Crohn’s disease (CD), a subtype of inflammatory bowel disease, is a growing health concern. In this study, we examined the influence of biologics on prescription trends and steroid dependency.
Methods
This retrospective longitudinal analysis of insurance coverage spanned at least 1 year before and 1 year after the inflammatory bowel disease diagnosis and enrolled 4476 patients with CD. The study period was divided into the pre-biologics and post-biologics eras according to the date when the first CD-related prescription was issued. We examined prescription patterns, steroid dependency rates, and concurrent use of immunomodulators or biologics.
Results
The CD incidence ranged from 1.6 to 1.3 cases per 100,000 patients between 2006 and 2018. During the pre-biologics era, the initial medications primarily comprised steroids (76.2%), followed by 5-aminosalicylic acid (44%) and immunomodulators (5.8%). During the post-biologics era, the initial prescription rates of steroids (69.8%) and 5-aminosalicylic acid (60.5%) remained high, and the Immunomodulators prescription rate increased to 14.7%. Steroid dependency was observed in 25.5 of 1000 and 22.1 of 1000 person-years during the pre-biologics and post-biologics eras, respectively. In the pre-biologics era, 6.1% of patients with steroid dependence received concurrent treatment with immunomodulators within the first 6 months. In the post-biologics era, this percentage increased to 24.2%, with some patients receiving immunomodulators or biologics.
Conclusions
The incidence rate in Taiwan showed a stable trend annually. Biologics approval and policy implementation resulted in increased immunomodulator use and decreased steroid dependency.
Prior Presentation: This manuscript is based on work that was previously presented as a poster at the ISPE’s 14th Asian Conference on Pharmacoepidemiology from October 21–23, 2022, in Tainan, Taiwan.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Key Summary Points
Why carry out this study?
The global incidence of Crohn’s disease (CD) is rising; however, few studies have analyzed trends based on disease severity.
In developed countries, biologics have been reimbursed as a treatment option for moderate-to-severe CD for many years, whereas in developing countries, their approval was delayed, and access remains restricted owing to stringent reimbursement criteria. Consequently, conventional therapies such as immunomodulators and corticosteroids are used more frequently.
In this study, we analyzed the impact of biologics availability on treatment patterns in Taiwan, including prescription trends and changes in steroid dependency.
What was learned from this study?
The steroid dependency rate has significantly decreased among patients with moderate-to-severe CD in Taiwan following the introduction of biologics.
Prescription patterns of immunomodulators, corticosteroids, and 5-aminosalicylic acid have shifted in the post-biologics era, indicating changes in treatment practices.
The number of patients with moderate-to-severe CD is increasing annually in Taiwan, whereas cases of mild-to-moderate CD remain stable.
Introduction
Inflammatory bowel disease, which includes Crohn’s disease (CD) and ulcerative colitis, represents an escalating global health concern with significant morbidity and societal impact. The Global Burden of Disease Study 2019 emphasized the increasing prevalence of inflammatory bowel disease. It also identified Taiwan as a hotspot because of its significant increase in age-standardized rates between 1990 and 2019 [1]. Previous studies in Taiwan have focused on patients with a catastrophic illness certificate for CD. However, this may have resulted in the underestimation of the actual number of patients with CD in Taiwan because some patients may not require their physician’s assistance to apply for a catastrophic illness certificate. A physician’s primary motivation for applying for a catastrophic illness certificate on behalf of a patient is to alleviate the financial burden associated with medical expenses and ensure access to biologics treatment.
Anzeige
The increasing prevalence of inflammatory bowel disease has resulted in challenges and opportunities for developing innovative treatment strategies. The escalating disease burden associated with inflammatory bowel disease leads to a pressing need for the medical community to introduce more effective and safer treatments to enhance the quality of life of patients. The introduction of biologics agents and subsequent reimbursement policies regarding biologics agents, which have been pivotal to the management of inflammatory bowel disease, have notably transformed the treatment landscape [2, 3]. In 1998, the United States Food and Drug Administration and the European Medicines Agency approved various antitumor necrosis factor agents for CD, subsequently expanding their use to other immune disorders [4, 5]. Although several biologics are now available to clinicians globally, it is noteworthy that Taiwan first approved adalimumab for CD in 2011. [2, 6, 7].
