Discussion
infection, tofacitinib-treated, UC
RECURRENCE, DISEASE, ULCERS, INFECTION, REMISSION
In this post hoc analysis of data from the phase 3 OCTAVE Sustain study, we examined the efficacy and safety of tofacitinib maintenance therapy in patients categorized according to OCTAVE Sustain baseline MES to determine whether a MES of 0 (endoscopic remission) following 8-week induction therapy is associated with superior long-term outcomes at 52 weeks compared with a MES of 1 in patients with moderate-to-severe UC.In general, a numerically higher proportion of tofacitinib-treated patients with a baseline MES of 0 at the start of maintenance therapy achieved efficacy endpoints at Week 52 compared to patients with a baseline MES of 1. This trend was observed regardless of prior TNFi exposure status or remission status at baseline of OCTAVE Sustain. When the proportion of patients achieving efficacy endpoints at Week 52 was stratified by change in MES from baseline to Week 8 of OCTAVE Induction 1 or 2, there was a slight trend for values to be numerically higher in patients who had a 2-point reduction in MES compared with those who had a 1-point reduction in MES. These results are broadly consistent with those of previous studies, which showed that patients with a MES of 0 have better outcomes compared with patients with a MES of 1, including a reduced risk of disease recurrence [In the tofacitinib 5 mg BID group, Week 52 results for clinical response showed a significant difference in the tofacitinib treatment effect for a baseline MES of 0 versus 1; however, this difference was not significant for remission, endoscopic remission, or endoscopic improvement in the 5 mg BID group or for any endpoint in the 10 mg BID group. This lack of statistical significance could at least in part be due to the small sample sizes, as a numerical trend was observed for most endpoints. In addition, for the tofacitinib 5 mg BID group, the difference in risk of treatment failure and loss of response versus placebo was significantly larger in patients with a baseline MES of 0 compared with those with a MES of 1. These differences were also not seen in the tofacitinib 10 mg BID group. These results suggest that remaining on the induction dose of tofacitinib 10 mg BID until endoscopic remission (MES of 0) is achieved may improve the probability of long-term efficacy with the 5 mg BID maintenance dose. This predictor of safe and effective dose reduction is particularly beneficial as current guidance recommends using the lowest effective dose for tofacitinib maintenance [Safety outcomes were consistent with the known safety profile of tofacitinib in UC, irrespective of baseline MES status. However, among patients receiving tofacitinib 5 mg BID, a lower proportion of patients with a baseline MES of 0 had infection AEs, compared with patients with a MES of 1. This trend was weaker but present in the tofacitinib 10 mg BID and placebo groups. This may suggest that patients with inflammatory burden, as suggested by a MES of 1, may be more susceptible to infection than those with a MES of 0 [Noted limitations of this analysis include the post hoc exploratory nature of the analyses and the small sample size, particularly of the TNFi exposure subgroups. Another limitation of these analyses is that the population of patients in the tofacitinib UC program may not be fully representative of the global UC population. It should also be noted that differences in baseline corticosteroid use between treatment groups and MES subgroups may have contributed to the observed trends for the tofacitinib 10 and 5 mg BID groups.Additionally, inherent limitations of the MES include the lack of validation, the inability to distinguish superficial ulcers from deep ulcers, and the fact that the score only evaluates the most severely affected visualized segment, with no minimal insertion length. The MES is also limited by subjectivity and potential operator variability, although central reading was employed in this study to minimize any potential bias. While confirmation of remission status via histological assessment would further improve the reliability of these results, histological data were not collected in the OCTAVE clinical programme as these studies pre-dated the current FDA guidance on the inclusion of a histological assessment as an exploratory endpoint.In conclusion, these analyses suggest that MES at the end of induction therapy may be an important factor in predicting long-term efficacy outcomes following maintenance treatment with tofacitinib. Aiming for endoscopic remission during induction with tofacitinib 10 mg BID may improve the probability of successful maintenance therapy with tofacitinib 5 mg BID.