Introduction: Crohn’s disease (CD) is a chronic inflammatory condition affecting any part of the gastrointestinal tract. Current therapies involve pharmacological efforts to dampen inflammation. Biologics are recommended for patients with steroid-dependent or steroid-refractory disease; however, little is known about current biologic use in real-world settings in Japan. Methods: This observational, longitudinal, cohort study utilized the Japan Medical Data Center (JMDC) database to analyze claims data of patients who were prescribed ≥1 biologic (adalimumab, infliximab, or ustekinumab) following a new CD diagnosis made between January 2009 and January 2019. We primarily assessed the type of first-line treatment prescribed within 6 months of a patient’s first CD diagnosis. Results: Of the 1,346 eligible patients, the most common prescriptions were 5-aminosalicylic acid (5-ASA) monotherapy (26.8%), 5-ASA plus biologic combination (26.3%), and biologic monotherapy (12.9%). First-line biologics were prescribed within 6 months of initial CD diagnosis in 61.1% of patients, either alone or in combination with other therapies. As an individual first-line treatment, the proportion of patients receiving prescriptions of infliximab was high (66.3%) and steroids, low (1.3%). Patients who had a procedure to inspect the small intestine, such as endoscopy (n = 508), were mostly treated with a nonbiologic therapy (74.8%), whereas those who had not (n = 838), mostly received biologics (alone or in combination, 82.8%) as a first-line treatment. Conclusions: In this study, we discovered the typical treatment pattern of patients with CD who received biologics and are registered in the JMDC database in Japan. Biologics were commonly used in the early phase of CD treatment. Treatment with traditional approaches such as steroids and nutritional therapy with evaluation for small intestine lesions, before turning to the use of biologics, may be prudent for achieving optimal outcomes.

© 2022 The Author(s). Published by S. Karger AG, Basel

Introduction

Crohn’s disease (CD) is a chronic, progressive, inflammatory bowel disease of unknown etiology [1-3]. It is characterized by young onset, a relapsing-remitting course, and symptoms which may include abdominal pain, diarrhea, hematochezia, fever, anal pain, weight loss, and fatigue, impacting markedly on patients’ quality of life [1-5]. CD may also result in extraintestinal complications in the joints, skin, eyes, and mouth, for example, as well as other organ systems [1-3]. In Japan, the prevalence of CD was 55.6 per 100,000 persons in 2015 [6]. As of December 2014, 40,885 patients in Japan were receiving treatment for CD, of which 70.7% were male [7]. The standard management of CD involves drug and nutritional therapies, with surgery considered for intestinal complications and cases that do not respond to noninvasive treatments [1-3]. In all cases, however, the main aims of treatment are to reduce bowel inflammation, control symptoms to halt disease progression, reduce the likelihood of complications, maintain nourishment, and optimize patient quality of life.

Options for the pharmacological treatment of CD include 5-aminosalicylates (5-ASAs), corticosteroids, biologics, thiopurine, methotrexate (which is not approved for CD in Japan), antimicrobials, and other immunosuppressants [1-3], all of which may be used as monotherapy or in combinations. Anti-tumor necrosis factor-α, adalimumab (ADA) and infliximab (IFX) and anti-interleukin-12/-23 ustekinumab (UST), are biologics currently recommended for induction and maintenance of CD remission in patients with steroid-dependent or steroid-refractory disease. Given the nature and associated risks of CD [1], early extensive biologics are typically considered for patients predisposed to a severe or complicated disease course, such as those with extensive small bowel disease, duodenal involvement, or anorectal involvement [8]. Little is known, however, about the use of biologics for CD treatment in real-world clinical practice in Japan [3]. Importantly, how biologics are used at the initial stage of treatment, how effective they are, and how long patients stay on the therapy is poorly understood. The role of small intestine inspection on biologic prescriptions is also unknown. Knowledge of these key aspects of treatment may help to optimize treatment regimens for patients with CD.

This real-world, claims-based study was undertaken to investigate treatment patterns in patients with newly diagnosed CD who were prescribed biologic therapy following diagnosis between 2009 and 2019 in Japan. We detail in these patients: the type of first-line treatment prescribed within 6 months of the first CD diagnosis; the use of biologic treatments and the average time between first CD diagnosis and treatment introduction; the frequency of small intestine inspections and their impact on biologic drug use and additional health screenings; and any discontinuations and surgical events following biologic treatment, as well as the duration of biologic persistence. The results of this analysis are expected to provide insights that may be used to inform clinical practice in Japan.