In Taiwan, adalimumab was first approved for the treatment of CD on July 1, 2011, marking the beginning of the ‘post-biologic era’ for patients with CD. Since then, the range of biologics approved for use in CD and ulcerative colitis has expanded, with corresponding reimbursement policies also extending to ulcerative colitis. Examples of these biologic agents include infliximab, vedolizumab, and ustekinumab, which are approved for both CD and ulcerative colitis, and golimumab, which is approved solely for ulcerative colitis. However, reimbursement for biologics is granted only when the disease remains poorly controlled by the use of conventional treatments, including 5-aminosalicylic acid, corticosteroids, and/or immunomodulators [8, 9].
According to the updated Selecting Therapeutic Targets in Inflammatory Bowel Disease guidelines, treatment objectives include achieving symptomatic responses, clinical remission, and endoscopic evidence of healing [10]. Therapeutic choices have evolved with the beginning of the biologics era. In Taiwan, the approval dates for infliximab, vedolizumab, and ustekinumab were May 1, 2017, October 1, 2017, and September 1, 2020, respectively. Moreover, prescription patterns have notably changed in Europe and the United States, as evidenced from previous studies [11‐13]. It is important to investigate whether similar trends are observed in Taiwan. Growing support for early biologics treatment for CD has emerged recently, emphasizing the advantages of initiating biologics therapy without prior use of conventional therapy [14].
According to Taiwan’s National Health Insurance criteria, patients with CD are eligible for biologics treatment under the following conditions: (1) the CD activity index remains ≥ 300 despite at least 6 months of conventional treatment with 5-aminosalicylic acid, corticosteroids, and/or immunomodulators, or if they experience serious drug-related side effects that make surgery unfeasible; (2) patients with CD who, after 6 months of treatment with 5-aminosalicylic acid, corticosteroids, and/or immunomodulators, fail to heal anal or abdominal fistulas despite surgical interventions, with CD activity index ≥ 100; or (3) patients who have undergone two or more surgical treatments within a year due to complications from CD and maintain a CD activity index ≥ 100 [8, 9, 15].
Anzeige
The use of biologics also serves to reduce steroid use. Corticosteroids, which are commonly prescribed in CD, are associated with several challenges. Waljee et al. highlighted that corticosteroids have been prescribed for extended durations, particularly among older patients, male patients, and those who frequently attend appointments with a gastroenterologist. This prolonged use has been associated with an increased incidence of complications such as venous thromboembolism, fragility fractures, and infections [16]. Steroid dependence has emerged as a significant concern associated with CD. Therefore, achieving steroid-free remission is a pivotal treatment objective. However, the shift in prescription trends following the introduction of biologics, and the extent of steroid dependence in Taiwan remain underexplored. Therefore, this study aimed to evaluate the overall incidence of CD in Taiwan, elucidate changes in prescription patterns specific to patients with CD, and ascertain the prevalence of steroid dependency among these patients.
Materials and Methods
Study Design and Data Source
This retrospective longitudinal study used data from the Taiwan’s National Health Insurance Database. Since its inception on March 1, 1995, Taiwan’s single-payer National Health Insurance program has provided coverage to 99.9% of the country’s population, comprising approximately 24 million individuals. The National Health Insurance Database provides comprehensive data regarding inpatients, outpatients, and pharmacy reimbursement records. To qualify for biologics prescriptions, patients with inflammatory bowel disease must obtain a catastrophic illness certificate that exempts them from copayments. The catastrophic illness certificate applications undergo rigorous assessments by members of a review committee who evaluate relevant clinical and laboratory data as well as the medication history [17]. Consequently, the diagnoses of patients who require a catastrophic illness certificate have a high degree of accuracy. To ensure the validity of our study, we cross-referenced the National Health Insurance Database with the Catastrophic Illness Registry to confirm the CD diagnoses in our study population [18]. The Institutional Review Board of the National Cheng Kung University Hospital approved this study (approval number A-EX-108-049; the informed consent requirement was waived). The requirement for informed consent was waived because the study used de-identified secondary data.
