Biologics did not reduce surgery rate but prolonged remission duration in patients with ulcerative colitis: analysis of a large retrospective Japanese cohort

Objective: To gain better understanding of the effects of biologics, we evaluated clinical outcomes in patients with moderate to severe exacerbations of ulcerative colitis (UC). Methods: This retrospective, multicenter study retrieved the entire clinical courses of UC patients who began treatments between 2004 and 2018. All exacerbations and clinical parameters, including treatment details for exacerbations and both remission and re-exacerbation dates, were identied during the observation period. Two different endpoints, the cumulative incidence rates of surgical resection and re-exacerbation, were evaluated separately in moderate to severe exacerbation events. Results: Among 1401 patients, 1626 exacerbation events were determined according to a partial Mayo score (remission: <2, mild: 2–4, moderate: 5–7, and severe: >7). During the observation period, as administration rates of biologics increased, both surgical resection and hospitalization rates decreased, for 959 moderate to severe exacerbation events. We conrmed that biologics signicantly reduced the cumulative re-exacerbation rate in moderate to severe exacerbation events during the study period compared with suboptimal therapies (a 0.507-fold decrease risk according to COX regression analysis, P <0.001). However, they had not enough impact in reducing the cumulative incidence rate of surgical resection in moderate to severe exacerbation events that were corticosteroid-refractory or dependent (a 0.878-fold decrease risk according to COX regression analysis, P = 0.606). Conclusions: Biologics may improve remission duration, but these agents had no signicant impact in reducing the risk of surgical resection in moderate to severe active UC.


Introduction
Ulcerative colitis (UC), a subtype of in ammatory bowel disease (IBD), is a chronic in ammatory disease of the colon, representing the most common distressing period of productive age and resulting in disability [1]. Although UC is associated with the Caucasian population in the United States and Europe, its incidence in newly developed countries, primarily in Asia, has been increasing rapidly over the past few decades [2][3][4][5]. Japan ranks second in the world in terms of the number of UC patients after the United States [3][4][5][6]. The sharp increase of UC cases in Japan appears to be associated with Westernized diets and environments, which affect the intestinal microbiome and increase the risk for UC in genetically susceptible individuals [7,8].
The primary treatment goals for UC patients are to induce and maintain remission. Speci cally, a surgical resection of the total colon due to an induction failure and an early re-exacerbation after remission are the two worst clinical outcomes in patients with UC [1]. 5-aminosalicylates (5-ASA), which are antiin ammatory agents, are the major choice of treatment to induce and maintain remission in patients with mild to moderate active UC [9,10]. Corticosteroids are a classical and most widely used treatment for inducing remission based on their con rmed high rates of immediate effectiveness [11][12][13]. Over half a century since the rst report, corticosteroids remain the rst-line treatment for moderate to severe exacerbations or when 5-ASA proves ineffective, as recommended by global guidelines [14][15][16][17]. However, roughly one-third of patients have not achieved clinical response or remission, while almost two-thirds of patients had required reintroduction of corticosteroids within two years and even they had achieved remission [18,19].
During the past two decades, there has been a dramatic paradigm shift in UC treatment with the introduction of biologics, primarily antitumor necrosis factor (anti-TNF) therapy, for both inducing and maintaining remission [9,14,15,17]. Well-designed randomized controlled trials have con rmed that biologics, including in iximab, adalimumab, golimumab, and vedolizumab, both improved induction and sustained remission rates compared with placebo in patients with moderate to severe active UC who had failed corticosteroid therapy or who had a history of corticosteroid refractory or dependent [20][21][22][23][24]. The rates of surgical resection and hospitalization in UC patients have decreased in both Eastern and Western populations [25,26]. However, the effects of biologics for patients with active UC, particularly focusing on overall long-term effectiveness of these new agents for maintaining remission, remain controversial and have not yet been clari ed su ciently. Therefore, this study was conducted to evaluate the clinical outcomes of biologics in UC patients with moderate to severe exacerbations using a large retrospective Japanese cohort over a long observation period.

