Drug Survival in Atopic Dermatitis: Comparison of Biologics and <scp>JAK</scp> Inhibitors in the <scp>BioDay</scp> Registry

With the expansion of targeted treatment options for atopic dermatitis (AD), comparative data are needed. Drug survival analysis can be used to evaluate real-world treatment performance by analyzing the time until treatment discontinuation, serving as a proxy measure for effectiveness and safety, influenced by both patient and physician preferences [1]. This study aimed to compare the 2-year drug survival of biologics and JAKi and identify associated predictors, and secondarily to evaluate the impact of new targeted therapies on dupilumab drug survival. Adult AD patients (≥ 18 years) treated with dupilumab, tralokinumab, abrocitinib, baricitinib, or upadacitinib in daily practice were included from the Dutch prospective, multicentre BioDay registry between January 2021 and October 2024. This period was choisen to ensure at least one alternative targeted therapy to dupilumab was available. Drug survival was visualized with Kaplan–Meier curves by biologic- and JAKi-naïve versus experienced status and by discontinuation reason: overall, adverse effects (AEs, with/without ineffectiveness); ineffectiveness (with/without AEs). Patients still on treatment, lost to follow-up, discontinuing due to pregnancy wish or well-controlled disease were censored. Multivariable Cox regression was performed to assess differences between treatments and identify predictors for discontinuation [2, 3]. Missing data were imputed 50 times and multiple testing was accounted for by the false discovery rate (FDR). The secondary analysis included all dupilumab treatment episodes (TEs) from 2017 through 2024. Alternative therapy availability was modeled as a time-dependent covariate [4]. Statistical methods are detailed in Data S1. The cohort comprised 865 dupilumab, 227 tralokinumab, 144 abrocitinib, 106 baricitinib, and 241 upadacitinib TEs. Dupilumab was primarily used as first-line targeted therapy (n = 710, 82.1%), tralokinumab in 44.9% (n = 102), while JAKi were mostly prescribed as subsequent-line therapy (abrocitinib n = 125, 86.8%; baricitinib n = 75, 70.8%; upadacitinib n = 203, 84.2%; Table 1; Table S1). After 1 and 2 years, biologic-and JAKi-naïve drug survival rates were: dupilumab 84.9%, 77.3%; tralokinumab 72.5%, 47.6%; abrocitinib 60.2%, 27.1%; baricitinib 46.7%, 42.8%; upadacitinib 72.6%, 63.5%, respectively (Figure 1A). Drug survival at 1 and 2 years was generally lower in biologic-/JAKi-experienced patients: dupilumab 82.9%, 68.1%; tralokinumab 59.8%, 49.6%; abrocitinib 53.7%, 27.8%; baricitinib 29.6%, 22.4%; upadacitinib 61.3%, 49.4% (Figure 1D). In both subgroups, discontinuation was mostly associated with ineffectiveness (n = 326, 20.6%), followed by AEs (n = 217, 13.7%), mainly ocular surface disease for biologics (dupilumab: n = 47, 36.3/1000 patient years [PY]; tralokinumab: n = 17, 73/1000 PY) and infections for JAKi (abrocitinib: n = 13, 94.4/1000 PY; baricitinib: n = 9, 89.9/1000 PY; upadacitinib: n = 17, 55.4/1000 PY) (Table S2). At the time of discontinuation due to ineffectiveness, 95.7% (n = 312/326) of patients had an Eczema Area and Severity Index > 7 and/or Numeric Rating Scale for pruritus > 4. The remaining 4.3% had predominantly facial or hand eczema or had started concomitant systemic medication. Multivariable analyses found superior overall drug survival for dupilumab compared to tralokinumab (naïve hazard ratio [HR] 2.9, 95% confidence interval [CI] 2.0–4.2, p < 0.0001; experienced HR 2.2, 95% CI 1.4–3.5, p = 0.003), abrocitinib (naïve HR 4.2, 95% CI 2.2–7.8, p < 0.0001; experienced HR 3.1, 95% CI 2.0–4.7, p < 0.0001), baricitinib (naïve HR 3.7, 95% CI 2.2–6.5, p < 0.0001; experienced HR 5.6, 95% CI 3.5–9.1, p < 0.0001), and upadacitinib (naïve HR 1.9, 95% CI 1.1–3.6, p = 0.08; experienced HR 2.2, 95% CI 1.4–3.4, p = 0.001), although the difference with upadacitinib was no longer statistically significant in naïve patients after FDR correction (Figure 2). Higher baseline NRS-pruritus scores and concomitant immunosuppressants were associated with shorter dupilumab drug survival (Figure S2). Interestingly, older age was associated with longer baricitinib drug survival. Secondary analysis showed that the introduction of new therapies resulted in a significant decline in dupilumab drug survival (HR 2.0, 95% CI 1.4–2.5, p < 0.0001). Few studies have compared biologic and JAKi drug survival in AD. Torres et al. (n = 2,038) reported higher 2-year drug survival for dupilumab (86.3%) versus tralokinumab (66.8%) and upadacitinib (78.7%), but observed similar drug survival for dupilumab and upadacitinib in naïve patients [5]. Schlösser et al. (n = 549) reported lower 18-month drug survival, varying between 70% for dupilumab and 20.4% for baricitinib [6]. Notably, these studies did not account for the absence of alternative targeted therapies for dupilumab between 2017 and 2021. This study highlights that the absence of alternative targeted therapies results in significantly longer drug survival, indicating that treatment availability influences drug survival outcomes. Additionally, drug survival was generally lower in biologic-/JAKi-experienced patients. Nevertheless, after the introduction of alternative treatments in 2021, dupilumab maintained superior drug survival across naïve and experienced subgroups, except among naïve patients treated with upadacitinib, where the difference was not statistically significant. This may partly be explained by dupilumab's well-established long-term effectiveness and safety, and possibly by greater physician and patient familiarity. Lian F. van der Gang: conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, software, validation, visualization, writing – original draft. Celeste M. Boesjes: conceptualization, investigation, methodology, resources, visualization, writing – review and editing. Nicolaas P. A. Zuithoff: conceptualization, formal analysis, methodology, software, supervision, validation, visualization, writing – review and editing. Inge Haeck: conceptualization, investigation, methodology, resources, supervision, visualization, writing – review and editing. Octavian Bacoş-Cosma: investigation, resources, writing – review and editing. Laura Loman: investigation, resources, writing – review and editing. Keneshka Atash: investigation, resources, writing – review and editing. Veroniek Harbers: investigation, resources, writing – review and editing. Simone Stadhouders: investigation, resources, writing – review and editing. Albert J. Oosting: investigation, resources, writing – review and editing. Anneke M. T. van Lynden-van Nes: investigation, resources, writing – review and editing. Klaziena Politiek: investigation, resources, writing – review and editing. Antoni Gostynski: investigation, resources, writing – review and editing. Floor M. Garritsen: investigation, resources, writing – review and editing. Wianda A. Christoffers: investigation, resources, writing – review and editing. Annebeth Flinterman: investigation, resources, writing – review and editing. Wouter R. H. Touwslager: investigation, resources, writing – review and editing. Berit Velstra: investigation, resources, writing – review and editing. Shiarra M. Stewart: investigation, resources, writing – review and editing. Francine C. van Erp: investigation, resources, writing – review and editing. Marlies de Graaf: conceptualization, funding acquisition, investigation, methodology, resources, supervision, visualization, writing – review and editing. Marie-Louise A. Schuttelaar: funding acquisition, investigation, methodology, resources, supervision, visualization, writing – review and editing. Marjolein S. de Bruin-Weller: conceptualization, funding acquisition, investigation, methodology, resources, supervision, visualization, writing – review and editing. We are grateful to all patients in the BioDay registry, whose participation made this study possible. Special thanks to Inge Klaassen, Petra Maas, and the entire BioDay data-entry team for their dedicated efforts. We also thank all dedicated dermatologists, nurses, and Nurse Practitioners for their ongoing valuable support in patient inclusion and follow-up. Patients included in this manuscript participated in the BioDay registry sponsored by Sanofi, Eli Lilly and Company, Leo Pharma, and Pfizer. However, this study was not funded. All decisions regarding the study's design and execution, data collection, management, analysis, interpretation, and manuscript preparation, review, and approval were made independently of any industry contributions. The BioDay registry was reviewed and approved by the local medical ethics committee (METC 18/239, Utrecht, The Netherlands) as a non-interventional study and was in compliance with the Declaration of Helsinki of 1975, as revised in 2024. All patients in this manuscript participated in the BioDay registry. Written informed consent was obtained from all participants. Lian F. van der Gang is a speaker for AbbVie and Sanofi, fees were paid in full to the institution. Celeste M. Boesjes has been a speaker for AbbVie and Eli Lilly. Nicolaas P.A. Zuithoff was involved in studies financed by Eli Lilly. Inge Haeck is a consultant, advisory board member, and/or speaker for AbbVie, Almirall, Amgen, Eli Lilly, Janssen, LEO Pharma, Pfizer, Sanofi, and Regeneron Pharmaceuticals. Keneshka Atash is a speaker for Sanofi. Simone Stadhouders-Keet is an advisory board member for LEO Pharma. Klaziena Politiek is a speaker for AbbVie, Novartis, Sanofi, and Janssen, and a consultant for LEO Pharma. Antoni Gostynski is an advisory board member for AbbVie, Eli Lilly, Janssen, LEO Pharma, Pfizer, Regeneron, UCB, and Sanofi, and he has shares in AbbVie, Janssen, GSK, Sanofi, UCB, and Pfizer, and is a speaker for AbbVie, Sanofi, and UCB. Wianda A. Christoffers is a consultant, advisory board member, and/or speaker for AbbVie, Genzyme, and LEO Pharma. Floor M. Garritsen is an advisory board member and/or speaker for AbbVie, LEO Pharma, Novartis, and Sanofi. Wouter R.H. Touwslager is an advisory board member for Sanofi and LEO Pharma. Marlies de Graaf is a consultant, advisory board member, and/or speaker for AbbVie, ALK, Almirall, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, and Sanofi. Annemie F.S. Galimont-Collen is a consultant, advisory board member, and/or speaker for AbbVie, LEO Pharma, and Sanofi. Marie-Louise A. Schuttelaar is an advisor, consultant, speaker, and/or investigator for AbbVie, Amgen, Eli Lilly, Galderma, Incyte, LEO Pharma, Pfizer, Sanofi, and Regeneron, and she has received grants from Novartis, Pfizer, Regeneron, and Sanofi. Marjolein S. de Bruin-Weller is a consultant, advisory board member, and/or speaker for AbbVie, Almirall, Aslan, Amgen, Eli Lilly, Galderma, LEO Pharma, Pfizer, Regeneron, Sanofi, and Takeda. Shiarra M. Stewart is a speaker for AbbVie. Octavian Bacoş-Cosma, Laura Loman, Veroniek Harbers, Albert J. Oosting, Anneke M.T. van Lynden-van Nes, Annebeth Flinterman, Berit Velstra, and Francine C. van Erp declare no conflicts of interest. Dr. Prof. Marjolein S. de Bruin-Weller (principal investigator) and Lian F. van der Gang (first author) have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1: all70187-sup-0001-DataS1.docx. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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