Identification of the Study Population
To ensure the inclusion of all patients diagnosed with CD and determine the date of the initial onset of disease, we defined the cohort based on diagnosis of inflammatory bowel disease because physicians require substantial evidence before confirming that the definitive diagnosis was CD or ulcerative colitis early during the disease course. The study included patients who were diagnosed with inflammatory bowel disease between 2004 and 2018 from the National Health Insurance Database. The diagnoses were validated using the International Classification of Diseases (9th revision) codes 555 and 556 as well as the International Classification of Diseases (10th revision) codes K50 and K51.
Stringent criteria were applied to ensure the accurate identification of patients. We ensured that patients had reimbursement coverage for 1 year before and 1 year after the initial diagnosis of inflammatory bowel disease. Within 3 years of the diagnosis, patients were required to meet both of the following criteria within any given year: (1) at least one hospitalization or four outpatient visits related to inflammatory bowel disease, and (2) at least four prescriptions for medications used in the treatment of inflammatory bowel disease, including 5-aminosalicylic acid, corticosteroids, immunomodulators, or biologics. To ensure that the patients had incident cases, patients who had undergone surgery related to inflammatory bowel disease within 1 year before the initial diagnosis were excluded. To uphold the integrity of the study, we established stringent criteria to ensure precise inflammatory bowel disease (IBD) diagnoses and minimize potential confounding variables, such as the use of corticosteroids for unrelated conditions. Furthermore, patients who exclusively used corticosteroid treatment within 1 year of their IBD diagnosis were excluded from the analysis. Additionally, the use of steroid monotherapy may indicate other immune conditions. Therefore, patients with CD typically receive additional or alternate medications as treatment. Finally, because this study focused on adults, patients diagnosed before the age of 18 years were excluded.
Eligible patients with inflammatory bowel disease were classified as having CD or ulcerative colitis based on their final diagnosis. The index date was defined as the date of the first prescription for medications used in the treatment of inflammatory bowel disease. The two eras identified during this study were the pre-biologics era (2004 to June 30, 2011) and the post-biologics era (July 1, 2011 to December 31, 2018). When patients had both CD and ulcerative colitis diagnosis codes during the study period, the most recent diagnosis code was used to determine the disease category. Finally, the patients were classified based on their catastrophic illness certificate status.
The cohort was restricted to patients with CD during the secondary phase of the study. This choice was based on the different timelines for biologics treatments included in the reimbursement policy of Taiwan’s National Health Insurance. Specifically, patients with CD became eligible for reimbursement for biologics treatments as of July 1, 2011. However, a similar provision for patients with ulcerative colitis was not implemented until October 2016. Hence, our analysis was temporally aligned with the post-biologics reimbursement era, thus providing a more robust framework for evaluating the prescription dynamics of CD.
Outcomes
In this study, the ‘index date’ was defined as the date when the first prescription for inflammatory bowel disease was issued after the initial diagnosis. The first phase of this study focused on determining the incidence rates and considered patients with index dates between 2006 and 2015. During the second phase of this study, the prescription patterns of all patients with CD were analyzed by assessing the distribution of medication prescriptions across eight 6-month intervals.
The observation period began when the first prescription of a CD-related medication was issued to each patient. Subsequently, every 6 months, the number of patients with CD served as the denominator for that specific 6-month period, and the numerator represented the number of patients with CD who had used medication during that period. Then, the rate of medication use was calculated for each 6-month interval. Within each interval, prescriptions were divided into the following four categories: 5-aminosalicylic acid, corticosteroids, immunomodulators, and biologics.
Anzeige
Additionally, we assessed the rate of steroid dependence and the proportion of patients who required immunomodulators or biologics. Steroid dependence was defined in accordance with the European Crohn’s and Colitis Organization guidelines [2] and further consultations with specialists. Patients were classified as steroid-dependent if they had been using steroids for over 3 months and had used a steroid dosage that exceeded the equivalent of 10 mg of prednisolone after the third month. Continuous steroid use was confirmed if the interval between two independent steroid prescriptions was less than 84 days. An interval that exceeded this duration was considered indicative of treatment interruption. We also compared the concurrent use of immunomodulators or biologics among patients with steroid dependence within the first 6 months of their initial steroid prescription.
