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INTRODUCTION
Crohn’s disease (CD) is a lifelong inflammatory condition of the gastrointestinal tract that requires medical treatment to prevent bowel damage and long-term disability [1-5]. The goals of treatment are to prevent disease progression by inducing and maintaining remission while minimizing treatment-related adverse effects. Over the past 10 years, there has been a shift from a conventional step-up approach, whereby treatment intensifies with disease progression, to a top-down approach, characterized by early, intensive intervention, particularly for patients at risk of severe disease [6-8]. Selection of the most appropriate treatment strategy is dependent on multiple factors that include local treatment guidelines; disease location, severity, and activity; the risk-benefit profile of the selected medication; patients’ previous responses to treatment; and the presence of any contraindications or comorbidities [1-4,9].
Several studies have been conducted to assess real-world treatment of patients with CD from Europe, the USA, and South Korea [10-12]. However, there is limited information on real-world medical treatments for CD or on how these treatments have changed over time in Japan [9,13]. The aims of this health insurance–based claims observational study were to investigate real-world treatment of patients with newly diagnosed CD in Japan, with a focus on the first year, and to evaluate trends in the real-world use of biologics over time.
METHODS
1. Study Design and Data Source
This retrospective, longitudinal, observational cohort study analyzed commercially available data from the JMDC Inc. (Tokyo, Japan) database of medical expense claims for company employees in Japan. The JMDC database includes health records of employees and their dependents from companies of any size in Japan (starting in 2005) and represents approximately 7% of the Japanese population. JMDC Inc. was responsible for collection of claims data and managing the database. Aggregated data were prepared and provided to the authors by JMDC Inc. in accordance with a research contract between JMDC Inc. and the study sponsor. The authors had no access to individual patient data.
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 [14]. The Japanese ethical guidelines do not require ethics review of studies that use de-identified data from databases comprising previously obtained secondary data. In accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan, informed consent was not required for this study. In addition, in accordance with the Kyorin University Ethics Review Committee, ethics review was not required because individual patient data were not collected; only secondary data that were already anonymized and aggregated by JMDC Inc. were analyzed in this study. 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.
2. Study Population
Any patient with a new diagnosis of CD (International Classification of Diseases, 10th Revision [ICD-10] code: K50) in the JMDC database during the index identification period (January 2010–December 2020) and who met the criteria below was included [15]. Because CD is a chronic disease associated with cycles of remission and relapse, it is difficult to identify a “true” new diagnosis. Therefore, patients without a CD claims record for ≥ 1 year before index (the month of the first definitive diagnosis identifiable in the database based on CD claims) were considered to be newly diagnosed patients. In this study, patients were included if they did not have a CD claims record for ≥ 12 months directly before index, had data available for ≥ 12 months after index, and were treated with ≥ 1 of the following pre-defined CD treatments after diagnosis systemic corticosteroids (SCS), immunomodulators, biologic therapies, enteral nutrition, or granulocyte and monocyte adsorption apheresis. Patients with a diagnosis of ulcerative colitis (ICD-10 code: K51) or Behçet’s disease (ICD-10 code: M352) were excluded from the analysis population.
3. Treatment Groups
Patients who met the inclusion criteria were classified into 4 groups based on their use of biologics and SCS within the first year of diagnosis. The no biologic group included patients with no prescriptions for biologics within the first year since diagnosis and comprised the SCS group (no prescriptions for biologics, ≥ 1 prescription for SCS) and the no bio/SCS group (no prescriptions for biologics nor SCS). The biologic group included patients with biologics prescribed within the first year since diagnosis and comprised the step-up group ( ≥ 1 SCS prescription before or within the same month of the first biologic prescription) and the top-down group (no prescription for SCS until the month of the first biologic prescription).
4. Outcomes
The primary outcome was the proportion of patients in each treatment group, which describes treatment decisions within the first year since diagnosis. Secondary outcomes reported in this study were the trend of proportions of the biologic group versus the no biologic group from 2010 to 2020, which is the proportion of patients treated with biologics in the first year since diagnosis; demographics comparison between the no biologic and biologic groups; the trend of proportions for the top-down group versus the step-up group from 2010 to 2020, which is the proportion of patients treated with a top-down approach; and demographics comparisons between the top-down and step-up groups. Exploratory outcomes in this study were persistence with a first biologic in the biologic group and the trend for the type of SCS (prednisolone or budesonide).
