Longitudinal utilization of systemic immunomodulators before and after dupilumab approval in children with atopic dermatitis

Abstract

In our cohort study, we sought to describe the utilization patterns of systemic immunomodulators in children with atopic dermatitis (AD) and how utilization changed after approval of dupilumab, the first systemic drug approved for the treatment of AD. Using US nationwide claims data, we identified children with AD who initiated a systemic therapy (dupilumab, cyclosporine, methotrexate, azathioprine, mycophenolate mofetil) from March 2015 to February 2021 and used Sankey plots to describe patterns of starting, switching and discontinuing these drugs. Dupilumab use among children increased from 19.4% before approval in children to 88.3% after approval in 2019-20. Adherence to dupilumab may suggest better tolerance and improved outcomes in children with AD.

Introduction

Atopic dermatitis (AD) is a common skin condition affecting up to 17% of children¹ in the US. Those with moderate to severe disease may require systemic immunomodulatory therapy for disease control.² Poor adherence to medication regimen has been recognized as a leading cause of treatment failure in AD.² In March 2017, dupilumab was the first drug approved for use in adults with AD.³ Dupilumab was approved for adolescents in 2019 and for patients above 6 months of age in June 2022.⁴ In this cohort study, we used a longitudinal claims dataset to describe the starting, switching, and discontinuing pattern of systemic immunomodulating drugs in clinical practice for children with AD, before and after the introduction of dupilumab.

Methods

For this study, we used data from Optum’s de-identifed Clinformatics® Data Mart Database, comprised of data from US based commercial and Medicare Advantage health plans. Patients entered the cohort upon having initiated dupilumab or any one of the non-biologic systemic drugs used in AD treatment - methotrexate, cyclosporine, mycophenolate or azathioprine. The minimum duration of a drug to be considered a line of therapy was 30 days and 14 days overlap for combination therapy. We required that patients be under 18 years of age, have a diagnosis of AD and use a topical agent for AD in the past 365 days, have 365 days of continuous enrollment in their insurance plan and a washout period of 365 days. To help ensure that off-label AD medications were being prescribed for AD, we excluded children who had other indications for starting the off-label study drugs (Table S2).

Patient follow-up started on the day after starting a systemic medication and lasted until 365 days reached, disenrollment, end of data, or death, whichever came first (Figure S1). The sequence of treatments after starting their first systemic medication were determined for each child at 90, 180 and 365 days. We calculated the proportion of patients taking each medication at these intervals and used Sankey plots to illustrate persistence during the following time periods in relation to dupilumab approval in the US: March 1, 2015 to February 28, 2016 (before dupilumab approval), March 1, 2017 to February 28, 2018 (dupilumab approval for adults) and March 1, 2019 to February 28, 2020 (dupilumab approval for adolescents). All analyses were conducted using Aetion Evidence Platform® (2020).⁵

Results

Of 81 million patients in the database, 69,298, 90,830 and 107,582 children with AD met the cohort entry criteria for the three cohorts. After exclusions, the number of children treated with a targeted systemic agent was 22, 36 and 265 in 2015-16, 2017-18 and 2019-20 respectively.

Before dupilumab approval (years 2015-2016), cyclosporine was the most prescribed systemic medication (36.4%). The proportion of patients discontinuing any systemic treatment at 90, 180 and 365 days after cohort entry was 33.3%, 55% and 63.2% respectively (Figure S2). In the year dupilumab was approved for adults (2017-18), cyclosporine was the most prescribed first systemic agent for AD among children (33.3%), followed by methotrexate (22.2%) and dupilumab (19.4%). By the end of that year, off-label dupilumab use among children increased to 32.3% (Figure 1). In the year dupilumab was approved for use in adolescents (2019-20), 88.3% of children who initiated systemic therapy were prescribed dupilumab compared to 4.9% who initiated cyclosporine. At 90, 180 and 365 days after cohort entry, 86.5%, 82.4% and 71.6% children received dupilumab. Of all children who were treated with dupilumab as initial therapy during this period, 3.8%, 5.7% and 13.7% discontinued it at 90, 180 and 365 days respectively (Table S3). At 365 days, the proportion of children who discontinued all systemic therapy was 24.4% (Figure 2).

Figure 1:

Drug utilization pattern among children with AD who initiated a systemic therapy in 2017-18 (Dupilumab approval in adults)

Figure 2:

Drug utilization pattern among children with AD who initiated a systemic therapy in 2019-20 (Dupilumab approval in adolescents)

Conclusion

Upon dupilumab approval for use in adolescents in 2019, we see a paradigm shift in prescribing patterns of systemic agents for AD. Among children, dupilumab was the first systemic agent prescribed to 19.4% in 2017-18, though it had not yet been approved for use in this age group at that time. Not only did dupilumab use surpass all non-biologic systemic drug use in children with AD, but also a larger proportion of children remained on dupilumab at 1 year after initiating treatment. Our study was limited by our use of commercial insurance data, with no representation of uninsured and Medicaid beneficiaries. Additionally, since all non-biologic drugs used for AD are used off-label, diagnosis codes may be misclassified. Though long-term safety is yet to be established, dupilumab approval makes effective systemic therapy now accessible to children as young as 6 months affected by this chronic illness.