- Indian Rheumatology association
It is not an understatement to assert that Janus Kinase inhibitors (JAKi) have revolutionized the treatment of specific rheumatic diseases. However, with every revolution, there are those who emerge as victors and those who suffer losses. While JAKi have demonstrated substantial clinical efficacy, the elevated risk of malignancy associated with their utilization has become a critical area of research and concern.
The proposed theory posits that JAKi inhibit the production of cytokines and intracellular pathways of immunosurveillance, potentially elevating the risk of cancer. This is largely variable between the various JAKi. For instance, tofacitinib inhibits the maturation and tumor lysis capacity of natural killer (NK) cells, which play a crucial role in cancer immunosurveillance. The potency of JAKi in inhibiting NK cells varies depending on their selectivity. Studies have indicated that tofacitinib exhibits the highest potency for inhibiting NK cells, followed by upadacitinib, baricitinib, and filgotinib.
JAKi in particular tofacitinib has been associated with increased risk of malignancy. The incidence of malignancies (lung cancer, non-melanoma, breast cancer and skin cancer). was notably elevated among patients with a history of atherosclerotic cardiovascular disease or an escalating cardiovascular risk, as evidenced in the ORAL surveillance trial.
Nevertheless, the data does not entirely favor a higher malignancy risk. A recently published study from the STAR-RA trial, involving over ten thousand patients treated with tofacitinib, did not reveal a significantly elevated risk of malignancy compared to the conventional risk. Real-world data from the Spanish BIOBADASER registry also did not demonstrate a substantial increase in malignancies among the patients who received JAKi treatment.
The primary challenge associated with JAKi in India stems from its widespread, often unscientific utilization. Notably, many patients are prescribed JAKi without undergoing a comprehensive risk assessment. Risk factors such as advanced age, smoking history, cardiovascular disease, and chronic lung disease are crucial considerations before initiating JAKi treatment. Evidence indicates a correlation between the duration and dosage of tofacitinib utilization and its malignancy risk. Furthermore, it is crucial to acknowledge that patients may acquire new risk factors during their treatment course, necessitating periodic risk evaluations. The prudent utilization of JAKi hinges on careful consideration of its benefits and risks, rather than solely relying on its availability.
There is insufficient data regarding the use of JAKI in patients with previously treated malignancies. JAK inhibitors can be utilized in patients with a history of treated malignancies, but the decision necessitates multidisciplinary approach including an oncologist, meticulous consideration of factors such as the underlying condition, the type of malignancy, and the risk of recurrence.
The black box warning for JAKi, issued by U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) was issued to ensure that both healthcare professionals and patients are fully aware of potential risks. Consequently, these warnings do not constitute a contraindication to their use.
To conclude, the relationship between malignancy and JAKi usage is not a straightforward yes or no answer. It is a multifaceted interplay of immune mechanisms and tumorigenesis risks that requires further elucidation. Nevertheless, the judicious application of these agents in suitable clinical settings remains paramount.
