Few studies to date have directly compared secondary drugs for IBD treatment. For patients with moderate to severe UC or CD showing failure of first-line anti-TNF therapy, choosing the best option for secondary treatment is critical, based on the efficacy and safety of the available second-line agents. This study focused on comparing the effectiveness of vedolizumab versus tofacitinib in patients with UC and vedolizumab versus ustekinumab in patients with CD who received second-line drugs because they were refractory or intolerant to anti-TNF therapy. The therapeutic goals for IBD patients can be reached by selecting an effective drug for second-line treatment.
Overall, the baseline characteristics were similar, but since our study was based on real-world data, there were inevitable differences in baseline characteristics between the groups. In the group using vedolizumab, the disease duration was relatively longer, and patients were older in the UC group. This reflects the known safety of vedolizumab in elderly patients and the fact that elderly people often have a longer disease duration. The concomitant use of tofacitinib and immunomodulators is contraindicated; therefore, only patients who received vedolizumab showed concomitant use of immunomodulators in the baseline analysis of UC patients. Likewise, for patients with CD, most of the baseline characteristics were similar between the two drug groups, with a few exceptions. The CDAI score, for instance, was higher in the ustekinumab group than in the vedolizumab group. In actual clinical practice, vedolizumab is administered more commonly to those with moderate disease activity than to those with severe disease activity since it takes time for vedolizumab to be effective. Analysis of data from observational cohorts, including those from clinical trials, suggests that the median onset of vedolizumab action, which involves the inhibition of leukocyte trafficking to the gut mucosa, may take 10 weeks in UC patients and as much as 14 weeks in CD patients.[22, 23] In addition, the concomitant use of immunomodulators was more often found in patients with severe disease activity. Since these differences in baseline characteristics could affect drug selection, caution must be taken when comparing these drugs. However, even with these considerations, there were no significant differences in clinical remission and relapse rates between the second-line drugs. Therefore, it is necessary to select an appropriate drug as the second-line biological agent for each patient with UC or CD based on not only the effectiveness of the drug itself but also the safety and onset of the action of the drug; it is also important to consider whether an immunomodulator is being used concomitantly.
Several previous studies have compared these drugs. Alric et al. found that for patients with CD refractory or intolerant to anti-TNF agents, the clinical remission (54.4% vs. 38.3%, OR 1.92; 95% CI 1.09–3.39) and treatment persistence rates (71.5% vs. 49.7%, OR 2.54; 95% CI 1.40-4.62) at week 48 were higher in the ustekinumab group than in the vedolizumab group. The Dutch Initiative on Crohn and Colitis (ICC) Registry, a prospective multicentre analysis, reported that tofacitinib was still effective in achieving clinical remission of UC after anti-TNF and/or vedolizumab failure. This supports the finding that more effective clinical remission can be achieved using second-line drugs with mechanisms different that those of anti-TNF agents. However, no significant differences between vedolizumab and tofacitinib in UC patients or between vedolizumab and ustekinumab in CD patients were found with respect to the achievement of clinical remission in patients who showed failure of anti-TNF therapy. These discrepancies may be due to racial differences or differences in treatment indications between countries. In addition, the number of patients enrolled is often small, and differences in study design may yield discrepancies in results. In the future, large-scale prospective studies and registration studies are needed, especially in Asia.
In patients with both UC and CD, at week 16, the drug response rates were lower in those with a longer disease duration.26,27 Moreover, UC patients with severe disease activity had a lower drug response rate. In the US VICTORY Consortium study, clinical remission (HR 0.54; 95% CI 0.31–0.95) and mucosal healing (HR 0.54; 95% CI 0.31–0.95) were found less commonly in CD patients with severe disease activity than in those with moderate disease activity. In patients with UC, at week 48, younger age and extensive disease were associated with a shorter time to relapse. A prospective longitudinal study in patients with UC reported that younger patients, particularly those in the 20–30 year age group, had a shorter time to relapse. This is consistent with the results of previous studies showing that in patients with extensive UC (E3), pancolitis was associated with a higher cumulative probability of relapse, indicating a poor prognosis. High CRP levels, a marker of inflammation, was correlated with disease activity in CD patients. This is consistent with a well-known finding that high CRP levels increase the clinical relapse rate. A recently emerging ‘top-down’ therapeutic approach for CD includes the early use of immunomodulators. In our study, patients with more severe CD were more commonly taking immunomodulators, and the results show that the prognosis was poor for these patients. In addition, it is well known that steroid use itself is related to high disease activity and poor prognosis.[30, 31]
The safety of vedolizumab, ustekinumab, and tofacitinib observed in our study was similar to that previously reported. Sands et al. showed that few differences were found between the adalimumab and vedolizumab treatment groups. In addition, Biemans et al. found that there were no differences in adverse events, infection rates, or hospitalisation rates between the vedolizumab and ustekinumab treatment groups. No serious side effects leading to severe infection or death were reported, and little difference was observed between the trial groups in the most commonly reported side effect measures.
Our study findings have several clinical implications. First, we were able to reliably assess the effectiveness of vedolizumab versus ustekinumab in UC patients and vedolizumab versus tofacitinib in CD patients after anti-TNF therapy failure in a real-life setting. Second, we followed-up the patients for a 48-week period, which was sufficient to reliably assess the clinical response in patients who had previously used anti-TNF agents. Moreover, the design of this study intentionally did not favour one of the two options for second-line therapy. In the future, in addition to clinical studies, translational studies are needed to identify predictive biochemical markers using biological samples.
This study has several limitations. First, the standardised choice of treatment could not be determined due to the retrospective observational design. Second, although we tried to increase the overall sample size of our study, the number of patients receiving second-line drugs after previous anti-TNF therapy failure was inevitably small, which may have biased the results. Third, therapeutic drug monitoring and changes in dosages during maintenance therapy were not systematically evaluated in our study. Finally, no objective or mandatory criteria were used for evaluating drug-related side effects.