Materials and MethodsStudy Design and Database

This observational, longitudinal cohort study utilized the Japan Medical Data Center (JMDC) claims database (JMDC Inc, Tokyo, Japan). The JMDC is an administrative database, containing health insurance claims from 2005 onward for employees and their families from several Japanese insurance societies. The database allows chronological tracking of medical records, even if the patient attends multiple institutions or transfers from one hospital to another. We analyzed claims from January 1, 2005, to January 1, 2019, in this study.

Patients

Eligible patients were newly diagnosed with CD between January 1, 2009, and January 1, 2019, and had no CD diagnosis between January 1, 2005, and December 31, 2008. Patients must have been prescribed at least one biologic (ADA, IFX, or UST) only after CD diagnosis. Exclusion criteria included: no prescription of a biologic between January 1, 2005, and January 1, 2019; prescription of a biologic before the first CD diagnosis; diagnosis for comorbidity requiring a biologic which is also used in CD within the 12 months preceding the first biologic prescription; and having a period of >6 months between first CD diagnosis and first prescription of any drug.

Outcomes

The primary outcome of the study was the type of first-line treatment prescribed within 6 months of the first CD diagnosis. If two different drug categories were prescribed within 7 days, the categories were classified as a combination. Secondary outcomes were the time from first-confirmed CD diagnosis to introduction of a biologic (ADA, IFX, or UST); incidence of a small intestine inspection within 12 months preceding, or at any time prior to, biologic introduction; time from the last small intestine inspection (if any) to biologic introduction; time from biologic introduction to discontinuation; time from biologic introduction to first surgery; and persistence of biologics treatment. Biologic discontinuation was defined as a lack of prescription of the same biologic the patient had been taking within a 63-day period (the 90th percentile of the time between two consecutive prescriptions of biologics in the database) from the last prescription. Biologic persistence was defined as an absence of biologic switch or discontinuation (where biologic switch was defined as ≥1 prescription of biologics within 63 days of the prescription of another biologic in patients who initiated treatment with the latter biologic).

Data Coding

Diagnosis of CD and anal fistula was identified by the World Health Organization’s International Classification of Diseases and Related Health Problems (10th ed.; ICD-10) codes K50 and K60, respectively, and standard disease names. Drugs were identified by the World Health Organization’s Anatomical Therapeutic Chemical (ATC) codes (L04AB04, L04AB02, and L04AC05 for ADA, IFX, and UST, respectively).

Gastrointestinal surgeries were identified by the procedure codes as listed in online supplementary Table S1 (for all online suppl. material, see www.karger.com/doi/10.1159/000527045). Similarly, codes used to identify tuberculosis (TB) and hepatitis B and C virus (HBV and HCV) are listed in online supplementary Table S1. First-line CD treatments assessed were biologics, 5-ASAs, immunomodulators (IMs) (azathioprine or 6-mercaptopurine), other immunosuppressants (cyclosporin, tacrolimus, or methotrexate), enteral nutrition, steroids, antimicrobials, or granulocyte and monocyte apheresis (codes listed online suppl. Table S1).

“Prior intestinal inspection” refers to procedures only of the small intestines. Such procedure includes small intestine endoscopy (which provides further inspection of the small intestine compared with normal colonoscopy and includes balloon-assisted, capsule, or others). Small intestine radiographic imaging is also considered a “prior intestine inspection” and includes computed tomography, magnetic resonance imaging, or small intestine barium contrast radiography (all codes used for prior intestinal inspection are listed in online suppl. Table S1).

Statistical Analysis

Analyses were undertaken in the total patient population and in subgroups of patients with or without a prescription for small intestine inspection in the 12 months prior to biologic introduction. Baseline characteristics, TB and HBV/HCV screening and incidence were described using standard, descriptive summary statistics. Categorical variables were compared between the subgroups of patients using a two-sided χ2 test (if ≤20% of the expected values had a frequency of <5) or Fisher’s exact test (if >20% of the expected values had a frequency of <5). A Student’s t test (for normally distributed data) or Wilcoxon signed-rank test (for non-normally distributed data) was used to compare continuous variables. Time to events was analyzed using Kaplan-Meier methodology and multivariate Cox proportional hazard models with adjustment for baseline characteristics to reduce patient selection bias. Kaplan-Meier estimates were compared using a log-rank test, with patients without an event censored at the end of the observation period. Multivariate Cox proportional hazard analyses of the whole study population were expressed as adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). The analyses in this study were not powered to specifically investigate data related to subgroups.

