Escalation to biologics after corticosteroids in patients with newly diagnosed Crohn’s disease in Japan: a claims analysis from 2010 to 2021
Article information
Abstract
Background/Aims
A previous health insurance claims study of Japanese patients with newly diagnosed Crohn’s disease (CD) reported an increase in “step-up” approach from 2010 to 2020, with biologic use in the first year remaining stable. This study examined systemic corticosteroid (SCS) use for newly diagnosed CD in Japan and compared patients who were escalated (“step-up”) and were not escalated to biologics.
Methods
This retrospective longitudinal cohort study used health insurance claims data (JMDC database). Patients diagnosed with CD from 2010 to 2020 who had no CD-related claims for ≥ 1 year before index, were traceable for ≥ 1 year after index, and treated with ≥ 1 pre-defined treatment were included. Patients classified by SCS and/or biologic use within 1 year after diagnosis were compared.
Results
Of 823 patients, 379 (46.1%) received SCS in the first year; of these, 43.5% escalated to biologics (step-up group) and 56.5% did not (SCS group). The proportion of patients receiving SCS increased from 25.8% in 2010–2011 to 55.5% in 2020; proportion escalated to biologics increased from 33.8% in 2016–2017 to 51.0% in 2020. The step-up group was significantly younger, more likely to have perianal lesions, and received more intensive treatments than the SCS group. In terms of SCS use, the step-up group was more likely to have shorter time-to-SCS initiation, and a higher initial SCS dose, than the SCS group.
Conclusions
Escalation from SCS to biologics in Japanese patients with newly diagnosed CD increased between 2016 and 2020, particularly in patients with younger onset CD or perianal complications.
INTRODUCTION
Crohn’s disease (CD) is a chronic relapsing-remitting inflammatory disease of the gastrointestinal tract, which, if left untreated, can progressively damage the bowel and cause disability [1]. Treatment strategies for CD typically aim to induce and maintain remission, prevent complications that require surgery, and halt disease progression, while minimizing treatment-related adverse effects [1,2]. These goals were traditionally achieved by starting patients on the least toxic agents, such as 5-aminosalicylic acid (5-ASA), and “stepping-up” to more intensive treatments, such as systemic corticosteroids (SCS; e.g., prednisolone or budesonide) followed by biologic agents, in the absence of adequate response [3]. However, in more severe cases, and to account for individual differences in disease course, a risk-stratified paradigm may be more appropriate, where intensive treatment with biologics is provided early to patients. Many treatment guidelines around the world today recommend making individualized treatment decisions based on a patient’s condition and characteristics, disease severity, disease location, and prognostic risk factors, although detailed therapeutic strategies need to be established further [2,4].
In Japan, inflammatory bowel disease, including CD, is one of the most prevalent intractable diseases [5], and the number of cases has continued to rise since 1950 [2]. Our previous study examined real-world treatment trends in Japanese patients with newly diagnosed CD by analyzing health insurance claims data on prescriptions obtained in the first year after diagnosis and found that prescriptions for biologics remained stable over the decade from 2010 to 2020 [6]. Interestingly, however, the use of SCS prior to biologics almost doubled during that period, especially after 2018, suggesting a rise in the step-up approach and a decrease in the top-down approach in Japan, and the authors speculated that approval of budesonide in 2016 was one of the reasons for the increase. In the recent multicenter open-label randomized controlled PROFILE study conducted in the United Kingdom, better clinical outcomes were reported in patients receiving top-down treatment than in those receiving step-up treatment [7]. However, all patients, including those in the top-down group, received an 8-week course of SCS treatment before randomization. Therefore, these treatment approaches may be defined differently depending on the study, and thus caution is needed when interpreting or comparing the results.
To better understand the increasing preference for the step-up approach in Japan observed previously [6], this secondary analysis focused on patients who received SCS in the first year after CD diagnosis. We examined the real-world use of SCS and compared the characteristics and use of SCS between patients who were and were not escalated to biologic therapy.
METHODS
1. Study Design and Patient Population
We conducted a retrospective, longitudinal, observational cohort study of claims data from the JMDC database, consisting of health insurance claims of inpatient, outpatient, dispensing, and medical examination data obtained from employees of various-sized companies and their dependents in Japan. The data are collected and managed by JMDC Inc. (Tokyo, Japan), who provides it to interested parties including pharmaceutical companies and universities for research purposes.
