We thank the editors for the opportunity to comment on the integrated safety analysis by Bunick et al., reporting safety data of up to 6 years from three phase 3 trials of upadacitinib in adolescents and adults with moderate-to-severe atopic dermatitis (AD).1 Long-term safety data are particularly relevant in a chronic disease such as AD, as many patients initiate treatment at a young age and may require sustained therapy over many years. Several findings of the study are of clinical interest. Higher rates of acne, oral herpes, herpes zoster, hepatic disorders, and laboratory abnormalities, including neutropenia and creatine phosphokinase elevations, were observed with 30 mg compared with 15 mg dosing. Notably, 49.3% of patients with a herpes zoster infection prior to treatment initiation experienced a recurrence during treatment, compared with 11.7% of those without prior infection. Furthermore, the higher rate of serious adverse events in adults aged ≥65 years treated with 30 mg, compared with 15 mg, reinforces the label-recommended lower dose in older patients. These observations are relevant for individualized dose selection in clinical practice. While the reported incidence rates of serious infections, malignancy, major adverse cardiovascular events and venous thromboembolism were generally low, their clinical interpretation warrants careful consideration. The authors provide exposure-adjusted incidence rates (EAIRs), defined as the number of patients with an event divided by the total time at risk. As also noted in a recent Letter to the Editor,2 such measures do not directly reflect the cumulative probability of experiencing an event over a defined period, and clinical interpretability is not straightforward. The authors conclude that there was no increase in adverse events over time and no evidence of cumulative increased risk. Indeed, cumulative event rates up to successive treatment durations (e.g. ≤2 years, ≤3 years) remained comparable across 6 years, suggesting that the annual hazard did not increase. However, the 6-month analyses presented by the authors in table S8 demonstrate that event rates may fluctuate across follow-up. For example, with 30 mg dosing, 7.4 herpes zoster events per 100 patient-years were observed between 12 and 18 months, compared with 4.2 events per 100 patient-years beyond 3 years. These interval-based analyses provide additional insight into how event rates vary over time. Beyond time-stratified analyses, the number of patients contributing data at later timepoints is important for clinical interpretability. As shown by the authors in table S1, 71%–76% of patients reached 2 years of treatment, whereas only 13.8% (15 mg) and 15.5% (30 mg) contributed data at 6 years. Consequently, long-term patient-years derive from a smaller subgroup of patients remaining on treatment. This pattern is also reflected in the higher rates of adverse events leading to treatment discontinuation in the first year compared with the overall 6-year average. Selection related to continued treatment is inherent to long-term extension analyses,3, 4 a key consideration is therefore not the presence of selection per se, but the clarity with which it can be evaluated. It remains unclear to what extent the decline in patient numbers reflects censoring (patients not yet having reached later timepoints), discontinuation due to adverse events or lack of effectiveness, or other reasons. More explicit reporting of the number of patients contributing data at each timepoint and reasons for discontinuation would allow readers to better contextualize the findings and their clinical relevance. In conclusion, the study by Bunick et al. provides important and generally reassuring long-term safety data for upadacitinib in AD. Complementary time-to-event analyses and more detailed reporting of discontinuation rates would further strengthen the clinical applicability of these findings. L.F. van der Gang is a speaker and/or consultant for AbbVie and Sanofi-Genzyme, all fees were paid to the institution, no personal fees were received. N.P.A. Zuithoff was involved in studies financed by Eli Lilly, no personal fees were received. M.S. de Bruin-Weller is a consultant, advisory board member and/or speaker for AbbVie, Almirall, Amgen, Eli Lilly, Galderma, LEO Pharma, Pfizer, Regeneron and Sanofi-Genzyme and she received grants from AbbVie, Almirall, Eli Lilly, LEO Pharma, Pfizer, Regeneron and Sanofi-Genzyme. All grants and speaker and/or consultancy fees were paid to the institution, no personal fees were received. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Gang et al. (Sat,) studied this question.