5. Statistical Analysis
The proportions of patients in each group were calculated as percentages with 95% confidence interval (CI). Comparisons between treatment groups were assessed using chi-square tests, the Fisher exact test, or the t test, as appropriate. Persistence with biologics was investigated using Kaplan-Meier survival analysis. Persistence with the first biologic (months) was defined as the duration until discontinuation, where discontinuation was defined as no prescription for a standard interval of each biologic plus 1 month (i.e., counting from the month after the last prescription). Patients who did not discontinue during the observation period were censored at the end of the observation period (November 2021). Multivariable analyses (logistic regression) were conducted to assess the factors associated with treatment decisions. Descriptive statistics were used for all other outcomes. 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. Treatment Decisions in the First Year of Diagnosis
Records for a total of 823 patients met the eligibility criteria and were included in the analyses (Fig. 1). Of the patients with newly diagnosed CD in the analysis population, 57.1% (470/823) were prescribed biologics within the first year after diagnosis and 42.9% (353/823) were not (Fig. 2). Of those who were prescribed biologics (biologic group), most received a top-down approach; specifically, 64.9% (305/470; 95% CI, 60.4%–69.2%) of the biologic group did not receive SCS before starting biologics (top-down group), and 35.1% (165/470; 95% CI, 30.8%–39.6%) of the biologic group received SCS before biologics (step-up group). Of those who were not prescribed biologics (no biologic group), 60.6% (214/353; 95% CI, 55.3%–65.8%) received SCS during the first year of diagnosis (SCS group), and 39.4% (139/353; 95% CI, 34.2%–44.7%) did not (no bio/SCS group).
2. Patient Demographics and Clinical Characteristics
Overall, the median age of patients in the analysis population was 24 years, 77.6% were male, 75.7% had adult-onset CD, and 34.4% had perianal lesions at index (Table 1). Patients who were prescribed biologics within the first year of CD diagnosis were younger than those who were not (median: 23 years in the biologic group vs. 28 years in the no biologic group), and a higher proportion had perianal lesions at index (43.0% in the biologic group vs. 22.9% in the no biologic group) (Table 1). The proportion of patients with perianal lesions was highest in those who started biologics without a prior SCS (47.5% in the top-down group) compared with those who received SCS before biologics (34.5% in the step-up group) and the rest (22.9% in the no biologic group). A small increase in the proportion of patients with perianal lesions was seen by 12 months in each group (SCS: +2.4%; no bio/SCS: +5.8%; step-up: +4.9%; top-down: +3.3%).
3. Trends in First-Year Treatment from 2010 to 2020
The proportions of patients who were (biologic group) and were not (no biologic group) prescribed biologics within the first year of CD diagnosis remained stable for the duration of the study period (Table 2). On the other hand, of the patients who were prescribed biologics within the first year of diagnosis (the biologic group), there was an increase in the proportion of those in the step-up group (i.e., those receiving SCS before initiating biologics [a step-up approach]), particularly after 2018 (Table 3). In parallel, there was a shift in favor of budesonide over prednisolone as the initial SCS from 2016 onwards, particularly after 2018 (Supplementary Table 1). The proportions of patients who initiated budesonide were 0% in 2010–2015, 43.5% in 2016–2017, 55.7% in 2018–2019, and 61.2% in 2020.
4. Comparisons of First-Year Treatment between the Biologic and Non-Biologic Groups
In addition to the younger age and higher proportion of perianal lesions in the biologic group, higher proportions of patients in the biologic group (patients who were prescribed biologics in the first year since diagnosis) received 5-acetylsalicylic acids (ASAs; 90.6% vs. 69.7%; P< 0.001) and enteral nutrition (77.0% vs. 63.7%; P< 0.001), and lower proportions received SCS (41.5% vs. 60.6%; P< 0.001) compared with the no biologic group (Table 4). There was no difference in the use of immunomodulators between the biologic and no biologic groups (23.0% vs. 20.1%) (Table 4). Additionally, among the 283 patients who had perianal lesions at index, 202 (71.4%) patients were prescribed biologics (Table 1). The factors significantly associated with a prescription for biologics within the first year of diagnosis by multivariable analysis were younger age, perianal lesions, gastrointestinal examinations, 5-ASA prescriptions, and no SCS prescriptions (Table 5).