Statistical Analysis
The incidence rate of CD calculated during this study was based on mid-year population data from annual surveys conducted by Taiwan’s Ministry of Interior as the denominator, and the numerator represented the number of patients with a new diagnosis of CD during that year. Continuous variables are represented as the mean ± standard deviation or median and interquartile range, whereas categorical variables are presented as numbers and percentages. For each 6-month interval, the proportion of each prescription category was determined by dividing the number of patients in a specific category by the total number of patients.
The Cochran–Armitage test was performed to assess linear time trends throughout the study, beginning with the commencement of CD-related prescriptions. We also performed a subgroup analysis of patients based on their catastrophic illness certificate status. The steroid dependence rate was calculated using all patients with CD during the observation period as the denominator and the number of patients with CD who experienced steroid dependency for the first time as the numerator. This rate was expressed as the number of cases per 1000 person-years. Statistical significance was set at p < 0.05. All statistical evaluations were conducted using SAS software (version 9.4; SAS Institute, Cary, NC, USA).
Results
Cohort Population and Baseline Characteristics
We identified 27,113 patients diagnosed with inflammatory bowel disease (Table 1). The initial cohort included both CD and ulcerative colitis cases due to potential diagnostic uncertainty in early-stage disease. Those who met the study inclusion criteria were enrolled. After applying stringent exclusion criteria—including patients with a history of surgery for inflammatory bowel disease within 1 year of diagnosis, those prescribed corticosteroids only, and those under 18 years of age; the study population comprised 4476 eligible patients with CD between 2004 and 2018 (Fig. 1). Among the excluded cases, 10,572 patients were classified as having ulcerative colitis based on their most recent diagnosis, which was the final step in defining the CD cohort. Of these, 2360 patients comprised the pre-biologics era (2004 to June 30, 2011), and 2,116 comprised the post-biologics era (July 1, 2011, to 2018).
Table 1
Baseline characteristics of patients with Crohn’s disease
Baseline characteristics
Crohn’s disease
Pre-biologics era
Post-biologics era
n = 2360
n = 2116
Age at first diagnosis, mean (SD)
53.3 (17.9)
49.7 (18.5)
Sex, male, n (%)
1166 (49.4)
1129 (53.4)
Follow-up perioda, days, median (IQR)
1126 (554, 1738.5)
1564.5 (970, 2141)
Duration from ID1 to PD1b, days, mean (SD)
334.1 (327.4)
236.6 (319.5)
Medical resource utilizationc, n (%)
Hospitalization
886 (37.5)
912 (43.1)
Emergency department visits
975 (41.3)
983 (46.5)
Endoscopic examination
1148 (48.6)
1372 (64.8)
Infectious diseasec, n (%)
Hepatitis Cd
62 (2.6)
36 (1.7)
Tuberculosis
53 (2.2)
25 (1.2)
Immune-mediated inflammatory diseasec, n (%)
Rheumatoid arthritis
119 (5)
58 (2.7)
Ankylosing spondylitis
46 (1.9)
50 (2.4)
Systemic lupus erythematosus
21 (0.9)
29 (1.4)
Psoriasis
21 (0.9)
20 (0.9)
Primary sclerosing cholangitis
10 (0.4)
10 (0.5)
Sacroiliitis
5 (0.2)
P
Extraintestinal manifestationsc , n (%)
Anemia
276 (11.7)
343 (16.2)
Arthropathy
310 (13.1)
212 (10)
Oral aphthous ulcers/aphthous stomatitis
66 (2.8)
83 (3.9)
Uveitis
22 (0.9)
18 (0.9)
Erythema nodosum
4 (0.2)
P
Scleritis and episcleritis
P
7 (0.3)
aThe follow-up period was defined as the duration from the first prescription date to the study end date (June 30, 2011 for the pre-biologics era and December 31, 2018 for the post-biologics era)
bThe duration from the date of the first diagnosis of inflammatory bowel disease to the date of the first prescription for inflammatory bowel disease treatment was calculated to represent the interval between initial diagnosis and treatment initiation
cAssessed 1 year before the first prescription date
dTaiwan has a high prevalence of Hepatitis C. These data reflect the proportion of patients with HCV within 1 year prior to the diagnosis date
Numbers less than 3 are not shown in accordance with Taiwan’s National Health Insurance Database confidentiality policies and are replaced with ‘P’ to maintain privacy
IQR interquartile range, SD standard deviation
Fig. 1
