Pharmacoepidemiologic studies of drug safety in pediatric chronic inflammatory disease

Safety evidence for use of pharmaceutical drugs in children, including treatments for serious conditions such as chronic inflammatory diseases, is generally scarce. Off-label use is common and clinicians need to rely on evidence from adults when prescribing to children. This is concerning because safety profiles might differ; the metabolism, distribution and absorption of drugs vary between children and adults. The overall aim of this thesis was to develop new, relevant, and pediatric-specific drug safety evidence for treatments of chronic inflammatory disease; both addressing specific safety concerns and screening for signals of previously unknown adverse events. Sub-aims were to evaluate the feasibility of these types of safety studies in the Scandinavian setting and to examine the differences between alternative pharmacoepidemiologic study designs. We conducted analyses based on data from Swedish and Danish national registers covering a source population of 5.3 million children; including 21,000 patients with confirmed chronic inflammatory disease.

In the first study, the aim was to investigate if there is an association between the use of azathioprine and the risk of acute pancreatitis in Swedish and Danish patients with pediatric inflammatory bowel disease (IBD). We found that azathioprine was associated with a 6-fold increased risk of acute pancreatitis during the first 90 days following treatment initiation, compared to no use, based on a sample of 8725 patients (n=3574 azathioprine users). In the second study, we investigated if there is an association between use of tumor necrosis factor-alpha (TNF-α) inhibitors and the risk of serious infection in patients with pediatric IBD in Denmark. We found no significant association between current use of TNF-α inhibitors and the risk of serious infection, based on 2817 patients (n=618 TNF-α inhibitor users), in comparison with no use. The aim of the third study was to perform data mining to detect previously unknown adverse events of TNF-α inhibitors in children with IBD or juvenile idiopathic arthritis (JIA) in Denmark. We used tree-based scan statistics on 1284 incident diagnoses identified during follow-up and found two significant signals, dermatologic complications and psychiatric adjustment disorders. Neither of these signals were considered relevant for further investigation. In the fourth study, we systematically described and compared various pharmacoepidemiologic designs, in particular alternatives to the active comparator new user design. We used target trial emulation as a common framework and drew two conclusions. That eligibility is the key design element that differentiates the designs and that many factors influence the choice of an ideal comparator, including indication, available comparator drugs, treatment patterns, potential effect modification, and sample size. In the fifth and final study, we investigated if there is an association between use of TNF-α inhibitors and the risk of serious infection in Danish patients with JIA. Based on 4493 JIA patients (n=578 TNF-α inhibitor users), we found that current use of TNF-α inhibitors was associated with a two-fold increased risk of serious infection, compared to methotrexate.

In summary, we provided data on three current drug safety concerns in children with chronic inflammatory disease; we showed that Scandinavian health registers are suitable for both targeted and adverse-event signal detection studies; and finally, we provided guidance on the factors that need to be considered when selecting comparators in pharmacoepidemiologic studies.

List of scientific papers

I. Wintzell V, Svanström H, Olén O, Melbye M, Ludvigsson JF, Pasternak B. Association between use of azathioprine and risk of acute pancreatitis in children with inflammatory bowel disease: a Swedish–Danish nationwide cohort study. The Lancet Child & Adolescent Health. 2019;3(3):158-165.
https://doi.org/10.1016/S2352-4642(18)30401-2

II. Wintzell V, Svanström H, Melbye M, Jess T, Olén O, Ludvigsson JF, Pasternak, B. Use of tumour necrosis factor-α inhibitors and the risk of serious infection in paediatric inflammatory bowel disease in Denmark: a nationwide cohort study. The Lancet Gastroenterology & Hepatology. 2019;4(11):845-853.
https://doi.org/10.1016/S2468-1253(19)30266-3

III. Wintzell V, Svanström H, Melbye M, Ludvigsson JF, Pasternak B Kulldorff, M. Data mining for adverse events of tumor necrosis factor-alpha inhibitors in pediatric patients: tree-based scan statistic analyses of Danish nationwide health data. Clinical Drug Investigation. 2020;40(12):1147-1154.
https://doi.org/10.1007/s40261-020-00977-5

IV. Wintzell V, Svanström H, Pasternak B. Selection of comparator group in observational drug safety studies – alternatives to the active comparator new user design. [Submitted]

V. Wintzell V, Svanström H, Melbye M, Ludvigsson JF, Pasternak, B. Association between use of tumor necrosis factor-alpha inhibitors and the risk of serious infection in juvenile idiopathic arthritis – a Danish nationwide cohort study. [Manuscript]