Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database

Abstract

Increasing number of Janus kinase (JAK) inhibitors have been approved for chronic haematopoietic neoplasms and inflammatory/autoimmune diseases. We aimed to assess safety of the first three approved JAK inhibitors: ruxolitinib, tofacitinib and baricitinib. In this retrospective observational study, pharmacovigilance data were extracted from the World Health Organization database. Adverse events are classified according to Medical Dictionary for Regulatory Activities hierarchy. Until February 28, 2021, all Individual Case Safety Reports [ICSRs] with the suspected drug ruxolitinib, tofacitinib or baricitinib were included. Disproportionality analysis was performed and the information component (IC) was estimated. Adverse events were considered a significant signal if the lower end of the 95% credibility interval of the IC (IC025) was positive. We identified 126,815 ICSRs involving JAK inhibitors. Ruxolitinib, tofacitinib and baricitinib were associated with infectious adverse events (IC025 1.7, especially with viral [herpes and influenza], fungal, and mycobacterial infectious disorders); musculoskeletal and connective tissue disorders (IC025 1.1); embolism and thrombosis (IC025 0.4); and neoplasms (IC025 0.8, especially malignant skin neoplasms). Tofacitinib was associated with gastrointestinal perforation events (IC025 1.5). We did not find a significant increase in the reporting of major cardiovascular events. We identified significant association between adverse events and ruxolitinib, tofacinitib and baricitinib in international pharmacovigilance database.

Figure 1

Proportion of Preferred Terms (MedDRA) with positive IC025 related to each JAK inhibitor according to the 27 different System Organ Classes. “Pregancy, puerperium and perinatal conditions” is not represented here because of no positive IC025 observed for any of the three drugs. Yellow curve represents tofacitinib, orange baricitinib and blue ruxolitinib. MedDRA: Medical Dictionary for Regulatory Activities; IC₀₂₅: lower limit of the 95% credibility interval of the information component. A positive IC₀₂₅ is the statistical threshold used in VigiBase.

Figure 2

Comparison between the three JAK inhibitors for selected adverse events. ICSR Individual Case Safety Report; ROR [95% CI] reporting odds ratio and 95% confidence interval. MedDRA Medical Dictionary for Regulatory Activities; HLT High Level Term in the MedDRA classification; HLGT High Level Group Term in the MedDRA classification; PT Preferred Term in the MedDRA classification.