5. Comparisons of First-Year Treatment Between Top-down and Step-up Approaches
In patients who started biologics without prior SCS (top-down group), the proportions of patients who were male (83.3% [254/305] vs. 73.3% [121/165]; P= 0.010) and those who had perianal lesions (47.5% [145/305] vs. 34.5 [57/165]; P= 0.007) were higher compared with those who received SCS before biologics (step-up group) (Table 6). In addition, in the top-down group, more patients received anti-tumor necrosis factor (TNF) therapies (85.2% [260/305] vs. 75.2% [124/165]; P= 0.007) and fewer patients received immunomodulators (18.7% [57/305] vs. 30.9% [51/165]; P= 0.003) compared with the step-up group. The factors significantly associated with a top-down treatment approach (no use of SCS before biologics) by multivariable analysis were male sex, perianal lesions, no immunomodulator prescriptions, and anti-TNF prescriptions (Table 7).
6. First Biologic-Related Findings
1) Persistence
Overall, 88.1%, 77.3%, 70.1%, 63.0%, 55.1%, and 45.5% of patients persisted with a first biologic at 12, 24, 36, 48, 60, and 120 months, respectively (Fig. 3A). In terms of having perianal lesions by the time of biologic initiation, persistence with the first biologic was lower after 36 months compared with patients without perianal lesions (Fig. 3B). There was no statistically significant difference in persistence rates between biologics nor between step-up and top-down approaches (Supplementary Fig. 1). Persistence rates with a TNF-α inhibitor or the interleukin (IL)-12/IL-23 antibody in the biologic group are shown in Supplementary Fig. 2.
2) Time to Initiation of Biologics
Time to initiation of biologics was analyzed in a modified biologic group (n = 420). These patients were those from the original biologic group (n = 490) who could be followed for ≥ 12 months from the first biologic (n = 429). Patients whose first biologic was vedolizumab (n = 9) were excluded because of the small number of patients in this group. The mean time to initiation of a first biologic was 1.8 months for infliximab, 2.5 months for adalimumab, and 3.6 months for ustekinumab in the biologic group (Table 8). The mean time to initiation of biologics in the top-down group was shorter compared with the step-up group. By definition in this study, the biologic group comprised patients who were given biologics within 12 months of diagnosis; therefore, patients who were given biologics > 12 months from diagnosis were not included in the analysis of the time to initiation of biologics.
DISCUSSION
This real-world analysis of CD treatments has shown that the proportion of patients prescribed biologics within the first year of diagnosis in Japan has remained stable over the past decade. Despite this, the use of SCS before biologics (i.e., using a step-up approach) has increased from 24% in 2010 to 49% in 2020. Patients who were most likely to be treated with biologics were those who were younger, had perianal lesions at diagnosis, gastrointestinal examinations within 12 months from diagnosis, a 5-ASA prescription, and no use of SCS. Patients who were most likely to be treated with biologics without a prior SCS were those who were male, had perianal lesions at diagnosis, no use of immunomodulators, and use of anti-TNFs. Overall, among 283 patients who had perianal lesions at index, 51.2% (145/283) were treated using a top-down approach. To break this down, 71.4% (202/283) were treated with biologics in the first year since diagnosis of CD, and of these 202 patients, 71.8% (145/202) were treated using a top-down approach.
Along with the increase in the use of a step-up approach with biologics from 2010 to 2020, which was most obvious after 2018, there was a quick turnover in prescriptions in favor of budesonide over prednisolone from 2016. These changes in treatment strategies were likely to be a result of (1) availability of budesonide in Japan, which was approved for induction of remission in mild-to-moderate CD in 2016, and (2) uptake of the Japanese guidelines for inflammatory bowel disease, as well as the European Crohn’s and Colitis Organisation guidelines [1,3], which recommend the use of a step-up approach for induction of remission in patients with moderate-to-severe CD [2]. In particular, budesonide is considered safe, with fewer adverse effects compared with prednisolone [16], which may have affected doctors’ willingness to prescribe SCS in patients with CD. Also, several studies have shown budesonide to be effective for the induction of remission (defined as a Crohn’s Disease Activity Index score ≤ 150 at week 8) in Japanese patients with mild-to-moderate active CD [17,18]. Based on these data, we consider that the use of budesonide contributed to an increase in the proportion of patients treated with the accelerated step-up approach.
