Overall, the final results of this PMS study in tofacitinib-treated patients with UC from Japan in a real-world setting were consistent with the previously published global studies in patients with UC treated with tofacitinib, except for generally lower rates of serious AEs and discontinuations [8, 11], and were also consistent with data from East Asian tofacitinib-treated patients with UC in the OCTAVE Open study [9].

In this study, AEs were observed in 661/1982 (33.4%) of patients. Previous studies investigating the safety of other Janus kinase inhibitors, and biologics in Japanese patients with UC have shown numerically higher rates of AEs when compared with tofacitinib; specifically, treatment emergent AEs for filgotinib 100 mg, filgotinib 200 mg, adalimumab 40 mg every week, and adalimumab 40 mg every other week were reported in 23/45 (51.1%), 24/44 (54.5%), 41/46 (89.1%), and 37/43 (86.0%) of patients, respectively [12, 13].

Of the AEs of interest assessed in this PMS study, serious infections were reported in a relatively small number of patients; HZ was the most reported infection and most cases were non-serious. These findings are consistent with previous findings that HZ (serious and non-serious) was the most commonly reported AE of interest in multiple global studies [8, 14, 15], and that this HZ risk appears higher in Asian versus non-Asian patients with autoinflammatory conditions [11, 15, 16]. Of note, the HZ IR reported in this study (IR 5.93 [95% CI 4.78, 7.27; 1551.56 PY of exposure]) was higher than that reported in patients with UC who received corticosteroids, immunosuppressants, or tumor necrosis factor inhibitors in the Medical Data Vision and Japan Medical Data Center databases (IR 1.00 [95% CI 0.85, 1.16; 16285 PY of exposure] and IR 1.82 [95% CI 1.27, 2.37; 2310.67 PY of exposure]), respectively [17]. However, the HZ IR reported here was lower than that reported in patients with rheumatoid arthritis in a PMS study in Japan (IR 8.02 [95% CI 7.05, 9.09; 3054.4 PY of exposure]) [18]. Moreover, the serious infection IR reported in this study (IR 1.51 [95% CI 0.97, 2.25; 1587.49 PY of exposure]) was numerically lower than the rates of hospitalized infections in the Medical Data Vision database (IR 1.73 [95% CI 1.52, 1.93; 16115 PY of exposure]) [17] and in the PMS study of patients with rheumatoid arthritis (IR 6.91 [95% CI 6.01, 7.91; 3066.2 PY of exposure]) [18]. These data are a reminder to healthcare professionals to continue to weigh risks against benefits when using tofacitinib or other advanced therapies.

The duration from tofacitinib treatment to the onset of HZ AE was considered to have no significant effect on the IR. However, risk factor analysis suggested that there were some baseline demographic and disease characteristics that may increase the risk of a HZ AE. These included previous infections and age ≥ 65 years versus < 50 years. The most common previous infection was herpes zoster (n = 28, 1.4%), and other infections included hepatitis B, and pneumonia. A recent retrospective cohort study in patients with UC and Crohn’s disease demonstrated that the HZ IR was higher in patients with versus without prior biologic exposure [19]. A post hoc analysis of data from this PMS study which focuses on patients with a history of HZ, tofacitinib dose at event onset, patients who started on low dose of tofacitinib (10 mg/day) and the difference in HZ incidence among sex, smoking status, and body mass index may provide further insight into the HZ risk in Japanese patients with UC. In addition, in a study of patients with UC from the tofacitinib UC clinical program, it was found that patients who were older, had prior tumor necrosis factor inhibitor failure, and were Asian had the highest HZ risk [16].

One of the reasons that patients with UC in Japan and Asia are at an increased risk of HZ may be their genetic background. A previous genome-wide association study meta-analysis in patients with rheumatoid arthritis or psoriasis treated with tofacitinib found that genes which confer susceptibility to HZ are different between European and East Asian patients. For example, the frequency of a risk allele was found to be higher in East Asian versus European patients (~ 12% vs < 0.2%) [20]. To help reduce the risk of patients with UC developing HZ, multiple vaccines are available, including the varicella vaccine live vaccine and the adjuvanted recombinant zoster vaccine [21]. Both vaccines are approved for use in Japan; however, live vaccines such as the varicella vaccine live are typically contraindicated for patients undergoing immunosuppressive therapy. While the recombinant zoster vaccine can be administered to these patients, it is still largely unknown if the vaccine reduces the risk of HZ in patients taking Janus kinase inhibitors [22].

