Treatment patterns and outcomes in patients with steroid-dependent ulcerative colitis in Japan: a claims database study
Article information
Abstract
Background/Aims
Guidelines recommend that steroid treatment for ulcerative colitis (UC) is tapered or withdrawn within 3 months of initiation, and thiopurine treatment or advanced therapy is administered for steroid-dependent UC. This study aimed to clarify real-world treatment patterns and outcomes in patients with steroid-dependent UC in Japan.
Methods
A retrospective analysis of JMDC (Japan Medical Data Center) claims data was conducted to identify patients with a new UC diagnosis between June 2010 and September 2019. Index dates were the UC treatment start date (initiation of any UC treatment), steroid dependence/resistance confirmation date (identification of steroid-dependent UC), and treatment intensification date (initiation of thiopurine treatment/advanced therapy).
Results
Of 5,602 patients with newly diagnosed UC, 986 (17.6%) initiated steroids within 12 months (85.4% [842/986] received 5-aminosalicylic acid at the UC treatment start date). Of these 986 patients, 429 (43.5%) were classified as steroid-dependent (steroid dependence/resistance confirmation date). Of these 429 patients, 128 (29.8%) initiated thiopurine treatment and 75 (17.5%) initiated advanced therapy (treatment intensification date); 226 (52.7%) continued with steroids only. Across these groups, 3-6% discontinued steroids within 3 months of initiation. Hospitalization due to UC in the 12 months after the treatment intensification date occurred in 24.2% (31/128) and 18.7% (14/75) of patients who initiated thiopurine and advanced therapy, respectively.
Conclusions
Over half of patients with steroid-dependent UC continued steroid treatment only. Steroid discontinuation within 3 months of initiation was low, irrespective of whether thiopurines or advanced therapy were initiated. Management of patients with steroid-dependent UC in Japan requires further treatment optimization toward guideline adherence.
INTRODUCTION
Ulcerative colitis (UC) is a chronic or relapsing inflammatory disease characterized by ulcers and erosions of the colonic mucosa [1]. During the active symptomatic phase of UC, patients experience bloody diarrhea, abdominal pain, and frequent bowel movements [1,2]. Treatment strategies for UC consider disease extent and severity, which ranges from mild to severe, and aim to induce and maintain long-term remission, as well as improve health-related quality of life [1,3]. Topical and systemic steroids and 5-aminosalicylic acid (5-ASA) remain key treatments for early management of UC [4]. Although steroids can induce remission [5], ongoing use is associated with major adverse effects, such as increased risk of infection, worsening of metabolic diseases such as diabetes and hyperlipidemia, and an increased risk of cardiovascular events [6]. Therefore, steroid use for the treatment of UC should be tapered or withdrawn within 3 months of initiation [1,4].
Patients are considered to have steroid-dependent UC if steroid treatment cannot be tapered within 3 months of initiation owing to recurrent active disease, or if a symptomatic relapse occurs within 3 months of stopping steroid treatment [7]. The most recent evidence-based clinical practice guidelines for inflammatory bowel disease from the Japanese Society of Gastroenterology, published in 2020, recommend using thiopurine drugs (azathioprine or 6-mercaptopurine) for patients with steroid-dependent UC [1]. If thiopurine drugs are not effective or not tolerated, then advanced therapies (e.g., adalimumab, filgotinib, golimumab, infliximab, tacrolimus, tofacitinib, upadacitinib, ustekinumab, or vedolizumab) or cytapheresis may be considered [1]. Patients with UC who do not respond to steroid treatment within 4 weeks are considered to have steroid-refractory UC (also known as steroid-resistant UC) [7]. Treatment options for patients with steroid-refractory UC also include cytapheresis and advanced therapies, as well as cyclosporine [1].
The number of patients with UC in Japan is estimated to be 219,685 [8]. However, there are limited data available regarding the proportion of Japanese patients with steroid-dependent UC who receive treatments other than steroids, such as thiopurine drugs, and the outcomes of these treatments in Japan. The aim of this study was to characterize real-world treatment patterns and outcomes in patients with steroid-dependent UC in Japan.
