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The Comparative Risk of Serious Adverse Events With Tofacitinib and TNF Inhibitors in Patients With Ulcerative Colitis: The Korean Experience as Revealed by a National Database

Tofacitinib is an oral, small-molecule Janus kinase inhibitor approved in South Korea for the treatment of moderate to severe ulcerative colitis (UC) on May 1, 2019. However, safety data are lacking. We investigated the incidence of serious adverse events (SAEs) in patients with UC using tofacitinib from the National Health Insurance Service database. In all, 1,026 UC patients were enrolled in this study. The overall incidences (100 person-years; 95% confidence interval) of SAEs were 4.06 (1.63–8.36) and 6.30 (4.59–8.43) in the tofacitinib and anti-TNFi groups, respectively. No thromboembolic event occurred and major cardiovascular events occurred in only three patients (two unstable angina and one congestive heart failure) in the tofacitinib group. The incidence of herpes zoster and tuberculosis did not differ between the two groups. There was no difference in the overall incidence of SAEs, including thromboembolic events, between tofacitinib- and TNFi-treated UC patients.

for research on JAK inhibitor-related thromboembolic events in Asians. Tuberculosis (TB) is another important issue in South Korea because of its high prevalence. 13 In one study, active TB associated with tofacitinib was reported in 0.5% of rheumatic arthritis (RA) patients, most of them in epidemic areas. 14 We evaluated the safety of tofacitinib in moderate to severe UC by analyzing the National Health Insurance Service (NHIS) database. We used the diagnostic codes defined by the International Classification of Diseases, tenth revision (ICD-10) and the V code in the rare intractable diseases database. 15 We enrolled UC patients identified by ICD-10 (K51.x) and V code (V131) from the NHIS database for May 1, 2019, to April 30, 2021. Tofacitinib was approved for the treatment of moderate to severe UC in Korea on May 1, 2019. To identify such patients, eligible patients were restricted to those prescribed an anti-TNF inhibitor (infliximab, adalimumab, golimumab)  Demographic features (age, sex, duration of disease), comorbidities, and UC medication use were collected. Comorbidities included hypertension (ICD-10 code, I10.x-I15.x), diabetes mellitus (E10.x-E14.x), chronic renal failure (N18.x), and liver cirrhosis (K74.x). We also collected data on UC medications, including 5-aminosalicylic acid, immunomodulators (azathioprine, mercaptopurine, cyclosporine, tacrolimus, and methotrexate), steroids, biologics (infliximab, adalimumab, golimumab, vedolizumab), and JAK inhibitors.
The overall incidences (100 person-years; 95% confidence interval) of SAEs were 4.06 (1.63-8.36) and 6.30 (4.59-8.43) in the tofacitinib and anti-TNFi groups, respectively. In the tofacitinib group, major cardiovascular events occurred in three patients (two UA and one CHF). CHF was more common in the anti-TNFi group, but there was no statistical significance. No thromboembolic event, such as ischemic stroke, PTE, or DVT, occurred in the tofacitinib group. PTE and DVT occurred in 6 (0.7%) and 12 (1.4%) patients, respectively, in the anti-TNFi group. The incidence of HZ and TB did not differ between the two groups ( Table 1).
Three patients with major cardiovascular events had DM and one patient had DM and hypertension. Of them, two patients were hospitalized for 3 and 7 days, respectively. The numbers of days to major cardiovascular events were 320, 122, and 126. HZ and TB occurred in four patients, and the average number of days to the events was 380. ( Table 2).
There was no difference in the incidences of major cardiovascular events between the tofacitinib and anti-TNFi groups. There were 20 major adverse cardiovascular events among patients receiving any TNFi, for an incidence of 0.51 per 100 person-years in the UC trial-like cohort, compared with 0.28 per 100 person-years (seven patients with major cardiovascular events) in the tofacitinib UC clinical trial overall cohort. 16 In a recent study of RA patients, the rate of major adverse cardiovascular events was 0.4 per 100 person-years. 14 Our results are similar to those findings. There were two patients with UA and one with CHF among 176 patients in the tofacitinib group. Interestingly, CHF was more common in the anti-TNFi group than the tofacitinib group, albeit the difference was not statistically significantly. An association between anti-TNF agents, such as infliximab and adalimumab, and CHF has long been established. 17 Our findings support that notion. In addition, the three patients with major cardiovascular events had DM and were older than the mean age of the study population. Therefore, we suggest caution when using tofacitinib in elderly and diabetic patients.
Pulmonary embolism and DVT, now the most important issue related to tofacitinib, were not found in this study; also, there were no cases of ischemic stroke. These findings do not correspond with recent reports of thromboembolic events in moderate to severe UC patients using tofacitinib. 18,19 However, a recent study that used claims data reported no pulmonary embolism or DVT but their rates were numerically higher in TNFi-treated patients, as in this study. 16 The discrepancy may have one or more of several possible explanations. First, tofacitinib was approved recently for the treatment of moderate to severe UC. Therefore, it is possible that the observation period was too short to confirm the occurrence of https://doi.org/10.3346/jkms.2022.37.e123 Safety of Tofacitinib 4/6 https://jkms.org thromboembolic events. Second, UC is an independent risk factor for venous thrombosis, the incidence of which in an Asian population was lower compared to a Western population. Third, there was no analysis of patients treated with both tofacitinib and TNFi. This study also had strengths. This is the first comparative study of tofacitinib-related SAEs in South https://doi.org/10.3346/jkms.2022.37.e123