Analyses were performed using SAS version 9.3 (SAS Institute Japan Ltd., Tokyo, Japan). Data extraction and analysis were undertaken by Creativ-Ceutical K.K. (Tokyo, Japan), under the direction of the authors.

Ethics Statement

This was a retrospective analysis of data within a nationwide claims database. Because of the anonymous nature of the analysis and the absence of direct patient involvement, no ethical approval or patient consent was required, based on Ethical Guidelines for Epidemiological Research issued by the Japanese Ministry of Health, Labor and Welfare.

ResultsPatient Characteristics

Of the patients who were diagnosed with CD between January 1, 2009 and January 1, 2019, 3,888 had no prior CD diagnosis between January 1, 2005 and December 31, 2008. Among 1,679 of those patients who were prescribed at least one biologic agent after first CD diagnosis, 1,346 were eligible and included in the study (shown in Fig. 1). Patients had a mean age of 32.5 years, with the majority being between 18 and 39 years of age (66.8%) (Table 1). Males accounted for 80.8% of the study population; about one-quarter of patients (23.6%) had a history of anal fistula in the 6 months prior to CD diagnosis. The mean Charlson Comorbidity Index score for the population was 0.6. Screening for TB, HBV, or HCV was not performed in the majority of patients.

Table 1.

Patient characteristics at the date of first-confirmed CD diagnosis

Fig. 1.

Patient flow. aComorbidities could include rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, ulcerative colitis, intestinal Behçet’s disease, ankylosing spondylitis, axial spondyloarthritis, and juvenile idiopathic arthritis. ADA, adalimumab; CD, Crohn’s disease; IFX, infliximab; UST, ustekinumab.

Treatment Pattern

5-ASA monotherapy or combination therapy was used in a large percentage of patients (74.8%). The most common first-line treatments prescribed following CD diagnosis were 5-ASA monotherapy (26.8%), 5-ASA plus biologic combination (26.3%), and biologic monotherapy (12.9%) (Table 2). As the first biologic, 32.2%, 66.3%, and 1.5% of patients were prescribed ADA, IFX, and UST, respectively (Table 3). IM and steroids were prescribed in 1.1% and 1.3% of patients, respectively. The biologics were prescribed within 6 months of initial CD diagnosis in 61.1% of all patients, either alone or in combination with 5-ASAs, IMs, steroids, or enteral nutrition (Table 2).

Table 2.

Prescribed first-line treatments in all patients

Table 3.Biologics

In the overall population, the mean time from diagnosis to first biologic introduction was 4.1 months (shown in Table 3; Fig. 2a). For the 757 (56.2%) patients who had their biologic treatments discontinued, the average time between biologic introduction to discontinuation was 14 months (Table 3). For patients who required surgery (21.7%), this was first conducted at a mean time of 21.8 months after biologic introduction (Table 3). We found that just over one-third (37.4%) of patients demonstrated persistence with their first biologic (Table 3), and the mean time from biologic introduction to loss of persistence was 14.1 months in the total patient population.

Fig. 2.

Kaplan-Meier survival curves for time from first CD diagnosis to biologic (ADA, IFX, or UST) introduction (N = 1,346). a All patients. b By small intestinal inspection in the 12 months prior to biologic introduction ADA, adalimumab; CD, Crohn’s disease; IFX, infliximab; UST, ustekinumab.

Small Intestine Inspection

Of the total patient population, 508 (37.7%) had received small intestine inspection within 12 months preceding biologic introduction and 838 (62.3%) had not (Table 4). Patients receiving small intestine inspection were slightly younger than those who were not inspected (median, 28 years vs. 33 years) and were more likely to have been diagnosed with anal fistula within the 6 months prior to CD diagnosis (31.1% vs. 19.0%) (Table 5). Patients receiving small intestine inspection had a longer time from first CD diagnosis to first prescription of any drug (median, 8 days vs. 0 days) and had higher rates of screening for TB and HBV/HCV within 6 months prior to biologic introduction (58.7–76.4% vs. 3.1–9.7%) (Table 5). As first-line therapy, most patients receiving small intestine inspection were treated with a nonbiologic therapy (74.8%), whereas those who were not inspected were mostly treated with biologics (alone or in combination, 82.8%) (Table 6). The time from first CD diagnosis to biologic introduction was longer in patients receiving small intestine inspection than in those who were not inspected (median, 2.5 months vs. 0 months) (shown in Table 4; Fig. 2b).