Study population and study design
Chiba City is inhabited by approximately 1 million people (the 12th largest population in Japan) with less migration compared with the central metropolitan area of Japan. Chiba University Hospital, Chiba Aoba Municipal Hospital, and Chiba Medical Center are the only three institutions to which well-trained specialists in IBD belong.
We retrospectively investigated the entire clinical courses of UC patients by reviewing the electronic medical records (EMR) in three institutions and identi ed all exacerbations according to the partial Mayo score [27]. We identi ed all exacerbation events during the entire observation period and acquired the following data: the date of exacerbation diagnosis, laboratory data and disease extent at the time of exacerbation, requirement of hospitalization, and medical treatments for exacerbation.
All participating hospitals received approval from IRB. The Institutional Review Board of Chiba University Hospital approved this study (approval number: 3399).
Informed consent was waived because this was a survey study using medical records and no written or verbal consent could be obtained from the research subjects. However, materials regarding opting out were posted to give patients the opportunity to refuse to participate in the study. We conduct our research in accordance with the "Ethical Guidelines for Medical Research Involving Human Subjects" established by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare of Japan.
Treatment strategies for UC UC diagnosis was based on the combination of conventional clinical, endoscopic, radiological, and pathological criteria [28]. 5-ASA is the rst choice for inducing and maintaining remission in patients with mild to moderate active UC. Corticosteroids are introduced for patients with moderate to severe active UC, and/or in those unresponsive to 5-ASA, and are tapered off over 8-12 weeks. Biologics (in iximab, adalimumab, golimumab and vedolizumab), and immunomodulators (i.e., thiopurines; azathioprine/6mercaptopurine), were considered in case of corticosteroid failure. Calcineurin inhibitors, apheresis, and surgical resection were considered rescue medical treatments in patients who were unresponsive to corticosteroids. Since tofacitinib was approved in Japan in May 2018 and had been use only a few patients, we excluded these patients form this study.
De nition of exacerbations according to partial Mayo score The degree of exacerbations during the observation period was assessed according to the partial Mayo score using three noninvasive parameters (stool frequency, rectum bleeding, and physician's global assessment) [26]. Each of the three categories were rated from 0 to 3 that was summed up to derive a total score in the ranges of 0-9 (remission: <2, mild: 2-4, moderate: 5-7, and severe: >7). Moderate and severe exacerbations were de ned as partial Mayo scores 5-7 and >7, respectively. The remission date was de ned as the rst date after the exacerbation event that we con rmed as clinical improvement according to a partial Mayo <2. The re-exacerbation date was de ned as the rst date after remission that we con rmed a change in clinical status according to a partial Mayo score ≥2.

Assessments of clinical outcomes of corticosteroids
Clinical outcomes of corticosteroids were evaluated for each exacerbation event. Corticosteroid-refractory was de ned if remission, which was assessed according to a partial Mayo score <2, could not be achieved by corticosteroid monotherapy. Meanwhile, cases of active disease revival while receiving reduced doses of corticosteroids were regarded as corticosteroid-dependent. We collectively reviewed the cases that showed corticosteroid-refractory or -dependent (COR-REF or DEP) in the analysis.

De nition of effectiveness evaluation and COR-REF or DEP cohorts
All moderate to severe active events in UC patients were classi ed as an effectiveness evaluation cohort for assessing the clinical outcomes of treatments during induction of, and maintaining remission after, excluding events that were inducted by 5-ASA alone. COR-REF or DEP cohorts were de ned when any of the following conditions were observed: 1) met the abovementioned criteria of COR-REF or DEP after taking corticosteroids for moderate to severe exacerbations or 2) had a previous history of the criteria of COR-REF or DEP inducted for exacerbations using treatments without corticosteroids.

Statistical analysis
Pearson's chi-squared test or Fisher's exact test was used, as appropriate. ANOVA test was used to compare the mean between independent groups. The cumulative incidence of surgical resection was analyzed using Kaplan-Meier plots, which was de ned as the duration from the date of exacerbation till the date of surgical resection, with the censoring date de ned as the day of the last follow-up or the date of re-exacerbation. The cumulative re-exacerbation incidence was analyzed using Kaplan-Meier plots, which was de ned as the duration from the date of exacerbation to the date of re-exacerbation, with the censoring date de ned as the day of the last follow-up. Cox regression analyses were performed to evaluate the factors for the cumulative risk of surgical resection and re-exacerbation in UC patients with moderate to severe exacerbations. All statistical analyses were conducted using the SPSS statistical software (version 25; SPSS-IBM, Chicago, IL, USA).  Table 1 shows the baseline characteristic of the study population at the time of the initial visit during the study period. The mean age was 39.8 years, and one-fourth of the patients were aged ≤22.0 years.