METHODS
1. Study Design and Participants
This was a retrospective observational study conducted using the Japan Medical Data Center (JMDC) claims database (provided by JMDC Inc.), which contains claims data received from a range of health insurance associations. As of September 2021, the JMDC claims database includes data for approximately 13 million insured Japanese individuals [9]. Real-world data derived from this database have been used extensively in UC cost-effectiveness and epidemiological analyses [10-13].
An overview of the study design is shown in Fig. 1. Japanese patients who received a new diagnosis of UC (International Classification of Diseases 10: K51) between June 2010 and September 2019, and who then received steroid treatment within 12 months of UC diagnosis, were identified. The UC treatment start date was defined as the date on which patients received their first prescription for any treatment for UC. Patients had to be at least 18 years of age at the UC treatment start date, had to have received their first treatment for UC within 6 months of diagnosis, and had to be continuously registered in the JMDC database for 12 months before and 36 months after the UC treatment start date. Patients were excluded if, during the 12 months before the UC treatment start date (baseline period), they had a prescription for UC treatment, underwent surgical treatment for UC, had a diagnosis of Crohn’s disease or Behcet disease, or had any cancer diagnosis. Behcet disease was excluded because drug treatments for intestinal lesions may overlap with UC treatments.
Study design. aFor patients with steroid-refractory ulcerative colitis (UC), the treatment intensification date was defined as initiation of any treatment in an inpatient or outpatient setting. Dashed lines indicate maximum follow-up periods. Solid lines indicate fixed observation periods.
Patients with steroid-dependent or steroid-refractory UC (see Study Cohort Definitions) were identified in the 12 months after the UC treatment start date (steroid dependence/resistance confirmation date). The treatment intensification date was defined as the date on which thiopurine treatment or advanced therapy was initiated in patients with steroid-dependent UC, or the date on which any treatment was initiated in an inpatient or outpatient setting in patients with steroid-refractory UC. The intervals between the steroid dependence/resistance confirmation date and the treatment intensification date were up to 15 months for steroid-dependent UC and up to 1 month for steroid-refractory UC. Thiopurine treatment included azathioprine and 6-mercaptopurine. Advanced therapy included adalimumab, cyclosporine, filgotinib, golimumab, infliximab, tacrolimus, tofacitinib, upadacitinib, ustekinumab, and vedolizumab.
2. Study Cohort Definitions
In clinical practice, systemic corticosteroids (SCS) are unlikely to be prescribed for a duration of less than 8 days in the treatment of UC [14]. Therefore, when identifying patients with steroid-dependent UC and steroid-refractory UC, patients with a SCS prescription duration of less than 8 days were excluded.
Patients with steroid-dependent UC were defined as those who used systemic steroids for at least 90 days, or who restarted systemic steroid treatment within 90 days after discontinuing, during the 12-month period after the UC treatment start date (Fig. 1). The 90-day timeframe for restarting steroid treatment was established based on expert opinion. This period was deemed appropriate for evaluating the resumption of steroid treatment within the same cycle, while excluding patients who restarted steroid treatment in a new treatment cycle.
Patients with steroid-refractory UC were identified as those with a lack of clinical response to systemic steroids, defined as receiving SCS more than 7 days and up to 60 days during the 12-month period after the UC treatment start date.
3. Data Collection
Baseline characteristics were collected for all patients with diagnosed UC at the UC treatment start date. Patient histories of medical facility visits, categorized as clinics (facilities with fewer than 20 beds that often provide primary care) or hospitals (facilities with 20 or more beds), were determined at the UC treatment start date. Age and sex were determined at the UC treatment start date. SCS prescription data were collected following patients’ first steroid prescription for UC. Changes in steroid dosage over time were examined in cases for which steroid dosage data were available. Treatment intensification data were collected up to 15 months after the steroid dependence/resistance confirmation date. Outcome data on treatment setting (inpatient vs. outpatient), hospitalization due to UC, and treatment change or intensification in inpatient and outpatient settings were collected for the 12-month period after the treatment intensification date for patients with steroid-dependent UC. Hospitalization due to UC was defined as inpatient claims with a UC diagnosis code. Treatment modification included drug changes between advanced therapies (i.e., a change in the same class of drug or a change across classes), replacing thiopurine drugs with advanced therapy, replacing advanced therapy with thiopurine drugs, or adding thiopurine drugs to advanced therapy. Treatment intensification included the addition of steroids, advanced therapy, or cytapheresis to existing treatments but excluded the addition of thiopurine drugs or carotegrast methyl.