Target population selection. *Grouped as CD according to the most recent diagnosis in the medical records in Taiwan. The initial cohort included both UC and CD cases due to potential diagnostic uncertainty at the time of first diagnosis. Patients were excluded if they had a history of IBD surgery within 1 year of diagnosis, were prescribed corticosteroids only, or were under 18 years of age. In the final step, 10,572 patients were excluded based on their most recent diagnosis of UC. The pre-biologics era comprised 2004 to June 30, 2011. The post-biologics era comprised July 1, 2011 to December 31, 2018. †The first diagnosis date refers to the date of the initial recorded diagnosis of IBD within the observation period. CD Crohn’s disease, CIC catastrophic illness certificate, Dx diagnostic date, IBD inflammatory bowel disease, NHID National Health Insurance Database, OPD outpatient department, UC ulcerative colitis
The patients had an average age of approximately 50 years, and there was a slight predominance of female patients. During the pre-biologics era, the mean time from initial disease suspicion to the first issuance of a CD-related prescription was 334 days (standard deviation ± 327 days). In contrast, during the post-biologics era, this mean time decreased to 236 days (standard deviation ± 319 days). For catastrophic illness certificate patients, who generally have more severe disease, the mean time from diagnosis to the first prescription was 34.5 days, with a median of 0 days, reflecting the urgency of treatment. (Supplementary Table 2). There were notable differences in medical resource utilization during the pre-biologics and post-biologics eras. During the post-biologics era, both hospitalization rates and the frequency of emergency department visits exhibited an upward trend.
Incidence of CD
Although this study focused on patients with Crohn’s disease, it initially included all cases of inflammatory bowel disease. After refining the criteria, the patients were classified as having CD or ulcerative colitis based on their most recent medical record data. Between 2006 and 2018, the incidence rate of CD decreased from 1.6 to 1.3 cases per 100,000 patients who received their first CD-related prescription. Within this period, for those with a catastrophic illness certificate, the incidence rate increased from 0.2 to 0.5 cases per 100,000 patients. In contrast, for those without a catastrophic illness certificate, the incidence rate decreased from 1.5 to 0.9 cases per 100,000 patients (Fig. 2).
Fig. 2
Incidence and prevalence of Crohn’s disease (CD) between 2006 and 2018 in Taiwan. The graph illustrates the number of newly diagnosed CD cases per 100,000 individuals during the observation period. CIC catastrophic illness certificate
A preliminary analysis revealed that the incidence of ulcerative colitis increased between 2006 and 2018 (Supplementary Fig. 1).
CD-Related Prescription Patterns During the Pre-Biologics Era (2004–2011)
During the first 6 months after the index date, corticosteroids had the highest prescription rate (76.2%), followed by 5-aminosalicylic acid (44.0%) and immunomodulators (5.8%) (Fig. 3A). As time progressed, a significant decrease in the prescription rates of corticosteroids and 5-aminosalicylic acid occurred (p < 0.05). However, the prescription rates of immunomodulators remained relatively stable, without any significant increase or decrease. Patients with CD and a catastrophic illness certificate (Supplementary Fig. 2A) had a very high 5-aminosalicylic acid prescription rate (93.4%) during the first 6 months, whereas the corticosteroids prescription rate was 58.4%. During the eight 6-month intervals observed, the prescription rate for 5-aminosalicylic acid significantly decreased but remained high (68.8%). However, the use of corticosteroids did not decrease significantly.
Fig. 3
Prescription patterns of patients with CD during the pre-biologics and post-biologics eras. A Patients with CD during the pre-biologics era. B Patients with CD during the post-biologics era. *p < 0.001 in the Cochran–Armitage trend test
Conversely, the immunomodulators prescription rate significantly increased from 5.6% during the first 6-month period to 13.3% during the eighth 6-month period. During the pre-biologics era, the rate of steroid dependency among patients with CD and a catastrophic illness certificate was notably high (81.9 per 1000 person-years) (Table 2). Moreover, only 6.1% of patients with steroid dependency were concomitantly treated with immunomodulators or biologics agents within 6 months of the initial diagnosis of steroid dependency (Table 3).