Study population and baseline characteristics
Supplementary Figure 2 presents the correlations between the year of onset and the mean age at initial UC diagnosis. The mean age at initial diagnosis appeared to be signi cantly higher along with the calendar year of onset (P < 0.001).  (Figure 1, upper row). Of the moderate to severe exacerbation events among the entire study population, 878 (91.5%) were con rmed as remission, and 81 (8.4%) were converted into surgical resection without achieving remission.
Next, we extracted the rst and second exacerbation events of clinical courses during the observation period for each patient from the overall exacerbation events. Of the identi ed 994 and 401 rst and second exacerbation events during the study period, respectively, 525 and 266 were distinguished as moderate to severe exacerbations, respectively (Figure 1, middle and lower rows). From now on, we will refer to rst exacerbation of study period as initial exacerbation, and second exacerbation of study period as relapse exacerbation. Table 2 shows the clinical characteristics of the overall, initial, and relapse exacerbations in patients with moderate to severe active UC.    We next veri ed the cumulative incidence of surgical resection in the effectiveness evaluation cohorts of overall, initial, and relapse exacerbation events in subgroups ( Figure 3). Classi ed as COR-REF or DEP were signi cantly high risk for surgical resection in moderate to severe exacerbation events ( Figure 3, the left column). However, biologics did not have a signi cant effect in reducing the risk for surgical resection ( Figure 3, the right column).
Cumulative risk of re-exacerbation in UC patients with moderate to severe exacerbations Results of the multivariate Cox regression model in overall moderate to severe exacerbation events in patients with UC are shown in Table 4. Biologics signi cantly reduced the risk of re-exacerbation. In contrast, induction by corticosteroids signi cantly increased the risk of re-exacerbation. Figure 4 shows the Kaplan-Meier curve of the cumulative incidence of re-exacerbation caused due to the administration of biologics. Our results con rmed that biologics reduced the risk of re-exacerbation in the whole, initial, and relapse exacerbations population in effective evaluation cohort ( Figure 4, the left column). We also evaluated that impact of induction of biologics on cumulative incidence rate of re-exacerbation in patients with COR-REF or DEP cohort. The cumulative incidence rate of re-exacerbation in whole exacerbations population was signi cantly decreased as well as initial exacerbations cohort ( Figure 4, the right column).

Discussion
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., cumulative incidence rate of surgical resection and re-exacerbation. Our ndings 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 endpoint [20][21][22][23][24]. Recent studies that con rmed the effectiveness of biologics used similar indicators [29,30]. Even remission rate is a de ne and convenient endpoint to assess effectiveness both induction and maintenance of remission in UC patients, endpoints with 44-, 52-, or 54-week remission rate appears 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 rst one to demonstrate the cumulative incidence rate of re-exacerbation of biologics in moderate to severe active UC using cohorts from the real-world practice. Our results suggested that administration of biologics signi cantly reduced the risk of re-exacerbation and prolonged remission duration in moderate to severe UC exacerbation. The cumulative risk of re-exacerbation events, which achieved remission by corticosteroids, was signi cantly higher than that achieved using biologics in the COR-REF or DEP cohort of our study. Altogether, these results demonstrated an important nding that the conspicuous effect of biologics is maintaining remission in patients with active UC. Based on the results of 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 high risk of surgical resection in case of reexacerbation have indications for biologics. Although the medical cost of biologics is a huge medical problem [31,32], biosimilar and generic drugs may help to solve the issue [33]. Further trials focusing on maintaining remission are required to clarify this clinical issue of UC.
Our study also con rmed the potential of corticosteroids in reducing the risk of surgical resection in moderate to severe UC exacerbations, although statistical signi cance 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 previously [11-13, 18, 19]. Surgical resection rates of the present cohort were similar those of a Korean cohort [26], although these rates were lower than those of a Western cohort [39]. Remarkably, the proportion of using immunomodulators (i.e., thiopurines) in the present cohort was lower than that in Western countries [40]. 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 populations [41,42]. 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 Asians [43]. 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 con rm 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 costs [26,34]. Biologics will become more essential agents for treating active UC patients, due to active development of biologics in the coming years [44,45]. 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.

Conclusion
Our study has con rmed that biologics signi cantly improved the duration of maintaining remission compared with suboptimal treatments in patients with moderate to severe active UC in a large retrospective Japanese cohort. However, they could not exert a signi cant effect in reducing the risk of surgical resection in patients with moderate to severe active UC with corticosteroid refractory. We believe that our study results would help gain a deeper understanding of the characteristics of biologics used for treating UC patients.

Declarations
Funding: This research did not receive any grants. Availability of Data and Materials:The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
IRB did not permit data sharing, because we did not inform patients of data sharing.