Tale of two studies: Thrombosis associated with JAK and TNF inhibitors for RA

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An analysis more than 42,000 individual case safety reports from the WHO’s VigiBase reaffirms the cautious use of JAK inhibitors in patients with rheumatoid arthritis at high risk of blood clots

An analysis more than 42,000 individual case safety reports from the WHO’s VigiBase – the single largest drug safety data repository in the world – reaffirms the cautious use of JAK inhibitors in patients with rheumatoid arthritis at high risk of blood clots.

Oral JAK inhibitors have dramatically improved the quality of life for some RA patients who fail methotrexate or other conventional therapies.

However, despite their demonstrated efficacy in reducing disease activity, there are persistent concerns for the risk of thrombosis associated with JAK inhibitors.

Both the European Medicines Agency and US FDA issued warnings for high-dose JAK inhibitors after a study in early 2019 reported an increased risk of blood clots in RA patients over 50 years old with high risk of cardiovascular disease who were treated with tofacitinib.

Now, the thromboembolic safety profiles of the first two JAK inhibitors used to treat RA, tofacitinib and baricitinib, have been examined using safety reports of deep vein thrombosis (DVT), pulmonary thrombosis (PT) and pulmonary embolism (PE) retrieved from VigiBase, the WHO global database of individual case safety reports.

Enriqueta Vallejo-Yagüe, a PhD candidate in pharmacoepidemiology at ETH Zürich in Switzerland, presented the study at the 2020 EULAR conference, held online last week.*

More than 40,000 reports for tofacitinib, and roughly 2,140 reports for baricitinib, available as of April 2019, were included in the analysis.

Reports of DVT, PT and PE for tofacitinib and baricitinib were compared with the expected reporting ratio of these thromboembolic events, based on every other drug in the database.

Higher than expected reporting of DVT and PT/PE was observed with tofacitinib use in Europe. In the US, tofacitinib was only associated with increased reporting of PT.

Baricitinib was associated with a three-fold increased risk of thromboembolic events in Europe. No reports for baricitinib were available from the US at the time of data extraction.

“This type of pharmacovigilance study is often one of the first steps taken to identify safety signals during the early approved life of new drugs. Subsequent real-world longitudinal studies will be required to address causality and analyse dose response,” Ms Vallejo-Yagüe said after presenting their findings.

Professor Peter Youssef, a rheumatologist at the Royal Prince Alfred Hospital in Sydney, said although the study was based on case reports (which were likely to be biased towards the side effects of interest) rheumatologists should continue to proceed with caution when considering the use of JAK inhibitors for RA patients at risk of thrombosis.

He also said that ideally, the thromboembolic safety of JAK inhibitors should be considered along with TNF inhibitors, such as adalimumab.

A separate study presented at the EULAR conference analysed the risk of venous thromboembolism (VTE) associated with the long-term use of biologic agents to treat RA compared to conventional synthetic DMARDs – and found TNF inhibitors are associated with a lower risk of thrombosis.

Epidemiologist Martin Schäfer and colleagues from the German Rheumatism Research Centre in Berlin, analysed data of more than 11,000 RA patients who had failed standard therapy, and were treated with either another csDMARD or switched to a biologic agent.

“By treatment with TNF inhibitors, the risk of major VTE events is reduced by almost half in comparison to csDMARDs,” said Schäfer in a statement, providing another treatment option for RA patients.


Thromboembolic safety profile of tofacitinib and baricitinib: an analysis of WHO VigiBase (Abstract) Ann Rheum Dis 2020, 2 June*

TNF inhibitors are associated with a reduced risk of venous thromboembolism compared to csDMARDs in RA patients (Abstract) Ann Rheum Dis 2020, 2 June

*Editor’s note (15 June, 2020): This study has now been published – Drug Safety 2020, 12 June.

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