Study Compares Safety of JAK Inhibitors Between Adolescent, Adult Patients

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Pediatric patients treated with Janus kinase inhibitors (JAKi) reporting adverse events (AEs) report higher numbers of lymphatic and blood disorders, recent findings suggest, whereas adults aged 18 years and older report greater numbers of AEs related to disorders of the nervous and musculoskeletal systems.¹

These data represented the conclusion of new research in which populations treated with JAKi both under and over the age of 18 were evaluated to determine, through clinical research and post-approval pharmacovigilance services, whether their safety profiles were comparable among both adult and pediatric patients.

This new research was led by Sahithi Talasila, BS, of Sidney Kimmel Medical College at Thomas Jefferson University. Talasila et al. noted that the US Food and Drug Administration (FDA) approval of JAK inhibitors such as ruxolitinib began, for adolescents, in 2019 and the pediatric approval of these drugs had included limited subject numbers to support their safety.

“This review includes a summary of the available and emerging JAK-inhibitors (JAKi), including industry-sponsored and real-world pharmacovigilance registry data relevant to the safety and efficacy of JAKi treatment for inflammatory skin diseases in children,” Talasila and colleagues wrote.

Trial Design

The investigators looked at reports on AEs which went from November 2011 - February 2023, extracting them from the FDA’s Adverse Event Reporting System (AERS) and CVAROD databases. They specifically assessed 5 JAK inhibitors which had received approval for pediatric patients: upadacitinib, baricitinib, ruxolitinib, abrocitinib, and tofacitinib.

In their collection of the necessary data, the research team searched both databases for each medication, combined the data into an Excel spreadsheet, and evaluated each 1 separately through the use of age filters and combined proportion calculations. The team then reviewed each of the AEs by 2 independent researchers, labeling the AEs based upon the Medical Dictionary for Regulatory Activities (MedDRA) system organ class.

Classification-related disagreements were fixed through the use of consensus discussions, with the investigators’ aim being maintenance of consistency in AE labeling and bias minimization. Their formula combined proportion calculations was the following: combined proportion (%) = (number of AEs noted for specific category/total number of events for the specific JAKi) × 100.

The research team did not include ritlecitinib, another JAKi example which had received pediatric use approval in 2023, within their original assessment. Likely due to the minimal amount of time since the therapy’s approva, the team’s follow-up database search for ritlecitinib-related AEs did not yield entries.

Major Findings

Overall, there were a total of 133,216 adult patients, with 399,649 reported AEs for upadacitinib, baricitinib, ruxolitinib, abrocitinib, and tofacitinib. This was based upon the searches of the FDA AERS and CVAROD databases.

The research team concluded that the AEs which had been most commonly seen among those over 18 had been in 5 principal categories: infections resulting from viruses, fungi, and bacteria among 16.8%; general administration issues and symptoms among 13.5%; musculoskeletal and connective tissue problems among 7.04%; issues with the gastrointestinal system among 5.8%; and disorders of the nervous system disorders among 5.0%.

The team noted that the most common concern had been infections across the adult population. Among those in the pediatric cohort, there were a reported 2,883 AEs among 955 patients total.

The investigators reported that the major AE categories were blood and lymphatic system disorders among 24.0%; infections among 17.2%; pyrexia, fatigue, and other general symptoms among 15.7%; gastrointestinal-related disorders among 13.6%; and respiratory problems among 5.3%.

The research team noted that ruxolitinib-related AEs among children mainly involved blood and lymphatic system issues among 35.2%, adding that there had been a higher incidence than that of adults (8.9%). With their use of baricitinib, children also were found by the team to have a greater proportion of gastrointestinal and respiratory events compared to adults, where infections were shown to be most frequent.

Among those using upadacitinib and abrocitinib, the cohort of children were found to have a high percentage of infections, especially with abrocitinib. Among children given abrocitinib, blood and lymphatic system disorders were more prevalent compared to other AEs.

Despite these types of variations in resulting AEs, the investigators concluded that overall AE patterns for both age cohorts had substantial overlap.

“JAKi are increasingly recognized as largely safe and effective treatments for cutaneous and extracutaneous disease,” the team wrote. “In this study, we describe AEs associated with commercially available JAKi and detected some variation in those reported for children compared to adults.”

References

1. ^{Talasila S, Lee E, Teichner EM, Siegfried EC, Jackson Cullison SR. Analysis of publicly available adverse events reported for pediatric patients treated with Janus kinase inhibitors. Pediatr Dermatol. 2024; 1-7. doi:10.1111/pde.15721.}
2. ^{Kunzmann K. The JAK Inhibitor Safety Conversation. HCPLive. June 10, 2024. https://www.hcplive.com/view/the-jak-inhibitor-safety-conversation. Date accessed: September 6, 2024.}