4. Compliance with Ethics Guidelines
Data in the JMDC database are anonymized and ethical review is not required as defined by the Japanese Ethical Guidelines for Medical and Health Research involving human participants. Given that all data in the JMDC claims database are anonymized and deidentified, participant informed consent was not required.
5. Statistical Analyses
This was a descriptive analysis, so categorical variables were summarized as counts (n) and proportions (%), and continuous variables were summarized as means (standard deviations) or medians (interquartile ranges).
RESULTS
1. Patient Flow
The patient flow for this study is presented in Fig. 2. In total, 5,602 patients received a diagnosis of UC between June 2010 and September 2019, of whom 986 (17.6%) initiated steroid treatment within 12 months. Of these patients, 85.4% (842/986) had received 5-ASA, and 27.7% (273/986) had received steroids (systemic or topical) at the UC treatment start date (initiation of any UC treatment). During the 12-month period after UC treatment was initiated, 429 (43.5%) of the 986 patients who initiated steroids were classified as having steroid-dependent UC (steroid dependence/resistance confirmation date). Of these patients, 128 (29.8%) went on to initiate thiopurine treatment and 75 (17.5%) went on to initiate advanced therapy (treatment intensification date); 226 (52.7%) continued with steroid treatment only. During the 12-month period after UC treatment was initiated, 30 (3.0%) of the 986 patients who initiated steroids were classified as having steroid-refractory UC. Of these patients, 4 (13.3%) went on to initiate any UC treatment in an inpatient setting and 26 (86.7%) went on to initiate any UC treatment in an outpatient setting at the treatment intensification date.
Patient flow. aPatients with ulcerative colitis (UC) diagnosed between June 2010 and September 2019.
2. Patient Characteristics
The characteristics of patients with steroid-dependent UC that were identified in the 12 months after initiation of any treatment are summarized in Table 1. The mean age of patients with steroid-dependent UC was 38.2 years and most patients were male (69.2%). Overall, 155 patients (36.1%) visited clinics and 274 patients (63.9%) visited hospitals at the first UC treatment.
Baseline Characteristics of Patients with Steroid-Dependent UC
Baseline demographics were generally similar between patients with steroid-dependent UC who went on to initiate thiopurine treatment or advanced therapy and patients who continued steroid treatment only. However, the proportion of patients who attended a clinic at the first UC treatment was higher in those who continued steroid treatment only (40.7%) than in those who went on to initiate thiopurine treatment (30.5%) or advanced therapy (32.0%).
3. Patterns of Steroid Use in Patients with Steroid-Dependent UC
Data on steroid use from initial prescription (by dose range) to week 12 in patients with steroid-dependent UC are shown in Fig. 3. The initial prescribed steroid dose was 30 mg/day or higher for 82.0% (105/128) of patients who initiated thiopurine treatment, 74.7% (56/75) of patients who initiated advanced therapy, and 64.2% (145/226) of patients who continued steroid use. Some tapering occurred from week 4 in patients who were prescribed steroids and went on to initiate thiopurine treatment or advanced therapy, or who continued steroid therapy only. However, steroid use rarely tapered off completely by week 12; this occurred in only 3% to 6% of patients across these subgroups. In addition, some patients who were prescribed an initial steroid dose of less than 20 mg/day continued steroid use without any dose reduction over the 12 weeks (Supplementary Table 1). Overall, the mean initial prescribed steroid dose was slightly lower in patients who continued steroid treatment (36.6 ± 36.9 mg) than in those who initiated thiopurine treatment (41.8 ± 20.7 mg) or advanced therapy (37.6 ± 18.0 mg) on the treatment intensification date.
Steroid use in patients with steroid-dependent ulcerative colitis prescribed an initial steroid dose of (A) ≥30 mg/day (n=306), (B) 20 to <30 mg/day (n=58), or (C) <20 mg/day (n=53).
