Using data from the Phoenix study, we analyzed the real-world treatment patterns, especially the use of systemic corticosteroids, over approximately 30 years in patients with UC or CD in Japan. Corticosteroid use as initial treatment was relatively stable in patients with UC but decreased in patients with CD who had an onset of disease after 2006, compared with those who had an onset between 1965 and 2005. In both UC and CD, cumulative corticosteroid doses were numerically lower in patients with an onset of disease after biologics became available than in those with an onset of disease before biologics became available. In CD, the proportion of patients receiving an initial corticosteroid dose of ≥ 30 mg/day increased from 2006 to 2020, with a decreasing trend in the proportion receiving long-term treatment (≥ 180 days). Patients with CD who had an onset of disease after biologics became available had a substantially lower surgery rate compared with those with an onset of disease before biologics became available. In UC, although less clear, the proportion of patients receiving long-term corticosteroid treatment decreased after 2001; however, no apparent trend in changes to initial corticosteroid dose was observed. Furthermore, in contrast to CD, the surgery rate appeared slightly higher in those with an onset of disease after biologics became available than in those with an earlier onset of disease. These results suggest that the availability of biologics has contributed to the more appropriate use of corticosteroids and reduced surgery rates, especially in patients with CD, although the use of corticosteroids in IBD can be further improved, particularly by using newer treatments that are available.

This study shows that the proportion of patients initially treated with corticosteroids was lower in those with a later disease onset than in those with an earlier disease onset in CD, but not in UC. Although a direct comparison of the results is not possible, a population-based analysis in Canada reported that patients receiving corticosteroids at any time decreased between 1997 and 2017 in both UC and CD [20]. In a previous retrospective database study of Japanese patients with UC, the proportion of patients receiving corticosteroids at any time decreased between 2009 and 2013 [17]. Another database study of Japanese patients with UC showed that corticosteroid use in UC decreased between 2006 and 2016 [15]. The Japanese guidelines for UC and CD were first published in 2006 and 2010, respectively [21]; therefore, no local guidelines were available for those with a disease onset before these years. Currently, corticosteroids are recommended only to induce disease remission [9, 22, 23]. European guidelines recommend 5-ASA and corticosteroids for mild-to-moderate UC, but only corticosteroids for active CD [22, 23]. Japanese guidelines recommend 5-ASA for mild-to-moderate UC (with corticosteroids only for patients who are unresponsive to 5-ASA), and both 5-ASA and corticosteroids for active CD [9]. In relation to these recommendations, UC is often treated using a “step-up” approach, whereas CD, particularly since biologics became available, is treated using a “top-down” approach [24, 25]. Therefore, the publication of the treatment guidelines, together with the differences in treatment approach and the approval of immunomodulators and biologics in Japan in the mid-2000s, may explain why a decreasing trend in corticosteroid use as initial treatment was observed in patients with CD, although no clear trend was observed in patients with UC. However, it is important to note that the results from the current study suggest that approximately one-third of patients with UC were treated with corticosteroids, either alone or in combination with other drugs (e.g., 5-ASA), as initial treatment regardless of the year of disease onset. Furthermore, in this study, the proportion of patients with CD prescribed corticosteroids as initial treatment was lowest in those who had a disease onset after 2006 (< 15%); in fact, the proportion of patients prescribed corticosteroids was lower than those treated with immunomodulators or biologics. Nonetheless, these results indicate that the overall use of corticosteroids has decreased in recent years since the approval of biologics, and that corticosteroids are used more appropriately as remission induction therapy, in line with the current treatment guidelines [9].

