We demonstrated the effect of biologics in patients with moderate to severe active UC in the Japanese real-world practice by setting two different endpoints, i.e., the cumulative incidence rate of surgical resection and re-exacerbation. Our findings indicated the distinctive potential of biologics and the strategic directions of using these drugs in patients.
This study established a unique endpoint, i.e., the cumulative incidence rate of re-exacerbation, and focused on the clinical impact of biologics on maintaining remission in moderate to severe exacerbation events of UC. In general, the clinical outcomes of biologics were assessed using the remission rate. Most randomized controlled trials of biologics have generally compared with placebo by selecting 44-, 52-, or 54-week remission rate as the primary endpoint20,21,22,23,24. Recent studies that confirmed the effectiveness of biologics used similar indicators29,30. Even though remission rate is a defined and convenient endpoint to assess the effectiveness of both induction and maintenance of remission in UC patients, endpoints with 44-, 52-, or 54-week remission rate appear to be suitable for clinical trials because it does not require long observation periods. However, considering the disease characteristics of UC, the potential of treatments should be evaluated separately based on induction and maintenance of remission. We believe that our study is the first one to demonstrate the cumulative incidence rate of re-exacerbation of biologics in moderate to severe active UC using cohorts from real-world practice. Our results suggested that the administration of biologics significantly reduced the risk of re-exacerbation and prolonged remission duration in moderate to severe UC exacerbation.
In this study, 63%, 28%, and 28% of the Biologics used in all events were IFX, ADA, and GLM, respectively, which are all anti-TNFα antibody drugs.
Since IFX was used in many cases and previous reports have shown no significant difference in the efficacy of maintenance treatment with anti-TNFα antibody drugs, we reviewed them together as biologics31.
The cumulative risk of re-exacerbation events, which achieved remission by corticosteroids, was significantly higher than that achieved using biologics in the COR-REF or DEP cohort of our study. Altogether, these results demonstrated an important finding that the conspicuous effect of biologics is maintaining remission in patients with active UC. Based on the results of the present study, biologics may be used not only in COR-REF or DEP patients, but also in patients achieving remission by corticosteroids for maintaining remission. We suggest that subpopulation of patients achieving remission by corticosteroids who have a high risk of surgical resection in case of re-exacerbation have indications for biologics. Although the medical cost of biologics is a huge medical problem32,33, biosimilar and generic drugs may help to solve the issue34.
There are some limitations in this study. First, this was a retrospective study, but we believe that this design was necessary to conduct a comparative study before and after the introduction of biologics. Second, this research was conducted within a limited area in Japan. Therefore, bias may exist when compared with a nationwide study. However, most of the IBD cases in a city of 1 million people are covered by the medical institutions in this cohort, and we consider this to be practical data.
Finally, this study did not include newer molecular target drugs, such as Tofacitinib, Vedolizumab, and Ustekinumab. Future studies should include these agents.
Our study also confirmed the potential of corticosteroids in reducing the risk of surgical resection in moderate to severe UC exacerbations, although statistical significance was not observed with the multivariate analysis. Corticosteroids’ potential for achieving remission and avoiding surgical resection should be re-recognized in moderate to severe active UC as reported previously11,12,13,18,19. Conversely, biologics showed no dramatic impact on reducing surgical resection risk compared with suboptimal treatments in the COR-REF or DEP population. In this cohort, 28 of the surgical cases received biologic agents, of which 13 (46%) were severe cases and one (3%) developed cancer; furthermore, the median time from deterioration to surgery was 83 days. Although a randomized controlled trial verified that infliximab reduced the risk of surgical resection compared with placebo20, a recent study reported by Murthy et al. demonstrated that anti-TNF therapy did not decrease UC-related intestinal resections in real-world practice35. Altogether, these results and ours indicate that biologics might not have the anticipated effectiveness for avoiding resection, especially in salvaging the COR-REF or DEP population with rapid exacerbation. Hence, there is a strong need to develop promising agents with similar or higher potential of achieving remission compared to corticosteroids.
The characteristics of the present retrospective cohort were generally illustrative to represent the Japanese UC population during the past few decades. First, both the number of UC patients and the median age at onset had been increasing36,37,38. Second, the rates of hospitalization and surgical resection in the entire population had decreased gradually, including other countries as well26,39. Surgical resection rates of the present cohort were similar those of a Korean cohort26, although these rates were lower than those of a Western cohort40. Remarkably, the proportion of using immunomodulators (i.e., thiopurines) in the present cohort was lower than that in Western countries41. It is well known that the incidence rates of adverse events, primarily leukopenia and hair loss, are higher in East Asian populations, including Japan, than in Caucasian populations42,43. Recently, Moriyama et al. reported that a variant in the nudix hydrolase 15 (NUDT15) gene (R139C, c415C > T) was associated with early severe leukopenia in Asians44. Currently, the assessment of NUDT R139C has been approved by the Japanese regulatory authority. Consequently, the opportunity to use thiopurines should increase. It would be necessary to confirm the clinical impact of thiopurines in Japanese UC patients in the near future. Regarding biologics, the administration rate is increasing, as in the rest of the world, and is almost equal or slightly higher than those in other countries due to the well-supported system of medical costs26,35. Biologics will become more essential agents for treating active UC patients, due to active development of biologics in the coming years45,46. We anticipate further studies in the future to investigate the effectiveness of biologics focusing on maintaining remission in other cohorts from all over the world.