Treatment Setting for Advanced Therapy in Patients with Steroid-Dependent UC
The proportion of patients with steroid-dependent UC who initiated advanced therapy at the treatment intensification date is summarized by treatment setting in Table 2. Advanced therapy was prescribed to 52.0% (39/75) of patients in the inpatient setting compared with 48.0% (36/75) of patients in the outpatient setting. Overall, 75.0% (18/24) of patients who initiated infliximab, 78.9% (15/19) of patients who initiated tacrolimus, and 23.1% (3/13) of patients who initiated adalimumab were treated as inpatients.
Advanced Therapies Prescribed to Patients with Steroid-Dependent Ulcerative Colitis at the Treatment Intensification Date
4. Time to Treatment Intensification Date in Patients with Steroid-Dependent UC
The distribution of days from the initial steroid prescription date to the treatment intensification date in patients who initiated thiopurine treatment or advanced therapy is shown in Fig. 4. The initial steroid prescription refers to the first prescription after the diagnosis of UC and not the first prescription after the confirmation of steroid dependence. Overall, 28.1% (36/128) of patients received a prescription for thiopurine treatment 1-30 days after their initial steroid prescription (58.3% [21/36] in an inpatient setting) and 25.8% (33/128) received a prescription for thiopurine treatment 31 to 60 days after their initial steroid prescription (15.2% [5/33] in an inpatient setting). In total, 34.7% (26/75) of patients received a prescription for advanced therapy 1 to 30 days after their initial steroid prescription (92.3% [24/26] in an inpatient setting) and 9.3% (7/75) of patients received a prescription for advanced therapy 31 to 60 days after their initial steroid prescription (42.9% [3/7] in an inpatient setting).
Distribution of days from the initiation of steroid treatment to the initiation of (A) thiopurine treatment (n=128) or (B) advanced therapy (treatment intensification date) (n=75).
5. Outcomes After the Treatment Intensification Date in Patients with Steroid-Dependent UC
Treatment outcomes in the outpatient setting during the 12-month follow-up period after the treatment intensification date in patients with steroid-dependent UC are summarized in Table 3. After the treatment intensification date, 24.2% (31/128) of patients who initiated thiopurine treatment and 18.7% (14/75) of patients who initiated advanced therapy were hospitalized owing to UC. Treatment change or intensification was reported for 35.9% (46/128) of patients who initiated thiopurine treatment and 48.0% (36/75) of patients who initiated advanced therapy during the 12-month follow-up period. Among the patients who initiated advanced therapy, 33.3% (25/75) switched to or intensified treatment with azathioprine, and 17.3% (13/75) intensified treatment with the addition of cytapheresis (Table 3). The median time between the treatment intensification date and treatment intensification with the addition of azathioprine was 81 days (Supplementary Table 2). Among the patients who initiated thiopurine treatment, 10.2% (13/128) changed treatment to adalimumab, 10.9% (14/128) changed treatment to vedolizumab, and 12.5% (16/128) intensified treatment with cytapheresis (Table 3). The median time between the treatment intensification date and changing treatment after receiving thiopurine drugs was 172.5 days when changing to vedolizumab and 107.0 days when changing to adalimumab (Supplementary Table 2).
Outcome during the 12-Month Follow-up Period after the Treatment Intensification Date in Patients with Steroid-Dependent Ulcerative Colitis
DISCUSSION
This retrospective study characterized real-world treatment patterns and outcomes in Japanese patients with steroid-dependent UC. Our study is the first to detail the clinical course of steroid dependence in Japan based on real-world clinical data from 2010 to 2019. Between June 2010 and September 2019, we found that over half of patients with steroid-dependent UC continued steroid treatment only without any treatment change or intensification. Our findings also show that a small proportion of patients discontinued steroid use for UC within 3 months of initiation, despite guidelines recommending that steroids should be tapered or withdrawn during this timeframe [1,4]. These results indicate that guidelines for steroid treatment for UC are not being widely implemented in daily medical practice in Japan. There is therefore substantial scope to optimize treatment strategies further for patients with steroid-dependent UC in Japan by increasing rates of treatment intensification and steroid tapering.
This study identified a subset of patients who continued steroid therapy without undergoing treatment intensification. A comparison of clinical outcomes between these patients and those who received intensified treatment could yield valuable insights for clinical practice. However, the data source employed in the present study lacks information on disease severity, thereby limiting our ability to adjust for this confounding factor and complicating direct comparisons between the 2 groups. Consequently, the current analysis remains descriptive in nature. Future investigations utilizing data sources that incorporate disease severity metrics would be warranted to enable a more rigorous evaluation of outcomes across treatment strategies.