Table 4.

Summary of outcomes by small intestine inspection

Table 5.

Patient characteristics by small intestine inspection

Table 6.

First-line treatment pattern by small intestine inspection

Multivariate Analysis

The association between clinical outcomes and factors related to treatment pattern was assessed using a multivariate Cox proportional hazard analysis (Table 7). Small intestine inspection was significantly associated with increased time to first biologic introduction (HR, 0.23; 95% CI0.19–0.28; p < 0.0001; Table 7), when compared with patients who did not undergo this inspection. Small intestine inspection had no impact, however, on the time between biologics introduction and surgery or loss of persistence (Table 7). While statistically significant, the association observed between patient age and time to loss of biologic persistence was weak (HR of approximately 1) (Table 7).

Table 7.

Multivariate Cox proportional hazard analyses (N = 1,346)

Discussion/Conclusion

This retrospective study analyzing existing data from the JMDC database provides information on the types of first-line treatment most commonly prescribed to Japanese patients newly diagnosed with CD who received biologics (ADA, IFX, or UST) during their treatment course. Baseline characteristics of the study population were broadly consistent with those previously reported [9-11]. We found that the majority of patients in our study were male, which supports previous reports of a male preponderance in Asian patients with CD [9, 10, 12, 13]. In accordance with the guidelines [1-3], most patients were prescribed first-line drug therapy soon after first diagnosis (mean of 9.7 days post-diagnosis). Following CD diagnosis, the type of biologic drug prescribed (ADA: n = 434, IFX: n = 892, and seminoma: n = 20) appeared to reflect the approval dates for each agent (2007, 1998, and 2019, respectively), with data showing high use of IFX, which was the first approved biologic for treatment of CD in Japan. The mean time between CD diagnosis and first treatment of biologics was 4.1 months.

In principle, patients with newly diagnosed CD should have an inspection of the small intestine to determine treatment strategy; however, the current study revealed that approximately 60% of patients had no evidence of such an inspection. Patients who had had small intestine inspections in the 12 months prior to biologic introduction experienced a significantly longer interval between first CD diagnosis and introduction of biologic treatment, compared with those who had not undergone these investigational procedures. This was probably due to the additional time needed to undertake the procedures and review the findings after the provisional diagnosis had been made. The data show a negative association between small intestine inspections and first-line biologic prescription in patients with CD, which highlights the impact of these inspections on the type of drug subsequently prescribed. Notably, patients who had had a small intestine inspection were more frequently screened for TB, HBV, and HCV. The target molecules of ADA, IFX (both anti-TNF), and UST (anti-IL12/23) possess potent immuno-protective functions against such infections [14, 15]. Screening, therefore, provides essential information that may impact decisions on the use of these biologics and is thus an important aspect of Japanese clinical practice. Some patients who did not undergo small intestine inspection during the study period were categorized as having small intestine CD. These patients most likely had their inspections prior to study commencement, which may also represent a limitation of this study.

Interestingly, a relatively low percentage of patients receiving biologics were prescribed monotherapy or combinations of first-line steroids (10.8%), compared to 5-ASAs (74.8%) or biologics (61.1%), which may reflect an avoidance of steroid prescription in Japan. A grant-in-aid program for intractable diseases, which applies to most patients with moderately to severely active CD in Japan, may also be contributing to the early introduction of biologics. Further investigation into the factors affecting these prescription choices would be of interest.

Small intestine inspections facilitate precise evaluations of CD and assist in treatment decisions [16]. In Western countries, these inspections are mostly conducted by cross-sectional imaging or capsule endoscopy. In Japan, however, balloon-assisted enteroscopy and small intestine double contrast barium studies are widely used [17]. While there are differences in diagnostic methodology between Western countries and Japan, the precise evaluation of small intestine lesions using appropriate inspection techniques for each patient is believed to be key to promoting optimal treatment. In our analysis, over half of the patients discontinued biologic treatment during their clinical course. Investigation into which treatments these patients were transitioned to would be of interest, particularly where the outcomes were surgery. The high rate of transition to surgical therapy following biologic discontinuation and the frequency of complications associated with surgical intervention and CD [18] may highlight some considerations for the use of biologics.

