CV and cancer risks with JAKi: EULAR perspectives

5 minute read

As regulators around the world act on JAK inhibitor safety, three presentations of registry data provide a real-world perspective on cardiovascular and malignancy risks.

Concern regarding the safety profile of Janus kinase inhibitors (JAKi) is a hot topic for our rheumatology community.

The recent boxed warning issued by the TGA has amplified the discourse, underscoring the need for more data to help us understand these drugs’ potential risks.

Evidence presented at the EULAR 2023 meeting in Milan challenges the prevailing narrative and provides a more balanced perspective.

Mr Romain Aymon presented JAK-POT study data on major adverse cardiovascular events (MACE) in RA patients treated with JAKi compared with bDMARDs (abstract OP0219).

It offered a detailed investigation into the real-world cardiovascular safety of JAKi compared with other biologic agents, utilising data from rheumatoid arthritis (RA) registers across Europe, Turkey and Québec. 

The study included almost 35,000 patients who had over 50,000 treatment initiations. Of these, almost 13,000 were exposed to JAKi treatment. The researchers reported 182 incident MACE over a mean follow-up period of 2.8 years. 

Interestingly, they found the crude incidence rate was higher for biologics with other modes of action (2.63/1000 patient-years) than for JAKi (1.76/1000 patient-years) and TNF inhibitors (1.86/1000 patient-years).

After adjustment, there were no significant differences in the incidence of MACE between JAKi vs TNFi, or between biologics with other modes of action vs TNFi.

A sub-analysis was performed on patients aged ≥50 years and ≥1 CV risk factor, mimicking the ORAL Surveillance trial inclusion criteria. This RCT-duplicate cohort accounted for 38.4% of treatment courses.

While the incidence of MACE for each treatment group in the RCT-duplicate cohort was higher than in the overall study population, no significant differences were observed between groups.

Rates of events seemed low, and the presenter acknowledged this as a limitation of reporting with registry data. However, he felt this would be a similar issue for all groups.

Corroborating these findings was Dr Calin Popa’s study on JAKi and risk of cardiovascular events in Dutch RA population (abstract OP0221), presented by Dr Merel Opdam. 

Drawing on data from IQVIA’s Dutch real-world data longitudinal prescription database, the team tracked over 15,000 unique RA patients starting a new bDMARD or JAK inhibitor from August 2017 to January 2022.

There were almost 21,000 treatment episodes, comprising over 2000 with JAKi (almost exclusively tofacitinib and baricitinib) and almost 19,000 with bDMARDs. This database covers about 63% of outpatient prescriptions in the Netherlands.

The study outcome was cardiovascular events, and this was defined as the start of platelet aggregation inhibitors during the study period. The use of this prescription surrogate marker potentially means there may either be an overestimation or underestimation of actual CV events.

They reported 681 cardiovascular events during the study period, with an adjusted IRR of 0.78 for JAKi compared with bDMARDs (95% CI, 0.56 – 1.10), indicating no significantly increased risk for JAKi users.

When analysed separately, patients using either tofacitinib or baricitinib also showed no difference compared with bDMARDs. The study also found that RA patients older than 65 years did not have a higher CV risk with JAKi therapy when compared with those treated with bDMARDs. 

In addition to cardiovascular safety, another concern has been the risk of malignancies associated with JAKi.

Dr Martin Schaefer’s team from Germany addressed this in their study of incident malignancies in RA patients in daily rheumatological care (abstract OP0218). 

Data from patients without cancer history from the RABBIT biologics register were included, covering treatment episodes from January 2017 to April 2022.

Incidence rates of malignancies (excluding non-melanoma skin cancer) per 1000 patient-years and corresponding hazard ratios were calculated for all patients, with a separate analysis of selected patients who met ORAL Surveillance inclusion criteria (age ≥50 years and ≥1 cardiovascular risk factor), to compare treatment groups to TNFi. 

The analysis included around 3000 JAKi, 3000 TNFi, 700 abatacept, 800 rituximab, 1100 IL-6 inhibitor and 1100 csDMARD initiations.

A total of 151 incident malignancies were reported with comparable IRs of between 7 and 11 events per 1000 patient-years across treatments. Among selected patients, IRs were higher overall and ranged from around 8 to 15, with 13.2 events per 1000 patient-years in JAKi patients.

In adjusted analyses, none of the treatments showed a significantly altered risk for malignancies compared with TNFi in unselected patients, with similar results in selected patients.

In conclusion, they found no statistical evidence of an increased malignancy risk with JAKi compared to TNF inhibitors, and the pattern of malignancies was similar to that of the general population.

Since our exposure to the ORAL Surveillance data, many rheumatologists around the world have altered their prescribing habits to move away from using JAK inhibitors in higher risk groups. This channelling bias may make future registry data difficult to interpret.

For now, these studies presented at EULAR 2023 offer a reassuring perspective on their use in clinical practice, and advocate a nuanced approach towards evaluating JAKi’s safety profile. 

Dr Irwin Lim is the editor of Rheumatology Republic. He is a Sydney-based rheumatologist and director of BJC Health.

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