In this study, a higher proportion of patients initiated thiopurine treatment or advanced therapy in hospitals (inpatient setting) than in clinics (outpatient setting). This observation may indicate that patients with more severe UC are more likely to visit a hospital than a clinic and therefore initiate thiopurine treatment or advanced therapy in the hospital setting. Alternatively, physicians at clinics may be less able to offer all of the available advanced therapies, or less accustomed to providing such therapies, compared with physicians at hospitals.
Among patients with steroid-dependent UC, 28.1% initiated thiopurine treatment and 34.7% initiated advanced therapy within 30 days of starting steroid treatment. These results indicate that treatment intensification was implemented even before the confirmation of steroid dependency. Some of these patients may have previously experienced steroid dependency. It is therefore possible that thiopurine treatment or advanced therapy was initiated soon after these patients started steroid treatment to limit their steroid use and to prevent steroid dependency from recurring.
Approximately one-third of patients who initiated advanced therapy were prescribed azathioprine in the 12 months following the treatment intensification date. Azathioprine may have been prescribed to reduce the immunogenicity of the tumor necrosis factor-α inhibitors infliximab and adalimumab. In a systematic literature review by Vermeire et al. [15], the proportion of patients with inflammatory bowel disease who had anti-drug antibodies was 0.0% to 65.3% for infliximab and 0.3% to 38.0% for adalimumab. In our study, the median time between the treatment intensification date and a treatment change or intensification with azathioprine was 81 days. Physicians may have prescribed azathioprine at later time points for some patients with UC if they were already receiving ongoing treatment with another immunosuppressive agent. Interestingly, most patients with steroid-dependent UC who initiated advanced therapy without thiopurine treatment received tacrolimus or infliximab as inpatients, with a wider distribution of advanced therapies used in the outpatient setting. While tacrolimus and infliximab are used to treat inpatients with steroid-dependent UC if disease symptoms worsen despite ongoing steroid treatment, they are also often used to treat inpatients who have steroid-refractory UC. It is possible that some patients in our study were misidentified as having steroid-dependent UC because of clinical inertia (i.e., a lack of timely adjustment to therapy by physicians), with some patients potentially receiving steroid therapy for over 3 months (and therefore meeting steroid dependency criteria) despite having steroid-refractory UC.
Real-world data on treatment following UC diagnosis showed that steroid prescription rates decreased annually in Japan from 2009 to 2013; however, 23.7% of patients continued to use steroids 6 months after initiation [11]. In our study, steroid tapering occurred more frequently in patients who were prescribed an initial steroid dose of 20 mg/day or higher than in those who were prescribed an initial dose of less than 20 mg/day. Similar findings were reported by Matsuoka et al. [14] in an analysis of Japanese claims data collected between 2006 and 2016, indicating that patients who were prescribed an initial steroid dose of less than 20 mg/day were more likely to require long-term steroid use than those who were prescribed an initial dose of at least 30 mg/day. This trend was consistent across patients in our study who initiated thiopurine treatment or advanced therapy, or who continued steroid treatment only. Patients who initiated thiopurine treatment or advanced therapy may have had more severe UC that was difficult to treat compared with those who continued steroids only. Combining thiopurine treatment or advanced therapy with steroids may have allowed these patients to taper their steroid treatment. Notably, the initial prescribed steroid dose was slightly lower in patients who continued steroid treatment only compared with those who initiated thiopurine treatment or advanced therapy. This suggests that the severity of UC symptoms in these patients may have been underestimated, resulting in a lower initial prescribed steroid dose than was needed, and a lack of treatment intensification over time, even though the initial dose did not control disease activity.
Importantly, our study found that just over half of patients with steroid-dependent UC continued their steroid treatment without any intensification. This observation may be due to several factors, including a lack of understanding among physicians about the need for treatment intensification with advanced therapies, the treatment preferences of both physicians and patients, and specific conditions of patients, such as adrenal insufficiency caused by long-term steroid use, that contribute to a continued reliance on steroid treatment. Educating physicians on the importance of treatment intensification, addressing patient concerns, and adapting treatment plans to individual patient needs may improve adherence to guidelines and enhance the overall management of steroid-dependent UC.