This study has several limitations. First, as this was a nonrandomized study, selection bias cannot be eliminated. However, an attempt was made to minimize the impact of selection bias on the outcome data by using adjusted models for the multivariate analyses. Second, as the JMDC database only includes employees aged 20–64 years, as well as their spouses or family members, results may not be generalizable to the wider patient population in Japan. The study was also limited by the information available in the JMDC database, and none of the following were captured: disease severity or activity; the reason for prescription; nonadherence to prescription including whether the drug was taken at the correct time of the day, or if extra doses were taken to compensate for forgotten doses. Third, screening for TB, HBV, or HCV was not performed in the majority of patients and so the impact of screening on prescription trends could only be analyzed for a small proportion of the total patient population. The study was not powered to specifically investigate data related to subgroups of small intestine inspections and the cost of examination of the small intestine inspection and hence we were unable to make any robust claims regarding them. Furthermore, drug-specific patterns in cases where biologics were switched were not analyzed and can be explored in future studies. Also, in JMDC claims database which is a de-identified secondary data source, there is a limitation to adjusting confounding baseline characteristics medical receipt data; hence, it was not possible to analyze the background of each patient case.

In conclusion, despite the abovementioned limitations, our results indicate that when biologics are used, they are likely to be introduced in the early phase of treatment in Japanese patients with CD. The data suggests that performing small intestine inspections may lead to closer adherence to guideline recommendations and the use of more traditional treatments such as steroids, rather than biologics. Our observations suggest that treatment with these traditional approaches may be prudent when aiming for optimal patient outcomes of CD.

Acknowledgments

The authors acknowledge Midori Kayahara of Firekite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this manuscript. Her service complied with Good Publication Practice 3 ethical guidelines [19]. They would also like to thank Maki Ueyama and Yoshie Onishi of Creativ-Ceutical K.K. (Tokyo, Japan) for their assistance in analyzing the data.

Statement of Ethics

This was a retrospective analysis of data within a nationwide claims database. Because of the anonymous nature of the analysis and the absence of direct patient involvement, no ethical approval or patient consent was required, based on Ethical Guidelines for Epidemiological Research issued by the Japanese Ministry of Health, Labor and Welfare.

Conflict of Interest Statement

Fumihito Hirai has received honoraria from AbbVie GK, EA Pharma Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K., and Takeda Pharmaceutical Company Limited. Mihoko Ota, Yukiko Takemura, Keisuke Tanaka, and Ryuichi Iwakiri are employees of Takeda Pharmaceutical Company Limited, Tokyo, Japan. Akihito Uda was an employee of Takeda Pharmaceutical Company Limited, Tokyo, Japan, while the research was conducted.

Funding Sources

Takeda Pharmaceutical Company Limited (Tokyo, Japan, https://www.takeda.com/jp/) funded this study and played a role in designing the study, collecting/analyzing data, deciding to publish, and preparing the manuscript. Services provided by Creativ-Ceutical K.K. (data analysis) and Firekite, an Ashfield company, part of UDG Healthcare plc (medical writing), were funded by Takeda Pharmaceutical Company Limited.

Author Contributions

Fumihito Hirai, Ryuichi Iwakiri, Keisuke Tanaka, Akihito Uda, Yukiko Takemura, and Mihoko Ota were involved with conceptualization of the study and contributed through the writing of the manuscript and data curation was performed by Mihoko Ota and Yukiko Takemura. Akihito Uda and Mihoko Ota contributed through the formal analysis of the research data and the study investigation was performed by Keisuke Tanaka. Analysis of the study methodology and supervision of the assessment of the data were performed by Ryuichi Iwakiri and administration of the project was performed by Mihoko Ota.

Data Availability Statement

The data that support the findings of this study are available from JMDC Inc. but were used under license for the current study; therefore, restrictions apply, and the data are not publicly available. For inquiries about access to the data set used in this study, please contact JMDC (https://www.jmdc.co.jp).

This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.