Clin Drug Investig. 2020 Dec;40(12):1147-1154. doi: 10.1007/s40261-020-00977-5.Epub 2020 Oct 26.

Viktor Wintzell ¹, Henrik Svanström ^2 3, Mads Melbye ^3 4 5, Jonas F Ludvigsson ^6 7 8 9, Björn Pasternak ^2 3, Martin Kulldorff ¹⁰

Author information

• Institutet, 17176, Stockholm, Sweden. viktor.wintzell@ki.se.
• ²Clinical Epidemiology Division T2, Department of Medicine Solna, Karolinska Institutet, 17176, Stockholm, Sweden.
• ³Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
• ⁴Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
• ⁵Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
• ⁶Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
• ⁷Department of Pediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden.
• ⁸Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK.
• ⁹Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.
• ¹⁰Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.

Abstract

Background and objectives: Tumor necrosis factor-alpha (TNF-α) inhibitors are efficacious and considered generally safe in adults. However, pediatric-specific safety evidence is scarce. The aim of this study was to screen for signals of previously unknown adverse events of TNF-α inhibitors in pediatric patients.

Methods: We conducted a data-mining study based on routinely collected, nationwide Danish healthcare data for 2004-2016. Using tree-based scan statistics to identify events with unexpectedly high incidence during TNF-α inhibitor use among patients with inflammatory bowel disease or juvenile idiopathic arthritis, two analyses were performed: comparison with episodes of no use and with other time periods from the same patient. Based on incident physician-assigned diagnosis codes from outpatient and inpatient visits in specialist care, we screened thousands of potential adverse events while adjusting for multiple testing.

Results: We identified 1310 episodes of new TNF-α inhibitor use that met the eligibility criteria. Two signals of adverse events of TNF-α inhibitors, as compared with no use, were detected. First, there were excess events of dermatologic complications (ICD-10: L00-L99, 87 vs. 44 events, risk difference [RD] 3.3%), which have been described previously in adults and children. Second, there were excess events of psychiatric diagnosis adjustment disorders (ICD-10: F432, 33 vs. 7 events, RD 2.0%), which was likely associated with the underlying disease and its severity, rather than with the treatment. The self-controlled analysis generated no signal.

Conclusions: No signals of previously unknown adverse events of TNF-α inhibitors in pediatric patients were detected. The study showed that real-world data and newly developed methods for adverse events data mining can play a particularly important role in pediatrics where pre-approval drug safety data are scarce.