The finding that younger patients were more likely to be prescribed biologics seems consistent with a recent finding from the Inception Cohort Registry Study of Patients with Crohn’s Disease, which showed that the prevalence of perianal lesions at CD diagnosis was higher in patients < 40 years of age [19]. In contrast, the lower likelihood of biologic prescription in older patients could be because older patients with inflammatory bowel disease are at greater risk of adverse events, irrespective of the treatment they receive (e.g., they have a greater risk of severe infection compared with younger patients when treated with anti-TNFs) [20]. It is also conceivable that older patients are less likely to have disease activity that requires treatment with a biologic [21]. Furthermore, gastroenterologists may intend to prevent future complications such as fistulas or stenosis by prescribing biologics early in patients with early-onset disease. The finding that the presence of perianal lesions at diagnosis was associated with an early use of biologics (i.e., top-down approach) is not surprising because perianal lesions indicate more severe disease activity, and management of these patients typically requires more intense treatment with agents such as anti-TNFs [2,22]. Compared with patients who were treated with SCS before biologics (step-up approach), patients who started biologics without prior SCS (top-down approach) were more likely to be male and have perianal lesions. Because males are more likely to have perianal lesions than females [23], it is possible that male sex was a confounding factor and that this result can be attributed to disease severity.
In this analysis, we also compared patient characteristics and treatments given in the first 12 months since a CD diagnosis between those who did (biologic group) and did not (no biologic group) receive biologics. Although differences in patient demographics and treatment history were observed between the groups, it is challenging to interpret the clinical significance of these differences because of the limited clinical information (e.g., disease activity and behavior) that is available in health insurance–based claims registries. Nevertheless, disease severity is expected to be less diverse in the biologic group because biologics are approved for treatment of moderate-to-severe CD. As expected, it was interesting to see that more anti-TNFs (85.2% vs. 75.2%) and fewer immunomodulators (18.7% vs. 30.9%) were prescribed in the top-down group compared with the step-up group. First, this is likely because immunomodulators are commonly added to SCS as part of a step-up approach (step-up group) and tend to be continued, even if anti-TNF therapy is initiated. Second, a higher proportion of perianal complications at index—which is considered a negative prognostic factor—in the top-down group (47.5% vs. 34.5%) would have resulted in a greater proportion of top-down use of biologics (mainly anti-TNFs). In addition, physicians’ concerns regarding adverse effects with concomitant use of immunomodulators when an anti-TNF is newly started may be the reason why immunomodulators were less likely to be combined with an anti-TNF in the top-down group. The tendency to avoid concomitant use of immunomodulators with anti-TNFs in Japan was even greater up until 2019. After 2019, the NUDT15 gene variant screening test, a pharmacogenetic biomarker for thiopurine-induced acute neutropenia and alopecia in patients with inflammatory bowel disease [24], was covered by the Japanese national health insurance. Our findings could support previous observations that anti-TNF monotherapy is preferred by physicians in the real-world [25,26] and suggest that some physicians may avoid using immunomodulators in patients with perianal abscesses in clinical practice.
Overall, persistence with a first biologic (infliximab, adalimumab, ustekinumab) was 88%, 77%, and 70% at 12, 24, and 36 months, with no observable differences between biologics nor between the step-up and top-down groups. When we compared patients with and without a claims record for perianal lesions before the first biologic, there was no statistically significant difference between these groups. However, it was noticeable that, after 36 months, persistence was lower for patients with perianal lesions than those without. This may suggest that patients with perianal lesions are more likely to switch to a second biologic after some time, most likely because of loss of response.
A key strength of our study was the use of the JMDC database, Japan’s largest health claims database, consisting of employer-based health insurance schemes. As long as individuals remain with their employer, all insured treatments from any hospital received by the employee and their dependents are captured in the database. Despite using the employer-based database, the cost would not have affected prescriptions because out-of-pocket payments are the same in Japan across different types of insurance. Moreover, the JMDC database is limited to patients < 75 years of age, it is unlikely to have contributed to bias in our study because CD is often diagnosed in younger adults (20–40 years) [10], and in fact, the patient characteristics in this study were similar to those of patients in a nationwide registry study [27]. Furthermore, this study was focused on the first year of treatment after diagnosis. The major limitation of this study is the lack of clinical data due to the nature of claims data. Because of this, detailed clinical assessment or direct treatment outcomes could not be included. The pre-defined therapies that were selected for this study were assumed to be prescribed for CD, which may be a limitation of this study because it is possible that the pre-defined therapies may have been prescribed for other conditions. Ulcerative colitis and Behçet’s disease were excluded to reduce the impact of this limitation because the treatments used for these diseases overlap with those used for CD.
In conclusion, this real-world analysis of health claims data has shown how the real-world treatment of CD in Japan has evolved in the past 10 years. Although a proportion of biologic prescriptions in newly diagnosed patients remained stable for a decade, there has been a shift to a step-up approach from a top-down approach after 2018, presumably because of the availability of budesonide and the uptake of revised treatment guidelines.
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