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In October, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a drug safety alert for tofacitinib, a treatment used for rheumatoid arthritis, psoriatic arthritis and ulcerative colitis.


The alert, issued thanks to the ORAL Surveillance study, which compared the safety of tofacitinib and TNF inhibitors (TNFi) in patients at increased risk of cancer or heart disease, says: “Tofacitinib should not be used in patients older than 65 years of age, people who are current or past smokers, or individuals with other cardiovascular or malignancy risk factors (such as diabetes or coronary artery disease) unless there are no suitable treatment alternatives.”


In younger patients, without these risk factors, there’s no evidence of any increase in cardiac events or cancers.


Dr James Galloway, consultant rheumatologist at King’s College London, explains what the alert means for rheumatology departments.


The ORAL Surveillance study

The study’s unusual in several respects. It’s an endpoint-driven non-inferiority design, designed to continue until a certain number of people had cancer or cardiac events. It tested whether tofacitinib was as safe as TNFi, but not whether it was either better or worse. This latter point is a subtle but important distinction; interpreting the study needs some caution.


The study wasn’t able to conclude that tofacitinib was non-inferior to TNFi. This doesn’t necessarily mean that tofacitinib is worse than TNFi, but the inevitable conclusion is that it might be. As clinicians, we always want to err on the side of caution when it comes to safety.


Important caveats: advice to departments

The challenge for departments is complex. Study data supports preferential use of a TNFi over tofacitinib in older patients or those at increased risk of cardiac event, but most of us would use a TNFi preferentially anyway, primarily due to lower costs. Unfortunately, we don’t have any head-to-head data for tofacitinib and other options in higher-risk populations.


Decisions need to be more nuanced, balancing likelihood of response and individualised risks of harm. Every drug we use carries some risk, and the rheumatologist’s role is to communicate these risks and benefits to patients so shared treatment decisions are made. Some patients may prioritise an available oral treatment, while others may rank safety a higher priority. Impacts on COVID-19 risks and vaccine responses are another dimension that add considerable complexity to the conversation.


Patient discussion

A key consideration is that as clinicians, we should try, where possible, to communicate information to patients using absolute risk terms, as opposed to relative risks. Concepts such as number needed to treat, or number needed to harm, can be very helpful in discussions.