Follow-up in German RABBIT registry is the key, researchers say.
Real-world data has linked janus kinase inhibitors to elevated malignancy risk in rheumatoid arthritis patients.
The large observational cohort study from Germany identified a modest but clinically significant increase in the risk of incident malignancies (excluding non-melanoma skin cancer) among patients with rheumatoid arthritis treated with JAKis, compared to those receiving biologic disease-modifying antirheumatic drugs (bDMARDs).
The study, which followed more than 6500 treatment episodes recorded in the RABBIT registry from January 2017 to June 2024, underscored the importance of long-term monitoring and personalised risk assessment in RA management, the researchers wrote in the Annals of the Rheumatic Diseases.
The researchers analysed 2285 JAKi and 4259 bDMARD treatment episodes, primarily involving baricitinib and tofacitinib among JAKis and tumour necrosis factor inhibitors among bDMARDs.
The incidence rate (IR) of malignancies was 11.6 per 1,000 patient-years (95% CI: 9.3–14.3) in the JAKi group versus 8.9 (95% CI: 7.4–10.5) in the bDMARD group. After adjusting for confounding factors via inverse probability weighted Cox models, the hazard ratio (HR) for malignancy was 1.40 (95% CI: 1.09–1.80) in favour of bDMARDs.
Notably, the elevated malignancy risk associated with JAKis emerged only after treatment durations exceeding 16 months, emphasising the necessity for extended follow-up in safety evaluations.
The increased cancer risk was more pronounced in specific patient subgroups:
- Patients aged ≥60 years at treatment initiation.
- Those with a history of ≥3 prior conventional synthetic DMARDs.
- Individuals with high RA disease activity.
For most individual cancer entities, event numbers were small. The most frequent malignancies were lung cancer (JAKis, 15; bDMARDs, 31), breast cancer (JAKis, 11; bDMARDs, 21), transitional cell/bladder cancer (JAKis, 8; bDMARDs, 12), prostate cancer (JAKis, 8; bDMARDs, 10), and gynaecological cancer (ovarian, endometrial, cervical, and vulva cancer) (JAKis, 8; bDMARDs, 6).
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“Compared to bDMARDs, in patients treated with JAKis, significantly increased HRs were observed for prostate cancer in male patients and gynaecological cancers in female patients, both overall and in patients aged ≥60 years,” the researchers wrote.
The findings align with the results from the ORAL Surveillance trial, which previously identified elevated malignancy risk with tofacitinib in older patients with cardiovascular comorbidities. While earlier registry and claims data studies showed mixed outcomes, the present real-world evidence supports regulatory concerns expressed by the European Medicines Agency, particularly for high-risk populations.
The study provides critical insights for rheumatologists and healthcare policymakers. The identification of patient subgroups at higher risk enables more informed treatment planning and may warrant intensified malignancy surveillance during and after JAKi therapy.
“To conclude, treatment with JAKis (predominantly baricitinib and tofacitinib) was associated with an increased HR of malignancies compared to treatment with bDMARDs in the overall study cohort, consistent with results from the OS trial,” the researchers wrote.
“The increase in the HR could only be detected in treatment episodes with follow-up lasting longer than 16 months. Behind the overall small risk increase attributed to JAKis compared to bDMARDs, with uncertain clinical implications, a more pronounced risk increase could be detected for some patient groups, including older patients starting treatment aged ≥60 years, patients with ≥3 csDMARD failures, as well as patients with high disease activity.
“This can help physicians to assess the individual risk of their patients and thus strengthen precision medicine, as well as to decide which patients should be more closely monitored.
“Given the risk stratification, the aforementioned clinical aspects, and the relatively high overall NNH, clinicians should carefully assess whether the described increased malignancy risk outweighs the potential risks of discontinuing a highly effective therapy like JAKis, including the known malignancy risk associated with an uncontrolled disease activity.”
However, the authors noted that it remained to be clarified whether the increased HR was a JAKi class effect.
“Selectivity for specific JAKs may influence the role of JAK inhibition in carcinogenesis, but a thorough, fair comparison of individual JAKi substances remains unfeasible in RABBIT (and other studies) at this stage due to different lengths of follow-up and the low exposure to filgotinib and, to some extent, upadacitinib,” they wrote.
“We thus only compared the individual JAKi substances by crude IRs, focusing on the ‘on treatment’ approach, which is probably least affected by differential follow-up.
“While the upadacitinib rate is numerically smaller than the rates for baricitinib and tofacitinib, further analyses based on greater follow-up times and more events are needed before inference on potential differences between specific JAKis can be undertaken.”