Table 2
Steroid dependence among patients with CD during the pre-biologics and post-biologics eras
Pre-biologics era
Post-biologics era
Cases of steroid dependence
Person-years
Steroid-dependency ratea
Cases of steroid dependence
Person-years
Steroid-dependency ratea
Patients with CD
180
7052.6
25.5
188
8493.3
22.1
With CIC
66
806.4
81.9
95
1509.9
62.9
Without CIC
114
6246.3
18.3
93
6983.3
13.3
aSteroid-dependency rate represents the number of new cases of steroid dependency per 1000 person-years of observation during the study period
CD Crohn’s disease, CIC catastrophic illness, IBD inflammatory bowel disease
Table 3
Concomitant use of immunomodulators or biologics in patients with CD and steroid dependence
Patients with CD and steroid dependence
Concomitant use of Immunomodulators/biologics (%)
Within
n
1 month
3 months
6 months
Pre-biologics era
180
2.7
4.7
6.1
Post-biologics era
188
8.9
16.8
24.2
CD Crohn’s disease
CD-Related Prescription Patterns During the Post-Biologics Era (2011–2018)
Changes in prescription patterns occurred during the post-biologics era (Fig. 3B). During the first 6 months, 14.7% of patients were prescribed immunomodulators, and 2.4% were prescribed biologics. Notably, biologics use significantly increased over time to 6.3% by the end of the study period. The overall trends for 5-aminosalicylic acid and corticosteroids mirrored those of the pre-biologics era. Regarding patients with a catastrophic illness certificate, 37.0% used immunomodulators during the first 6 months of the observation period. However, this rate significantly increased to 51.0% by the end of the observation period (p < 0.05) (Supplementary Fig. 2B).
Additionally, a significant increase in prescription rates of biologics was observed. This rate increased from 9.8% during the first 6-month period of the study to 29.2% during the eighth 6-month period of the study (p < 0.05). Regarding all patients with CD, steroid dependency was observed in 22.1 cases per 1000 person-years. However, for patients with CD and a catastrophic illness certificate, this number was substantially higher (62.9 cases per 1000 person-years) (Table 2). Among these patients with steroid dependence, 24.2% were concomitantly administered immunomodulators and corticosteroids within the first 6 months of initiating corticosteroid treatment (Table 3).
Discussion
This study represents the first comprehensive longitudinal examination of prescription patterns among patients with CD in Taiwan. Our findings revealed a significant number of mild CD cases that were often overlooked during previous studies in Taiwan. Therefore, this study provides a more accurate representation of the current landscape of patients with CD in Taiwan. Policy measures in Taiwan have influenced prescription patterns and have resulted in changes such as an increase in the proportion of immunomodulators prescriptions during the post-biologics era. Additionally, an increased number of biologics prescriptions was observed among patients with a catastrophic illness certificate. This study also highlighted the reduction in steroid dependency.
Analyses performed in other epidemiological studies often focused on patients with inflammatory bowel disease and a catastrophic illness certificate [19, 20]. Therefore, the reported incidence or prevalence rates may not include patients with IBD without a catastrophic illness certificate. Previous research analyses primarily reported on patients with CD and catastrophic illness certificate as the basis [21]. This discrepancy may be attributable to Taiwan’s incidence data, which rely exclusively on catastrophic illness certificate registration. Our study included patients without a catastrophic illness certificate, thus providing a more accurate representation of the entire population with IBD in Taiwan and highlighting the potential underestimation of the disease burden that can result from relying solely on the presence of catastrophic illness certificate for data collection. Therefore, when patients without catastrophic illness certificate in Taiwan were considered, the incidence of CD was very close to that in Korea and Japan. The observed decline in incidence among certain groups may be attributed to demographic changes and delayed treatment initiation. Specifically, the shrinking population aged 30–49 years in Taiwan could contribute to a reduced incidence rate within this age group. Additionally, treatment delays among non-catastrophic illness certificate patients, which may extend up to 2 years, likely impacted the inclusion of cases and led to an underestimation in the later study period. However, the overall incidence rate of CD in our study (including non-catastrophic illness certificate patients) reflects real-world data and more closely resembles the incidence rates observed in other Asian countries. The socioeconomic status in Taiwan has not changed significantly during the study period, so the incidence rate of Crohn’s disease is likely to remain stable, similar to that observed in certain Western countries.
