Cardiovascular and malignancy risk with janus kinase inhibitor is it dose dependent

Janus kinase (JAK) inhibitors, a new class of targeted synthetic disease-modifying antirheumatic medicines (DMARDs), have been demonstrated to be safe and effective in rheumatoid arthritis (RA) and are currently being explored extensively in autoimmune and inflammatory illnesses.

The Food and Drug Administration (FDA) has issued new cautions for several (JAK) inhibitors. The FDA has noted that there is an elevated risk of major heart-related events such as heart attack or stroke, blood clots, and death with the arthritis medicines after reviewing a large, randomized safety clinical trial of tofacitinib. In this study, tofacitinib was compared to tumor necrosis factor (TNF) inhibitors in patients with RA, a Lower dose of tofacitinib was found to increase the risk of blood clots and death and a proportional increase in risk was noted for a higher dose.

The FDA announced that the same warning may be applicable for other JAK inhibitors namely, Baricitinib, and Upadacitinib due to related mechanisms of action, However, these two drugs have not been investigated in the same way as tofacitinib in safety trial.
Although JAK inhibitors have been demonstrated to be more effective than methotrexate in multiple randomized controlled trials, there are considerable worries about their safety. Researchers have evaluated the risk for developing cancer among RA patients receiving treatment with JAK inhibitor.

Lopez-Olive et al .conducted a systematic review and meta-analysis involving around 13000 patients in randomized trials to assess the risk of adverse events and JAK inhibitors when compared to methotrexate.

Malignancies were reported at a range of 0% to 1.9%, with lung and nonmelanoma skin cancers being the most prevalent, Serious infections were noted in 0.40 -5.45% of patients.

There was no statistically significant difference in the incidence of malignancy between patients treated with JAK inhibitors alone or in combination with methotrexate against methotrexate monotherapy. She also highlighted that patients treated with JAK inhibitors had numerically greater rates of malignancy than those treated with adalimumab, and those rates were equivalent between JAK inhibitors and placebo.

Tofacitinib is (JAK) inhibitor, which acts by inhibiting the cytokine signaling in the pathophysiology of inflammatory illnesses such as ulcerative colitis. In placebo-controlled randomized controlled studies tofacitinib 10 mg twice daily has been found to be effective in induction of clinical and endoscopic remission at 52 weeks in moderate to – severe ulcerative colitis.

Due to the small incidence rates, and the lack of evidence on the effect of tofacitinib in severe adverse effects, further research is needed to evaluate the long-term effectiveness and safety of tofacitinib and other oral JAK inhibitors as maintenance therapy in patients with moderate to severe ulcerative colitis in remission.

January 2021, Pfizer has shared the co-primary endpoint results of a post-marketing safety study of tofacitinib in subjects with RA. The study involving 4362 subjects has noted the occurrence of major adverse cardiovascular events (MACE) in 135 subjects and malignancies in 164 subjects. The corresponding most frequently reported MACE and malignancy were myocardial infarction and lung cancer.

The occurrence of these events was more predominant in subjects with a higher prevalence of known risk factors for MACE and malignancy such as older age and smoking.

Currently phase 4 trials evaluating the flexible dosing of 5 vs 10 mg for the management of ulcerative colitis in stable remission is ongoing.