The types of malignancies reported in this PMS study were similar to those reported in PMS studies of patients with other autoinflammatory conditions. Here, a total of 17 patients reported malignancies (IR 0.62 [95% CI 0.36, 1.00]; 2729.70 PY of exposure), with the most reported being colon cancer (three cases), neoplasm malignant (two cases), and testis cancer (two cases). There were also reports of lymphoma, lymphoproliferative disorder, carcinoma (hepatocellular, basal cell, cervix, esophageal, and pancreatic), and adenocarcinoma. In an interim analysis of safety data from a PMS study in Japanese patients with rheumatoid arthritis, a total of 25 patients reported all-cause malignancies (IR 1.25; 4874 PY of exposure), of which five patients had lymphoma/lymphoproliferative disorder and three patients had breast cancer [23]. Moreover, in an analysis of PMS data in patients with rheumatoid arthritis (439,370 PY of exposure) and psoriatic arthritis (20,706 PY of exposure), there were reports of lung neoplasm malignant, colon cancer, basal cell carcinoma, and squamous cell carcinoma [24], and in another PMS study in patients with rheumatoid arthritis (3247.6 PY of exposure), the most common malignancies reported were lung cancer, lymphoma and other lymphoproliferative disorders, and colon/rectal cancer [18].

Overall, two cardiovascular events were reported, specifically one subarachnoid hemorrhage and one subdural hematoma. The patient with subarachnoid hemorrhage was aged 53 years with no cardiovascular comorbidities, and the patient with subdural hematoma was aged 46 years and had a medical history of diverticula. Both cardiovascular events were not adjudicated and the physician in-charge ruled that there was no causal relationship. There were no cardiovascular events reported in those over 65 years old; one patient had a smoking history. One patient died following an intestinal abscess; this was a 79-year-old female who had a medical history of a digestive tract disorder and tuberculosis. In addition, this patient had comorbidities of diverticula, hypertension, lung damage, osteoporosis, and sleeplessness, and was receiving concomitant medication of iscotin and mesalazine.

Five venous thromboembolism AEs and three ADRs were reported, which included thrombophlebitis, venous thrombosis limb, and deep vein thrombosis. These were classified as venous thromboembolism due to the usage of the Preferred Terms in the Standardized MedDRA Query. The IR for venous thromboembolism in this analysis was 0.31 (95% CI 0.10, 0.73; 1592.23 PY of exposure), which was consistent with a previous real-world analysis of Japanese patients with inflammatory bowel disease in the Japan Medical Data Center claims database that reported a venous thromboembolism IR of 0.40 (95% CI 0.35, 0.47) in patients with UC [25], and numerically higher than the IR of deep vein thrombosis (IR 0.04 [95% CI 0.00, 0.23; 2403.6 PY of exposure]) and pulmonary embolism (IR 0.16 [95% CI 0.04, 0.41; 2403.6 PY of exposure]) reported in the tofacitinib UC clinical program [26].

In this PMS study, approximately half of the patients (52.4%) had discontinued tofacitinib treatment by week 60. The most common reason for treatment discontinuation was inadequate clinical response, which has also been found to be one of the most common reasons for discontinuation in multiple other cohorts of tofacitinib-treated patients with UC and rheumatoid arthritis (59% and 53.6%, respectively) [27, 28].

Effectiveness was observed throughout the PMS study, with most evaluable patients being in partial Mayo score remission at week 60. Previous studies have reported contradictory results on the potential effect of age on treatment effectiveness. In a longitudinal study of Spanish patients with UC who were in clinical remission (partial Mayo score ≤ 2), a univariate analysis found that age was not significantly associated with an increased risk of disease relapse [29]. In contrast, in a post hoc analysis of a Phase 3, randomized controlled trial assessing maintenance effectiveness in patients treated with golimumab, a multivariate regression analysis showed that it was more difficult for patients to achieve mucosal healing with increasing age, and this measure of effectiveness was not achieved by any patients over 60 years of age [30].

The strengths of this PMS study included the real-world setting and the large number of patients that were analyzed, which was most likely the largest cohort used to-date to evaluate the safety of tofacitinib. In addition, using an all-case surveillance approach further strengthened this study. Moreover, even though the study was conducted during the COVID-19 pandemic, the rate of serious infection AEs remained low. The PMS study also had some limitations. It was an observational study and healthcare professionals could adjust doses at their discretion; therefore, the analysis was limited in identifying the correlation between ADRs/AEs and tofacitinib dose. In addition, safety events were not centrally adjudicated. Moreover, the number of patients with evaluable total Mayo scores was small, which is partly due to the low number of patients with an endoscopic subscore that could be calculated.

In conclusion, the final results from the PMS analysis were generally consistent with the previously published results from the tofacitinib OCTAVE studies and the previous interim analyses of this PMS study. The overall safety profile during the treatment period was generally comparable with tofacitinib safety data previously reported in PMS reports from Japan and worldwide, and in the tofacitinib UC clinical program. However, rates of HZ were higher in this analysis than in the tofacitinib UC clinical program. The rates of AEs for tofacitinib reported in this analysis were lower when compared with data reported for other Janus kinase inhibitors and biologics used for the treatment of UC. Effectiveness of tofacitinib in Japanese patients with UC in a clinical practice setting was similar to that previously reported in the tofacitinib UC clinical program, with most patients with evaluable partial Mayo scores in remission during the 60-week observation period. Overall, no new safety concerns were identified and these results suggest that tofacitinib is effective in patients with UC in Japan.