The current study has several strengths and limitations. A key strength is that the JMDC claims database collects treatment records, so we were able to identify treatment change or intensification in both the clinic and hospital settings. In addition, the JMDC claims database is one of the largest claims databases in Japan; it contains information from approximately 13 million insured Japanese individuals (as of September 2021), allowing us to collect sufficient sample sizes for analysis [9]. A limitation of the current study is that the JMDC claims database is derived from health insurance associations and does not capture data from retired individuals; the proportion of elderly individuals included in our study is therefore small. Furthermore, information regarding UC disease severity is not available from JMDC data. The inability to adjust for disease severity between the treatment-intensified group and the non-intensified group poses challenges in ensuring comparability between the 2 groups. Additionally, the purpose of a drug prescription cannot be identified using the JMDC database. It is therefore possible that steroids and other drugs were prescribed for comorbidities (such as rheumatoid arthritis) rather than UC, although any such occurrences are likely to have been rare and are unlikely to have significantly affected our results.
In Japanese medical practice between June 2010 and September 2019, over half of patients with steroid-dependent UC continued steroid treatment only without any intensification. Steroids were rarely tapered off completely within 3 months of treatment initiation among patients with steroid-dependent UC, irrespective of whether a treatment change or intensification occurred. Treatment strategies for patients with steroid-dependent UC could be further optimized through treatment intensification and steroid tapering.
Notes
Funding Source
This work was supported by Gilead Sciences K.K. (Tokyo, Japan), Eisai Co., Ltd (Tokyo, Japan) and EA Pharma Co., Ltd (Tokyo, Japan).
Conflict of Interest
Saruta M has received grants or contracts from AbbVie GK, CMIC CMO Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., PPD-SNBL K.K., and Zeria Pharmaceutical Co., Ltd.; and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AbbVie GK, EA Pharma Co., Ltd., Gilead Sciences K.K., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nobelpharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Viatris Pharmaceutical Co., Ltd. Sugiyama T and Tajima T are employees of JMDC Inc. Nagakura C and Kaise T are employees of Gilead Sciences K.K. and shareholders of Gilead Sciences, Inc. Zhong Y is an employee and shareholder of Gilead Sciences, Inc. Except for that, no potential conflict of interest relevant to this article was reported.
Data Availability Statement
Gilead Sciences shares anonymized individual patient data upon request or as required by law or regulation with qualified external researchers based on submitted curricula vitae and reflecting non-conflict of interest. The request proposal must also include a statistician. Approval of such requests is at Gilead Science’s discretion and is dependent on the nature of the request, the merit of the research proposed, the availability of the data, and the intended use of the data. Data requests should be sent to datarequest@gilead.com.
Author Contributions
Conceptualization: Saruta M, Kaise T. Data curation: Sugiyama T, Tajima T. Data interpretation: Saruta M, Sugiyama T, Nagakura C, Zhong Y, Kaise T. Formal analysis: Saruta M, Sugiyama T, Tajima T, Zhong Y, Kaise T. Writing - original draft: Saruta M, Kaise T. Writing - review & editing: Sugiyama T, Tajima T, Nagakura C, Zhong Y. Approval of final manuscript: all authors.
Additional Contributions
The authors are grateful to Yasushi Fujitani (formerly of Gilead Sciences K.K.) for his contributions to the study. The authors also thank Angelica Papanicolaou PhD and Michael Molloy-Bland PhD of Oxford Pharma Genesis, Melbourne, Australia for providing medical writing support, which has been funded by Gilead Sciences K.K., Tokyo, Japan, Eisai Co., Ltd., Tokyo, Japan, and EA Pharma Co., Ltd., Tokyo, Japan.
Supplementary Material
Supplementary materials are available at the Intestinal Research website (https://www.irjournal.org).
Supplementary Table 1.
Steroid Use in Patients with Steroid-Dependent Ulcerative Colitis
Supplementary Table 2.
Time between the Treatment Intensification Date and Treatment Change or Intensification in Patients with Steroid-Dependent Ulcerative Colitis