Dupilumab treatment for atopic dermatitis is associated with decreased utilization of psychostimulants for attention deficit hyperactivity disorder: A retrospective cohort study

To the Editor: Recently, atopic dermatitis (AD) has been associated with an increased propensity for concomitant attention deficit hyperactivity disorder (ADHD).1Strom M.A. Fishbein A.B. Paller A.S. Silverberg J.I. Association between atopic dermatitis and attention deficit hyperactivity disorder in U.S. children and adults.Br J Dermatol. 2016; 175: 920-929Crossref PubMed Scopus (114) Google Scholar,2Xu Y.C. Wang J.P. Zhu W.J. Li P. Childhood atopic dermatitis as a precursor for developing attention deficit/hyperactivity disorder.Int J Immunopathol Pharmacol. 2020; 34 (2058738420962902)Crossref Scopus (7) Google Scholar Dupilumab, a monoclonal antibody targeting the IL-4R alpha, is approved by the Food and Drug Administration for moderate-to-severe AD (age ≥6 months). Dupilumab therapy has been shown to improve AD related symptomatology; however, it is unknown if dupilumab affects ADHD in patients with AD. This study characterized the prevalence of psychostimulant and nootropic (ie, natural or synthetic substances known as “cognitive enhancers”) use amongst individuals with AD and ADHD, with and without dupilumab treatment, as well as the prevalence of psychostimulant and nootropic use before and after dupilumab initiation. AD and ADHD patients were queried using validated ICD-10 (International Classification of Diseases 10th Revision)-Clinical Modification diagnoses, L20 and F90, respectively via TriNetX's Research Network. The index event was defined as the start of dupilumab for the dupilumab exposed cohort and the first diagnosis of AD and ADHD for the dupilumab nonexposed cohort. To assess the association of dupilumab use with psychostimulant and nootropic use, the observation period for outcome analysis was defined as 1 to 5 years following the index event. To compare the effects of dupilumab use before and after exposure, the observation periods for outcome analysis were defined as 1 to 5 years prior to and after the index event in the dupilumab exposed cohort. The primary outcome studied for each analysis was the use of medications from the N06B therapeutic subgroup of the Anatomical Therapeutic Chemical classification system: psychostimulants, agents used for ADHD, and nootropics (Anatomical Therapeutic Chemical:N06B). A total of 109,586,506 patient records from 78 Healthcare Organizations were available on the TriNetX Research Network at the time of analysis. Of which 56,525 patients concurrently had diagnoses of AD and ADHD (754 treated with dupilumab; 55,771 never treated with dupilumab). The 1 to 5-year incidence of psychostimulant and nootropic use for ADHD was significantly decreased following dupilumab exposure in patients with AD compared to those who were never on dupilumab (relative risk [RR] [95% confidence interval (CI)]: 0.85 [0.75-0.96]); males (RR [95% CI]: 0.75 [0.63-0.89]); and females (RR [95% CI]: 0.99 [0.84-1.16]) (Table I). Likewise, psychostimulant and nootropic use decreased in patients with AD and ADHD after initiation of dupilumab compared to prior initiation of dupilumab (RR [95% CI]: 0.72 [0.62-0.82]); males (RR [95% CI]: 0.67 [0.54-0.84]); and females (RR [95% CI]: 0.77 [0.62-0.95]). Our study suggests that dupilumab treatment for AD is negatively correlated with the utilization of psychostimulants for ADHD.Table IRelative risk of psychostimulant and nootropic use in patients with atopic dermatitis and attention deficit hyperactivity disorder with versus without exposure to dupilumabAtopic dermatitis and ADHDTotal†Totally, 14 participants did not identify as either male or female.MalesFemales(n = 56,525)(n = 34,089)(n = 22,422)−Dupilumab No. of patients55,77133,68622,071 Age of index (year, ±SD)14.3 ± 12.611.8 ± 10.218.1 ± 14.1+Dupilumab No. of participants754403351 Age of index (year, ±SD)24.1 ± 15.920.4 ± 15.028.4 ± 15.7 No. of participants on psychostimulants and nootropics before index311 (41.2%)160 (39.7%)151 (43.0%) No. of participants on psychostimulants and nootropics 1-5 y after index201 (26.7%)95 (23.6%)106 (30.1%)RR of psychostimulant and nootropic use in patients with versus without exposure to dupilumab [95% CI]0.85 [0.75-0.96]0.75 [0.63-0.89]0.99 [0.84-1.16] P-value.007∗Significance = P < .05.<.001∗Significance = P < .05..860RR of psychostimulant and nootropic use in patients before and after starting dupilumab [95% CI]0.72 [0.62-0.84]0.67 [0.54-0.84]0.77 [0.62-0.95] P-value<.001∗Significance = P < .05..005∗Significance = P < .05..017∗Significance = P < .05.ADHD, Attention deficit hyperactivity disorder; CI, confidence interval; No., number; RR, relative risk; SD, standard deviation.∗ Significance = P < .05.† Totally, 14 participants did not identify as either male or female. Open table in a new tab ADHD, Attention deficit hyperactivity disorder; CI, confidence interval; No., number; RR, relative risk; SD, standard deviation. This study has limitations. Only patients who sought medical care are included in the database, missing those with mild or asymptomatic disease. Severity of AD was not evaluated, nor was treatment response to dupilumab. Due to reliance on coding, potential for misclassification exists. Individuals may have been prescribed psychostimulants or nootropics not intended for ADHD. Likewise, dupilumab may have been prescribed for asthma. Currently, no data supports dupilumab use for treatment of behavioral disorders. AD's chronicity is associated with pruritus.3Lyons J.J. Milner J.D. Stone K.D. Atopic dermatitis in children: clinical features, pathophysiology, and treatment.Immunol Allergy Clin North Am. 2015; 35: 161-183Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Chronic itching is linked to insomnia and cognitive behavioral issues.4Lee J. Suh H. Jung H. Park M. Ahn J. Association between chronic pruritus, depression, and insomnia: a cross-sectional study.JAAD Int. 2021; 3: 54-60Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Dupilumab improves both itch and sleep disturbances.5D'Ippolito D. Pisano M. Dupilumab (dupixent): an interleukin-4 receptor antagonist for atopic dermatitis.P T. 2018; 43: 532-535PubMed Google Scholar We hypothesize that dupilumab may decrease the need for medical management of ADHD by improving AD symptoms. None disclosed. Clinical information on electronic medical records including diagnoses, procedures, medications, laboratory values, and genomic information was combined into a single medical language system to create longitudinal records for each patient. Data were curated to a controlled set of vocabulary based on the International Classification of Diseases (ICD), Systemized Nomenclature of Medicine - Clinical Terms (SNOMED-CT), Logical Observation Identifiers Names and Codes (LOINC), and RxNorm. The research network captured over 109 million unique patients from 2002 to 2022 across 78 health care organizations. As a federated network, TriNetX received a waiver from Western Institutional Review Board since only aggregated counts and statistical summaries of deidentified information is distributed, no protected health information is received, and no study-specific activities are performed in retrospective analyses.