Reply to letter to the editor: baricitinib and toxicity is a rare occurrence

We agree with the concerns of baricitinib and its associated safety signals. In our analysis [1], we found 84 cases where spontaneous reports were classified into ‘hepatobiliary disorders’ in terms of SOCs (system organ classes). PTs (preferred terms) belonging to ‘hepatobiliary disorders’ reached threshold criteria for disproportionality include ‘hepatocellular injury,’ ‘cholestasis,’ ‘hepatitis,’ ‘liver injury,’ and ‘hepatic steatosis.’ Only four cases were nominated as ‘drug-induced liver injury’ as the PT, which did not reach statistical significance (ROR = 1.51, 95% CI, 0.57–4.03). The number of cases for a drug or suspected drug adverse reaction not only depends on the frequency of the adverse reaction but also on the condition, duration, and dose of drug use. The effects of baricitinib with respect to liver injury rely on several factors, including but not limited to underlying conditions and co-morbidities, duration and dose of drug exposure, host genetics and also use of other drugs. The drugs reported are assigned as any of ‘primary suspect,’ ‘secondary suspect,’ ‘concomitant,’ or ‘interacting’[2]. Among the 84 cases, 58 were assigned as ‘primary suspect’ (‘primary suspect’ is a description chosen by the person who submitted a report and is their estimate of which drug, if the subject was taking more than one, was likely responsible for the observed adverse event [3]), 19 were secondary suspect drugs, and 7 were concomitant drugs. Among the 58 cases of ‘primary suspect,’ medicines taken alongside included methotrexate (25 cases, 43.1%), prednisolone (13 cases, 22.4%), acetaminophen (5 cases, 8.6%), tacrolimus (4 cases, 6.9%), which might be liable for liver injury.

In a study of 527 patients with rheumatoid arthritis who were treated with baricitinib (2 or 4 mg) or placebo for 24 weeks, serum aminotransferase elevations occurred in up to 17% of baricitinib-treated patients compared to 11% in placebo recipients, but no patient developed alanine aminotransferase elevations over 5 times the upper limit of normal (ULN) or suffered a liver-related serious adverse event [4]. Monitoring of serum aminotransferase levels is however recommended for patients starting JAK inhibitors. In coronavirus disease-19 (COVID-19) patients, use of baricitinib has been associated with a transaminitis that resolved without cessation of the drug [5], but this awaits confirmation in randomized studies, such as the National Institutes of Allergy and Infectious Diseases adaptive ACTT2 phase 3 trial including a remdesevir arm; such studies are clearly the optimal way to interrogate safety and efficacy [6]. Due to its spontaneous reporting nature, adverse events that may present during treatment with a drug, do not necessarily infer a causal relationship, therefore, safety signals of FAERS results must be interpreted with caution.

The global public health crisis has challenged scientists and clinicians to accelerate drug development and implementation, as well as repurposing of existing therapeutics. The main message of our study is consistent with concerns highlighting the requirement for pharmacovigilance, including with use of repurposed medicines.

Declaration of interest

J Stebbing has sat on SABs for Vaccitech, Heat Biologics, Eli Lilly, Replete, Alveo, Certis Oncology Solutions, Greenmantle and Benevolent AI, and has consulted with Lansdowne partners and Vitruvian. He sits on the Board of Directors for BB Biotech Healthcare Trust. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.