New insights into the long-term safety of upadacitinib in rheumatoid arthritis

Integrated analysis presented at EULAR 2026 offers new insight into long-term malignancy risk with the JAK inhibitor upadacitinib.

Upadacitinib is a Janus kinase inhibitor (JAKi) approved for the treatment of adults with moderate-to-severe rheumatoid arthritis (RA), following positive findings from the phase 3 SELECT clinical trials. However, concerns over the long-term malignancy risk associated with JAK inhibitors have underscored the need for further safety data on newer agents.

In this interview, Editor-in-Chief Prof. Jérôme Avouac (Rheumatology department, Cochin Hospital, Paris Cité University, Paris, France) discusses the aims, methodology and findings of his integrated analysis assessing malignancy risks associated with upadacitinib in the overall SELECT population and in patients with a higher CV risk.

Abstract: Long-Term Risk of Malignancies with Upadacitinib in Comparison to Adalimumab in Rheumatoid Arthritis Up to 5 Years: Post Hoc Analysis of Six Clinical Trials. EULAR 2026, June 3– 6, London, UK.

touchIMMUNOLOGY coverage of EULAR 2026

What was the rationale for your study into long-term malignancy risk with upadacitinib in RA?

There are still concerns regarding the risk of cancer in patients treated with JAK inhibitors. This is mainly due to the results of the ORAL Surveillance study, which demonstrated an increased risk of cancer in patients treated with tofacitinib compared to those treated with TNF-alpha inhibitors.

More recently, we had a study from the RABBIT registry showing a potential risk of cancer in patients treated with JAK inhibitors. These results mainly include the first generation of JAKis, including tofacitinib and baricitinib. I think it is important we get some data with the newer JAKis, such as upadacitinib.

What were the aims and methodology of your integrated analysis?

We aimed to assess the risk of cancer in patients treated with upadacitinib compared to adalimumab in moderate-to-severe rheumatoid arthritis patients with an exposure up to 5 years. It is important to have a higher exposure to demonstrate the risk of cancer.

We carried out the analysis by pulling 6 randomized control trials from the SELECT program in rheumatoid arthritis. We evaluated the risk of cancer, excluding non-melanoma skin cancers, in the overall population and in selected patients with higher cardiovascular risk.

What were the findings in terms of the malignancy risk across the treatment groups?

Firstly, an important result was that the cancer rate was low in this population and there was not much difference between patients treated with upadacitinib or adalimumab. For instance, the frequency of cancer was 2.5% in upadacitinib-treated patients compared to 2.1% in adalimumab-treated patients. When we performed the exposure-adjusted incidence analysis, the incidence was 0.8 per 100 patient-years in upadacitinib-treated patients and 1.1 per 100 patient-years in adalimumab-treated patients. So quite reassuring data.

Did these findings differ across patient populations?

It was also important to assess the high-risk cardiovascular population, and in this specific population the results were the same. There was no significant difference in the risk of cancer between upadacitinib- and adalimumab-treated patients.

We have to be cautious with these results because this was a post-hoc analysis with a very low number of events and with very few patients receiving adalimumab. But the data in these high-risk patients also appears reassuring.

How will these findings impact clinical practice?

Firstly, the data are really reassuring. In this population, the risk of cancer was low with no difference according to the treatment received. But this was a selection of phase 3 randomized controlled trials with a population of patients which might differ to the patients we see in clinical practice, who may be older with a higher burden of comorbidities.

We have to remain cautious regarding the results of the RABBIT registry and carefully evaluate patients before initiating targeted therapies, especially JAKis, considering age, smoking, and cardiovascular risk factors. It is important to carry out an individualized evaluation and follow the guidelines before starting these treatments. For instance, we have French recommendations for assessing the risk of cancer.