According to Taiwan’s strict health insurance regulations, patients with CD must undergo treatment with 5-aminosalicylic acid, corticosteroids, and immunomodulators for at least 6 months before they qualify for biologics therapy. Consequently, the results of this study confirmed that policies have an impact on physicians’ prescription habits. Our study found a high rate of steroid prescriptions among patients with CD during the first 6 months of the observation period, both during the pre-biologics and post-biologics eras. Initially, up to 70% of patients received steroid treatment. However, the prolonged use of steroids is associated with safety concerns. An analysis performed in the United States indicated that long-term steroid use by patients with IBD significantly increases the risk of venous thromboembolism [16]. These findings emphasize the importance of limiting long-term steroid use and identifying alternative treatment strategies for inflammatory bowel disease.
The introduction of immunomodulators and biologics treatments has initiated a debate regarding their impact on the prevalence of steroid dependency. Notably, a study conducted in the United Kingdom segmented patients into different periods and reported a decrease in prolonged steroid exposure between the era comprising 1990–1993 and that comprising 2002–2005 [13]. In contrast, our study included a unique temporal analysis. Although steroid use remained high during the first 6 months, the prescription rate decreased to 50% during the next 6 months. By the end of the eighth 6-month period, only 34–35% of patients used steroids. This signified a notable decrease (from 25.5 to 22.1 per 1000 person-years) in steroid dependency during the post-biologics era.
Furthermore, our analysis revealed a trend during the post-biologics era. Patients with CD and steroid dependency were increasingly prescribed immunomodulators or biologics during the initial 6 months. This contrasted with the findings of a study performed in the United States that found that corticosteroid treatment was transitioned to immunomodulators and antitumor necrosis factor therapy for 65.8% and 21.6% of patients, respectively [16]. In this study, a notable aspect requiring clarification is the duration of steroid dependency among patients. Physicians tend to combine the use of immunomodulators or biologics in post-biologics era. According to policy regulations, patients are required to have at least 6 months of experience with conventional therapy before using biologics. Taiwanese physicians may not necessarily transition to conventional therapy, resulting in situations where combination therapy is administered. This study observed a range of corticosteroid users over the course of 1 year, our research specifically targeted those with steroid dependence, as defined by the European Crohn’s and Colitis Organization over a 6-month period. Our findings showed that 41% of patients with CD, steroid dependence, and a catastrophic illness certificate concomitantly used immunomodulators during this period (Supplementary Table 1).
As a further point, the analysis of the study data revealed an increasing trend in immunomodulators prescriptions during the post-biologics era [13]. In our study, only 6% of patients with CD received prescriptions for immunomodulators in the pre-biologics era, compared to 16% in the post-biologics era. A cohort study revealed that immunomodulators use increased to 70.8% between 2006 and 2011. Our study findings are consistent with international research. Most studies indicate that the combination of immunomodulators and antitumor necrosis factor drugs is more effective than monotherapy; hence, one of the anticipated primary reasons for this trend. [22, 23]. This phenomenon is attributed to policy adjustments in Taiwan, which require patients with CD to complete at least 6 months of treatment with 5-aminosalicylic acid, corticosteroids, and immunomodulators before becoming eligible for biologics therapy. The increase in prescriptions for immunomodulators is primarily attributed to policy regulations. Additionally, in Taiwan, over 90% of patients with CD receiving biologics therapy use adalimumab, whereas less than 10% use infliximab [24]. Because the usage rates of antitumor necrosis factor and immunomodulators have increased, it is crucial to compare these rates. However, concerns regarding the safety of using both treatments concurrently for a prolonged duration remain significant.
