Patients With a Smoking History and Atopic Dermatitis: Long-Term Safety of Upadacitinib for Major Adverse Cardiovascular Events, Venous Thromboembolism, or Malignancy (Excluding Nonmelanoma Skin Cancer)

Introduction & Objectives An integrated safety analysis of data from phase 3 studies of upadacitinib (UPA) demonstrated that the incidence of major cardiovascular adverse events (MACE), venous thromboembolism (VTE), and malignancy (excluding nonmelanoma skin cancer [NMSC]) in patients with moderate-to-severe Atopic Dermatitis (AD) treated for up to 6 years was comparable to or lower than background rates reported in the general AD population. Tobacco smoking is a well-known risk factor for developing MACE, VTE, and malignancy; we evaluated long-term incidence rates of MACE, VTE, and malignancy (excluding NMSC) according to baseline smoking history among patients with AD with up to 6 years of UPA treatment. Materials & Methods Adolescents and adults (aged 12–75 years) with moderate-to-severe AD were randomized 1:1:1 to receive either once-daily oral UPA 15 mg, UPA 30 mg, or placebo as monotherapy (Measure Up 1 and 2) or with concomitant topical corticosteroids (AD Up) for 16 weeks. At week 16, patients receiving placebo were rerandomized 1:1 to UPA 15 mg or 30 mg, while patients initially randomized to UPA continued their assigned treatment. Incidence of MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), VTE (deep vein thrombosis or pulmonary embolism [fatal and nonfatal]), and malignancy (excluding NMSC) was assessed as exposure-adjusted incidence rates per 100 patient-years (n/100 PY). Background rates of MACE, VTE, and malignancy (excluding NMSC) in the general United States AD population were assessed in a retrospective observational analysis using claims-based data from the Optum Clinformatics Data Mart. The real-world reference population was restricted to patients aged 12–75 years with a diagnosis of AD during the study period (March 2017–September 2024) determined by International Classification of Diseases 9th or 10th edition codes (≥ 1 inpatient or ≥ 2 outpatient claims for AD), and rates were estimated using weights to mimic the age and sex distribution in the UPA phase 3 population. Risk stratification was based on self-reported smoking history at baseline (current/former smoker vs never smoked). Results A total of 2683 patients from the UPA phase 3 studies were included in the analysis (UPA 15 mg, n = 1337, PY = 4435.2; UPA 30 mg, n = 1346, PY = 4752.5). Real-world background rates of MACE, VTE, and malignancy (excluding NMSC) from the claims-based study were assessed in a cohort of 50,447 patients with AD. Among patients treated with UPA, long-term incidence rates in the smoker and nonsmoker cohorts by dose were low for MACE (all ≤ 0.3 n/100 PY), VTE (all ≤ 0.2 n/100 PY), and malignancy excluding NMSC (all ≤ 0.7 n/100 PY), and were below or consistent with real-world incidence rates in patients with AD in the United States for both smokers and nonsmokers. Conclusions Among patients with moderate-to-severe AD who received UPA treatment for up to 6 years, incidence rates of MACE, VTE, and malignancy (excluding NMSC) were low. These rates were lower than or consistent with background rates observed in a real-world population of patients with AD, regardless of smoking history.