Details of the study design are described elsewhere [6]. Briefly, claims data in the JMDC database from 2009 to 2021 were screened, and patients who were diagnosed with and treated for CD (International Classification of Diseases, 10th Revision [ICD-10] code: K50) were identified. Patients with a diagnosis of ulcerative colitis (ICD-10 code: K51) or Behçet’s disease (ICD-10 code: M352) were excluded. For each patient diagnosed with CD, the index month was defined as the month of the earliest definitive diagnosis of CD recorded in the database from 2010 to 2020. If there was no CD-related claims record for ≥ 12 months prior to index, we defined the patient as having newly diagnosed CD; these patients were further narrowed down to patients who were traceable for ≥12 months after index. Patients also had to have been treated with ≥ 1 of the following pre-defined CD treatments within 12 months after diagnosis: SCS, immunomodulators, biologic therapy, nutritional therapy, or granulocyte and monocyte adsorption apheresis.
The study was conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labour and Welfare, Japan [8], which waived the need for informed consent for this type of study. The Kyorin University Ethics Review Committee waived the need for ethics review due to the use of secondary anonymized data.
2. Treatment Groups
Patients were classified into 4 groups according to treatment with SCS and/or biologics in the first year after diagnosis: (1) “no biologic group” comprised patients who did not receive biologics, which was further divided into the (1-1) “SCS group,” where patients received SCS without subsequent escalation to biologics, and the (1-2) “no biologic/SCS group,” where patients received neither SCS nor biologics; (2) “biologic group” comprised patients who received a prescription for biologics, which was further divided into the (2-1) “step-up group,” who received ≥1 SCS prescription before escalation to biologics, and the (2-2) “top-down group,” who received no SCS prior to the first prescription for biologics. This manuscript focuses on patients who were escalated to biologics from SCS (2-1 step-up group) and those who were not (1-1 SCS group).
3. Outcomes
The primary outcome was the proportion of SCS use alone versus SCS use that was escalated to biologics (SCS group vs. step-up group) in the first year after diagnosis, analyzed for every 2 calendar years from 2010 to 2019, and for 2020. The secondary outcomes were comparison of SCS use between patients on SCS who were and were not escalated to biologics (step-up group vs. SCS group); patient characteristics of patients who were escalated to biologics (step-up group); factors associated with the escalation to biologics; and the trend in the type of SCS used (prednisolone vs. budesonide).
4. Statistical Analysis
Demographic and clinical characteristics are reported as mean (standard deviation) or median (minimum, maximum) for continuous variables and number (%) for categorical variables. In trend analyses for the primary outcome, patients in each group are reported as number (%). Treatment groups were compared using chi-square tests (or Fisher exact test when appropriate) for categorical variables and Student t tests for continuous variables. Multivariable logistic regression analysis was used to identify the factors associated with the step-up to biologics among patients who received SCS. Amazon Redshift version 1.0.40182 (Amazon Web Services, Inc., Seattle, WA, USA) was used as the data warehouse platform and statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA).
RESULTS
1. Baseline Demographics
A total of 823 patients met the eligibility criteria and were included for further analyses (Fig. 1). Of these, 77.6% were male, the mean age was 28.5 years, and 75.7% had adult-onset CD (Table 1) [6]. Almost half (42.9%; 353/823) received conventional therapy, namely, 5-ASA, SCS, or nutritional therapy, without biologics (no biologic group), whereas 57.1% (470/823) were prescribed biologics (biologic group) within the first year after diagnosis of CD. In all, 46.1% (379/823) of patients received SCS as a first-line treatment in the first year after diagnosis of CD (SCS group + step-up group); of these, 43.5% (165/379) were escalated to biologics after SCS (step-up group), while 56.5% (214/379) did not receive a subsequent prescription for biologics (SCS group).
Patient flow diagram. aIncludes patients diagnosed with both ulcerative colitis and Behçet’s disease. CD, Crohn’s disease; SCS, systemic corticosteroids.
Patient Demographics and Clinical Characteristics
2. Trends in First-Year Treatment Decisions among Patients Receiving SCS
The proportion of patients who received SCS (SCS group + step-up group) increased over the analysis period from 25.8% in 2010–2011 to 55.5% in 2020, especially spiking from 2018 (Table 2). Among those who received SCS, the proportion of patients who were escalated to biologics (step-up group) in the first year after diagnosis was the lowest in 2016–2017; this started to increase after 2016–2017 and exceeded 50% in 2020.
Treatment Decisions among Patients Who Received SCSs as Initial Treatment
3. Comparison of Patients Who Were and Were Not Escalated to Biologics
Patients who were escalated to biologics (step-up group) differed in several clinical features from those who remained on SCS in the first year after diagnosis (SCS group) (Table 3). Patients who received the step-up approach were significantly younger at index (median: 21 years vs. 29 years; P<0.001) and a higher proportion had a Montreal classification age at diagnosis ≤40 years (89.1% vs. 69.6%; P<0.001). A significantly greater proportion of these patients (step-up group) also had perianal lesions (P<0.001), underwent imaging tests (P<0.001), and received 5-ASA (P<0.001), immunomodulators (P=0.016), or nutritional therapy (P<0.001) compared with those who remained on SCS. Multivariable regression analysis also revealed that patients who were escalated to biologics (step-up group) were significantly more likely to have received 5-ASA (odds ratio [OR], 3.279; 95% confidence interval [CI], 1.581–6.804; P=0.001) and nutritional therapy (OR, 2.609; 95% CI, 1.535–4.436; P<0.001), and less likely to have a Montreal classification age at diagnosis >40 years (OR, 0.444; 95% CI, 0.225–0.875; P=0.019) (Table 4).
