humanitas Research Hospital, Milan, Italy
2 Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
3 Department of Dermatology, Centro Hospitalar Universitário do Porto, University of Porto, Porto, Portugal
4 Departamento de Dermatología, Hospital Universitario Ramón y Cajal, Madrid, Spain
5 Eli Lilly and Company, Indianapolis, Indiana, USA