New analysis to guide individualised assessment and clinical decision-making around use of tofacitinib in RA

Risks of cardiovascular disease or cancer on tofacitinib are higher in people aged 65 or older with a history of smoking

Rheumatoid arthritis is a chronic inflammatory disease that mainly affects a person’s joints, causing pain and disability among other symptoms. Rheumatoid arthritis can affect people of all ages, but it most often starts between the ages of 40 and 60. It is more common in women than men.

There are many treatments available for rheumatoid arthritis, including disease-modifying antirheumatic drugs (often shortened to DMARDs). The term DMARD includes traditional drugs such as methotrexate, as well as newer biologic and targeted synthetic therapies (b/tsDMARDs). These work by targeting specific molecules that cause inflammation. By doing so, they decrease pain and disease worsening. Tofacitinib is a tsDMARD which works by inhibiting a molecule called Janus kinase, or JAK. TNFi (short for tumour necrosis factor inhibitors) are a group of bDMARDs, including adalimumab and etanercept. All drugs go through clinical trials as part of their development.

What did the authors hope to find?
The authors wanted to find subpopulations of people with different relative risks. They hoped that this information would help doctors to make treatment choices for people according to their personal circumstances and risks.

Who was studied?
This analysis included 4,362 people with rheumatoid arthritis who took part in ORAL Surveillance. It also included data from 7,964 people with rheumatoid arthritis from other studies of tofacitinib, plus 783 people with psoriatic arthritis, and 1,157 with ulcerative colitis.

How was the study conducted?
This was a post-hoc analysis based on ORAL Surveillance. This means that the analysis used data that had already been collected in previous trials.

The original ORAL Surveillance trial was designed to compare how often two important events happen in people taking either tofacitinib or a TNFi. The events studied were malignancies (except skin cancer), and major adverse cardiovascular events (MACE). The MACE events included having a heart attack or a stroke, or dying from a cardiovascular cause. To ensure it captured enough events in a reasonable timeframe, the trial enrolled people with higher-than-average risk: everyone taking part had to be at least 50 years old and have at least one other health problem that increased their chance of developing cardiovascular disease, such as smoking, high blood pressure, high cholesterol, diabetes, or a personal or family history of coronary artery disease.

What were the main findings of the study?
The main finding from this analysis is that risks of cardiovascular disease or malignancy are different for people taking TNFi or tofacitinib depending on their age and smoking history.

For people under the age of 65 who had never smoked, the chances of having cancer, cardiovascular events, heart attacks, blood clots, or death from any cause were similar with both tofacitinib and TNFi. These people represent a low-risk group.

But for people aged 65 years or older or for those who had smoked at any point in their life, the chances of having cancer, cardiovascular events, heart attacks, blood clots, or death from any cause were higher for those taking tofacitinib than those taking TNFi. These people represent a high-risk group.

Are these findings new?
It was already known that age and smoking can affect people’s health. But what is new is that this analysis shows that age and smoking can be used to put people into different categories. These easily identifiable and clinically practical subgroups of people with different relative risks can be used to guide individual assessments and clinical decision-making about treatment with tofacitinib.

What are the limitations of the study?
This was a post-hoc analysis, which means there are some limitations around the exploratory nature and the lack of statistical evidence. Two different TNFi were used as comparator depending on the region that people were being treated in. Those in North America received adalimumab, and people everywhere else received etanercept.  Finally, the average follow-up time for data that was taken from other tofacitinib trials was shorter than that from ORAL Surveillance.

What do the authors plan on doing with this information?
The authors have presented these findings at major rheumatology conferences. Educational materials have been developed to make this information widely available. They are currently working on additional analyses to get a deeper understanding about the population at risk.

What does this mean for me?
If you have rheumatoid arthritis, these findings might help to make benefit–risk assessments based on your own personal circumstances. This could guide clinicals about whether you received treatment with tofacitinib.


If you have any concerns about your disease or its treatment, you should talk to your doctor or a healthcare professional involved in your care.

Date prepared: December 2023
Summary based on research article published on: March 2023
From: Summary from Kristensen LE, et al. Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: an analysis of the open label, randomised controlled study ORAL Surveillance. Ann Rheum Dis 2023;82(7):901–10. doi:10.1136/ard-2022-223715

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