Clinical Characteristics of Patients Who Received SCSs Who Were and Were Not Escalated to a Biologic Within 1 Year of Diagnosis
4. Use of SCS
Analysis of how SCS were used by patients who were and were not escalated to biologics revealed distinct differences in time to first SCS prescription, SCS type, and initial SCS dose (Table 5). Those who were escalated to biologics (step-up group) had a shorter time-to-SCS initiation (mean: 1.0 vs. 1.7 months; P=0.008) and received a higher initial dose of SCS (mean dose: 36.5 mg/day vs. 30.4 mg/day; P<0.001) than patients who remained on SCS (SCS group) in the first year after diagnosis. A greater proportion of patients who received treatment with the step-up approach used budesonide compared with patients who remained on SCS (47.9% vs. 33.6%; P=0.005). Duration of SCS use, however, was not different. In terms of SCS type, trend analysis showed that the use of budesonide increased more quickly in the step-up group compared with the SCS group after its approval in 2016, such that 61.2% of patients in the former group and 44.7% in the latter group were using budesonide in 2020 (Fig. 2).
Systemic Corticosteroid Use in Patients Who Were and Were Not Escalated to Biologics
Trend in prescription of prednisolone and budesonide in the first year after diagnosis from 2010 to 2020 for (A) all patients who received systemic corticosteroids (SCS group + step-up group), (B) patients who received systemic corticosteroids and were not escalated to biologics (SCS group), and (C) patients who received systemic corticosteroids and were escalated to biologics (step-up group). Trends in SCS prescription (prednisolone vs. budesonide) in the first year after diagnosis were categorized into analysis periods based on the year of their CD diagnosis; as patients with CD diagnosis up to 2020 were included in the study, the analysis period was divided into 2-calendar year intervals from 2010 to 2019 and a single year of 2020 for the final analysis period. SCS, systemic corticosteroids; CD, Crohn’s disease.
DISCUSSION
This real-world analysis of claims data in Japanese patients with CD revealed that the proportion of patients who were escalated to biologics after receiving SCS (step-up group) in the first year after diagnosis increased from 33.8% in 2016–2017 to 51.0% in 2020. This implies that a treatment strategy of achieving deep remission from an early stage with advanced therapies in necessary cases [9], as suggested in guidelines and expert consensus statements [2,10], is gradually being accepted. After the approval of budesonide in Japan in 2016, its uptake occurred rapidly, such that it was used in 30.9% of the SCS-treated patients in the following year. This quick growth was more obvious in the step-up group than in the SCS group (43.5% in 2016–2017 and 61.2% in 2020 vs. 24.4% in 2016–2017 and 44.7% in 2020). The greater growth in budesonide prescriptions in the step-up group than in the SCS group supports the theory posed in the previous study that budesonide contributed to an increase in the proportion of patients treated with the step-up approach [6]. This trend may be influenced by changes in physicians’ perception of the safety of newer steroids, particularly budesonide [11]. Consistent with the previous findings [6], we further speculate that these factors (use of biologics at an early stage and the availability of a safer steroid) are likely to have contributed to the wider adoption of the step-up approach in Japan.
The PROFILE study reported that top-down treatment demonstrated significantly better outcomes (sustained steroid-free and surgery-free remissions) than step-up treatment [7]. The authors concluded that top-down treatment should be considered as the standard of care for newly diagnosed CD [7]. Conversely, our study showed an increase in the step-up approach from 2016 to 2020, appearing to conflict with the results observed in the PROFILE study. However, all patients in the PROFILE study, including those in the top-down group, received an 8-week course of oral corticosteroids before randomization, unlike in our study, where a stricter definition was applied, with the top-down group including only patients with no record of SCS prescription before biologic prescription. Therefore, the top-down group in the PROFILE study would have been classified as part of the step-up group in the current study. Moreover, given that the Japanese clinical guideline recommends biologics for CD in patients with insufficient response to conventional treatments, including SCS [2], the findings from our study align with the current local recommendations. In our previous report [6], mean time to initiation of biologics was 1.8 to 3.6 months, depending on the biologic, with no indication of a delay in biologics initiation in the step-up group (2.0–3.7 months) versus the top-down group (1.7–3.4 months). Together, these results indicate the importance of a timely escalation to biologics where appropriate.