The dose and duration of corticosteroids affect the incidence and severity of most corticosteroid-related adverse events [26]. The current Japanese treatment guideline recommends oral prednisolone 30–40 mg/day for UC and 40 mg/day for CD initially, reducing to < 10 mg/day within 3 months [9, 14] to minimize the potential long-term adverse events associated with corticosteroids [13]. In a previous Japanese database study of UC conducted between 2006 and 2016, low initial corticosteroid dose was associated with long-term use (≥ 180 days) of corticosteroids (P < 0.001) [15]. This same database study showed that the proportion of patients using an initial corticosteroid dose ≥ 30 mg/day gradually increased between 2006 and 2016. Conversely, in the current study, most patients with UC received an initial corticosteroid dose of ≥ 30 mg/day across all time periods with no apparent trend of changes in initial dose over time between 1965 and 2020. However, the proportion of patients using corticosteroids ≥ 30 mg/day was substantially higher in this study than in the previous database study [15], and the proportion of patients treated for ≥ 180 days generally decreased after 2001. In contrast, in patients with CD, a gradual increase in the proportion of patients receiving an initial corticosteroid dose of ≥ 30 mg, with a gradual decrease in those treated for ≥ 180 days, was observed after 2006. In both UC and CD, the availability of biologics also appeared to have reduced the cumulative corticosteroid doses used. However, it should be noted that the sample size was limited, and the disease duration was longer in patients who had a disease onset before biologics became available. Although corticosteroids are recommended for short-term use (≤ 3 months) only [9], during the remission induction phase, there is a possibility that some patients may have had extraintestinal complications (e.g., pyoderma gangrenosum) that may require treatment with long-term corticosteroids. The results from this study collectively indicate that the corticosteroid doses used are in line with the current guideline for most patients with UC or CD, reducing the proportion of patients being treated for a long duration (≥ 180 days) after the appearance of biologics. However, because there are still patients who are treated for an intermediate duration (90–179 days), it may be important to consider the use of immunomodulators and biologics where appropriate to further reduce long-term corticosteroid use, thus preventing corticosteroid-related complications.

During the course of the disease, surgery will be required in 35% of patients with UC and up to 70% of patients with CD [27]. However, surgery is associated with postoperative complications, such as suture failure and intestinal obstruction in UC and short bowel syndrome in CD [9]. Therefore, current treatment guidelines recommend surgery in patients with severe disease or in those with cancer or dysplasia [9]. Results from the phase 3, randomized, placebo-controlled CHARM trial [28] of adalimumab also showed that the major surgery rate was significantly lower in patients with CD receiving adalimumab every other week compared with the placebo group (0.4% vs. 3.8%, P = 0.01). In a previous retrospective study in Japan, infliximab was associated with improvement of the cumulative nonoperative rate in patients with CD [29]. A recent systematic review and meta-analysis revealed that the 5-year cumulative risk of surgery was 7.0% for UC and 18.0% for CD after 2000, which has significantly decreased over time [30]. Furthermore, in a Korean study, a CD diagnosis after 2003—the first year an anti-tumor necrosis factor-α antibody agent was reimbursed in Korea—compared with a CD diagnosis before 2003 was an independent predictor for intestinal resection [31]. Consistent with these previous findings, the surgery rate in CD in this study was substantially lower in patients who had an onset of disease after biologics became available in 2002 (i.e., when the first biologic, infliximab, was approved) and in 2007 (i.e., when infliximab was approved for maintenance therapy). However, it should be noted that the surgery rate was higher, and the decrease in surgery rate after the availability of biologics was more pronounced, in this study compared with the Korean study. These results may be because this study included core IBD treatment hospitals and therefore possibly included patients with more severe disease. In contrast to CD, the surgery rate in UC in this study was slightly higher in patients with onset of disease after biologics were available compared with patients with earlier disease onset, although the overall surgery rate was low and comparative data were limited to 9 years after onset. This may be explained again by the fact that patient data were collected from core IBD treatment hospitals; data from patients with more severe UC may have been concentrated in these hospitals, with an increased overall number of patients in Japan over time resulting in the higher surgery rate in patients with onset of disease after biologics were available. These results indicate that the use of biologics may reduce corticosteroid use, prevent corticosteroid-related and/or postoperative complications, and improve treatment outcomes in IBD, especially in CD. However, given that data in this study were collected retrospectively, and only in the Hokkaido region in Japan, large-scale or prospective studies may be required to further investigate the impact of biologics on surgery rates in patients with IBD in Japan.

The main strength of this study was the use of a real-world database of patients with IBD, which contains data on patients’ clinical findings, including treatment details, dosing status, treatment duration, and outcomes, for approximately 30 years. This study also included all patients with IBD diagnosed at age ≥ 10 years. The extent of the database enabled analysis of time-dependent treatment patterns in patients with IBD, including those with onset of disease before 1990, who are undergoing long-term treatment. A limitation of the study was that data were only collected from five core IBD treatment hospitals in Hokkaido, Japan; therefore, the results may not reflect clinical practice in other hospitals and may be subject to selection bias. In addition, the patients included in this study may not reflect the true IBD population in Japan and, as noted above, they may have more severe IBD. The sample size was small for some subgroups, especially patients with an earlier disease onset, because the study was initiated in 2018. The accuracy of the data before 1990 may also be limited because the database was started from 1990. Additionally, the accuracy of data on enteral nutrition in patients with CD (e.g., intake per patient) may also be limited. Lastly, patients’ medical information (e.g., previous or current treatment history) was not tracked or recorded if the patient was treated at a different hospital, and the follow-up time for some analyses was limited.