LAUSR

The Janus Kinase (JAK) inhibitors tofacitinib and baricitinib are new targeted treatments for rheumatoid arthritis. Recent concerns regarding the risk of thrombosis have led to warnings by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA)1,2.To examine the safety reporting of tofacitinib and baricitinib, with focus on thromboembolic events.Individual case safety reports (ICSRs) for tofacitinib and baricitinib were retrieved from the World Health Organization (WHO) global database (VigiBase) in April 2019. The primary outcomes were deep vein thrombosis (DVT) and pulmonary thrombosis (PT) or pulmonary embolism (PE). A disproportionality analysis was conducted by estimating the reporting odds ratio (ROR) and 95% confidence intervals (CIs) to compare the observed versus expected reporting ratio of DVT or PT|PE for tofacitinib or baricitinib. The ROR were calculated worldwide and stratifying by reporting from Europe or the US. In a secondary analysis, further thrombotic-related outcomes were investigated.In both tofacitinib (n=40,017) and baricitinib (n=2,138) ICSRs, patients with reported DVT or PT|PE were older and had higher reporting of pro-thrombotic medications (e.g., contraceptives) or indicators of thromboembolic risk (i.e., antithrombotic treatment). The use of tofacitinib was associated with a significant increased reporting for DVT (ROR: 2.37 95% CI 1.23-4.56) and PT|PE (ROR 2.38 95% CI 1.45-3.89) in Europe. In the US, tofacitinib was only associated with an elevated reporting of PT (ROR: 2.05 % CI 1.45-2.90). Baricitinib was associated with a 3-fold increased risk of reporting for DVT (ROR: 3.47 95% CI 2.18-5.52) or PT|PE (ROR: 3.44 95% CI 2.43-4.88) in Europe, which accounted for 97% of all baricitinib ICSRs. Secondary thrombotic-related outcomes were poorly reported overall in VigiBase.This study supports the cautious use of JAK inhibitors in patients with rheumatoid arthritis who have a high thrombotic risk profile. Moreover, a potential class effect of JAK inhibitors cannot be ruled out.[1]FDA Drug Safety Communication. Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. Food and Drug Administration (FDA)http://www.fda.gov/drugs/drug-safety-and-availability/safety-trial-finds-risk-blood-clots-lungs-and-death-higher-dose-tofacitinib-xeljanz-xeljanz-xr(2019).[2]EMA confirms Xeljanz to be used with caution in patients at high risk of blood clots. EMA/608520/2019.https://www.ema.europa.eu/en/documents/referral/xeljanz-article-20-procedure-ema-confirms-xeljanz-be-used-caution-patients-high-risk-blood-clots_en.pdf(2019).We are thankful to every pharmacovigilance centre and contributor to the WHO Programme for International Drug Monitoring and VigiBase.While the authors used data from the VigiBase, the WHO global database of ICSRs as a source of information, the conclusions do not represent the opinion of the Uppsala Monitoring Centre (UMC) or the WHO.Enriqueta Vallejo-Yagüe Employee of: Synovo GmbH 2012-2018 (not related to this abstract), Stefan Weiler Consultant of: Gedeon-Richter for drug safety 2017 (not related to this abstract), Andrea Michelle Burden: None declared