Although the top-down approach remained the dominant strategy overall (64.9%; 305/470) in the original analysis of Japanese patients who received prescriptions for biologics in the first year after CD diagnosis (biologic group) [6], we reported an increase in the adoption of the step-up approach between 2010 and 2020 (from 23.8% to 48.5%). These results suggested that SCS use may be playing a role in the increasing preference for the step-up approach. In the current analysis, we performed a closer examination on patients who received SCS, and, likewise, we discovered an increasing proportion of patients being escalated to biologics between 2016 and 2020. Interestingly, while the step-up group was associated with shorter time-to-initiate SCS and higher dose of initial SCS, it was not associated with duration of SCS use. These may be an indicator that the use of SCS has become more appropriate in recent years with the development of advanced therapies. In addition, patient characteristics that were found to be associated with the step-up group in this study indicate that physicians are making treatment decisions based on patient background, considering negative prognostic factors such as younger age or the presence of perianal lesions [12-14].
The strengths of the present study include the use of the JMDC database, Japan’s largest health claims database of employer-based health insurance schemes, which captures all insured treatments of patients <75 years and their dependents. This is one of a few real-world studies in CD treatment trends in Japan, which, along with Korea and China, and in contrast to plateauing cases in Western countries, continues to experience increasing numbers of patients with CD [5,15-17]. However, because this study was based on health insurance claims, clinical data and treatment outcome data (e.g., treatment persistence with SCS, hospitalization and surgery rates) were not available, which limits the interpretation of the results. Finally, although we performed trend analyses over a decade, the total population in the JMDC database was smaller in the earlier years. Therefore, there were fewer patients with CD during 2010–2013, although this number gradually increased over time.
The present real-world analysis of claims data on CD treatment in newly diagnosed Japanese patients revealed that the proportion of patients who were escalated to biologics after receiving SCS in the first year after diagnosis increased between 2016 and 2020. Patients who were stepped up to a biologic were younger and had more perianal complications compared with those who did not. Moreover, the step-up group also had a shorter time-to-initiate SCS and a higher dose of initial SCS, and the use of budesonide increased more quickly in the step-up group than in the SCS group.
Our findings suggest that the use of SCS is going through optimization in Japan; treatments are carefully considered accounting for various factors such as patient’s condition, prognosis, and future treatment plans. Further studies are needed to understand clinical challenges in real-world settings, and to improve treatment strategy for CD with further elaboration in the use of biologics and SCS.
Notes
Funding Source
This work was supported by Takeda Pharmaceutical Company Limited. Takeda Pharmaceutical Company Limited was involved in the study design, data collection, data analysis, and preparation of the manuscript.
Conflict of Interest
Matsuura M has received honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AbbVie GK, EA Pharma Co., Ltd., Janssen Pharmaceuticals K.K., JIMRO Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co. Ltd., Pfizer Japan Inc., Sandoz AG, Takeda Pharmaceutical Company Limited, Viatris Inc., and ZERIA Pharmaceutical Co., Ltd. In addition, Matsuura M has a leadership or fiduciary role as a member of the Clinical Epidemiology Committee of the Japanese Society for Inflammatory Bowel Disease, a member of the Committee on Public Information of the Japanese Society for Mucosal Immunology, and a Council member of the Japan Small Intestine Society. Yoon A was an employee of Takeda Pharmaceutical Company Limited. Miyoshi J has received honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AbbVie GK, Janssen Asia Pacific, Janssen Pharmaceuticals K.K., Mitsubishi Tanabe Pharma Co., Ltd., Miyarisan Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Company Limited. Hisamatsu T has received grants or contracts from EA Pharma Co., Ltd., JIMRO Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Company Limited, and ZERIA Pharmaceutical Co., Ltd.; consulting fees from AbbVie GK, Abivax, Bristol Myers Squibb, EA Pharma Co., Ltd., Eli Lilly and Company, Gilead, Janssen Pharmaceuticals K.K., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Company Limited; and has received honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AbbVie GK, EA Pharma Co., Ltd., Gilead, Janssen Pharmaceuticals K.K., JIMRO Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Company Limited.
Data Availability Statement
The dataset generated and analyzed during the current study is not publicly available because it was used under contract from JMDC Inc. but is available from the corresponding author on reasonable request.
Author Contributions
Conceptualization: Yoon A, Hisamatsu T. Investigation: all authors. Methodology: Matsuura M, Miyoshi J, Hisamatsu T. Project administration: Yoon A. Supervision: Hisamatsu T. Validation: Matsuura M, Miyoshi J. Writing - original draft: Matsuura M. Writing - review & editing: all authors. Approval of final manuscript: all authors.
Additional Contributions
The authors thank Yuji Honma (JMDC Inc.) for his contributions to project management of this study, Michinori Arimitsu (JMDC Inc.) for statistical support, and Hana Nomura and Rebecca Lew (ProScribe K.K. – Envision Pharma Group) for editorial and medical writing support.