From the Guidelines
Tofacitinib is associated with an increased relative risk of venous thromboembolism (VTE) compared to TNF inhibitors, with a 3-fold higher risk at 10 mg twice daily and a 1.5-fold increased risk at 5 mg twice daily, as supported by the most recent evidence from 1 and 1. The increased risk of VTE with tofacitinib is a significant concern, particularly in patients with pre-existing cardiovascular risk factors or those over 50 years of age. Key factors that contribute to this increased risk include:
- History of thrombosis
- Smoking
- Obesity
- Hormone therapy use
- Immobility As noted in 1 and 1, the mechanism behind this increased risk likely involves JAK inhibition effects on platelet function, endothelial cells, and coagulation pathways. Due to this safety concern, tofacitinib carries a boxed warning for thrombosis, and clinicians should carefully assess VTE risk factors before prescribing. Lower doses should be considered when possible, especially in high-risk patients, and patients should be monitored for signs of thrombosis such as sudden leg pain, swelling, chest pain, or shortness of breath during treatment, as recommended by 1 and 1. It is essential to weigh the benefits of tofacitinib against the potential risks, particularly in patients with a history of VTE or those at high risk of developing VTE, as discussed in 1. Overall, the available evidence suggests that tofacitinib increases the risk of VTE, above the underlying effect of rheumatoid arthritis itself, especially in patients with cardiovascular risk factors, but the risk is low and with unclear pathogenic mechanisms, as noted in 1.
From the FDA Drug Label
Thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. The incidence rate of DVT per 100 patient-years was 0.22 for XELJANZ 5 mg twice a day, 0.28 for XELJANZ 10 mg twice a day, and 0. 16 for TNF blockers. The incidence rate of PE per 100 patient-years was 0.18 for XELJANZ 5 mg twice a day, 0.49 for XELJANZ 10 mg twice a day, and 0.05 for TNF blockers
The relative risk of Venous Thromboembolism (VTE) with Tofacitinib (Xeljanz) is increased, with a higher incidence of DVT and PE compared to TNF blockers. The incidence rates of DVT and PE per 100 patient-years were:
- DVT: 0.22 for XELJANZ 5 mg twice a day, 0.28 for XELJANZ 10 mg twice a day, and 0.16 for TNF blockers
- PE: 0.18 for XELJANZ 5 mg twice a day, 0.49 for XELJANZ 10 mg twice a day, and 0.05 for TNF blockers 2
From the Research
Relative Risk of Venous Thromboembolism (VTE) with Tofacitinib (Xeljanz)
- The relative risk of VTE with tofacitinib is a concern due to the potential for increased risk of thromboembolic events 3, 4, 5, 6.
- Studies have reported varying incidence rates of VTE with tofacitinib, ranging from 0.17 to 0.54 per 100 patient-years 4, 5, 6.
- A systematic review and indirect meta-analysis found that tofacitinib was not associated with an increased risk of VTE and may even have a protective effect, particularly at lower doses 7.
- However, other studies have reported a higher risk of VTE with tofacitinib, particularly in patients with cardiovascular risk factors or a history of VTE 3, 6.
- The risk of VTE with tofacitinib appears to be dose-dependent, with higher doses associated with a greater risk of thromboembolic events 4, 6, 7.
Risk Factors for VTE with Tofacitinib
- Prior VTE is a significant risk factor for VTE with tofacitinib 3, 6.
- Other risk factors for VTE with tofacitinib include older age, body mass index greater than or equal to 35 kg/m2, and history of chronic lung disease 6.
- Disease activity, as measured by the Clinical Disease Activity Index, may also be a risk factor for VTE with tofacitinib 6.
Comparison to Other Treatments
- Tofacitinib has been compared to tumor necrosis factor inhibitors (TNFi) in terms of VTE risk, with some studies suggesting a higher risk of VTE with tofacitinib 4, 6.
- However, other studies have found similar rates of VTE between tofacitinib and TNFi 5.
- A systematic review and indirect meta-analysis found that tofacitinib had a superior safety profile to baricitinib in terms of VTE risk 7.