During this study, a prescription pattern involving a notably high proportion of 5-aminosalicylic acid prescriptions for patients with CD and a catastrophic illness certificate was observed. This might appear counterintuitive because most evidence implies that 5-aminosalicylic acid has a limited role in the treatment of CD. For instance, the European Crohn’s and Colitis Organization guidelines do not recommend 5-aminosalicylic acid for the induction of CD remission because of its weak moderate-quality evidence [2]. In contrast, although Japanese guidelines have recognized the clinical efficacy of 5-aminosalicylic acid for mild CD, particularly in the remission phase, it is important to note that the effectiveness of 5-aminosalicylic acid to maintain remission is limited and has not been conclusively proven, despite its minimal side effects [25]. This perspective aligns with more recent insights that have indicated that the effect of 5-aminosalicylic acid on CD is generally less significant than its effect on ulcerative colitis. Although it may suppress active CD, its ability to sustain result remission remains unverified [26].
The guidelines in Taiwan strongly support the use of 5-aminosalicylic acid for mild CD, with a high level of agreement (73.3%) [9, 27]. Several factors contribute to the high prescription rate of 5-aminosalicylic acid in Taiwan. Health insurance regulations play a significant role in shaping prescribing patterns. Specifically, the mandatory stepwise reimbursement policy requires patients to have prior use of 5-aminosalicylic acid before initiating biologic therapy. As a result, patients with catastrophic illness certificate, despite the presumed severity of their disease, tend to receive more 5-aminosalicylic acid prescriptions. Additionally, the lack of budesonide as a treatment option may further increase reliance on 5-aminosalicylic acid as an initial therapeutic choice. On the other hand, 5-aminosalicylic acid has a better safety profile than immunosuppressants. Furthermore, 5-aminosalicylic acid consists of locally acting anti-inflammatory compounds that reduce colonic mucosal inflammation through specific release profiles, which may also be beneficial in preventing postoperative recurrence in Crohn’s disease [28]. Given these constraints, the observed higher use of 5-aminosalicylic acid in catastrophic illness certificate patients likely reflects a reimbursement-driven prescribing pattern rather than its clinical efficacy in severe cases. Notably, a study performed in China revealed that over 50% of patients with newly diagnosed CD received 5-aminosalicylic acid within the first month of the diagnosis [29]. Similarly, claims data in Japan indicated that 77.5% of patients with CD received 5-aminosalicylic acid as their initial treatment [30]. Although 5-aminosalicylic acid remains frequently used in Taiwan due to reimbursement considerations and limited access to budesonide, it is important to acknowledge that 5-aminosalicylic acid is not recommended for the treatment of Crohn’s disease, and has not been shown to be effective in preventing post-surgical recurrence, as stated in current European Crohn’s and Colitis Organization and American Gastroenterological Association guidelines [31, 32].
Our study had several strengths. First, it included patients without a catastrophic illness certificate, providing a more comprehensive representation of the population with inflammatory bowel disease. The inclusion and exclusion criteria were carefully determined through detailed consultations with experts in the field. Second, we analyzed prescription patterns before and after the biologics era among patients with CD in Taiwan, thus providing insights into the changes in treatment approaches over time. Finally, we used rigorous criteria to define steroid dependence, thus ensuring a robust analysis and discussion of this important aspect of CD management.
Our study also had some limitations. Despite our efforts to minimize bias, there may have been inherent bias in the inclusion and exclusion criteria. We believe that referencing validation studies conducted in other countries provides sufficient evidence to support the accuracy of the diagnoses and prescriptions included in our study. However, the validation process still relies on accessing robust data, such as laboratory data from electronic health records, which remain the gold standard for confirming CD cases [33, 34].
Another limitation of this study is the lack of analysis on steroid duration and the different types of biologics used. Although adalimumab was the predominant biologic before 2018, this study primarily focused on medication usage trends rather than specific biologic agents. Future research could explore these aspects in greater detail, including the impact of steroid duration and the effects of various biologics. Our analysis was limited by the absence of specific clinical categorizations and perianal fistula data in the National Health Insurance database. Factors such as disease phenotype (B1/B2/B3) and disease extent (L1/L2/L3/L4) are important for treatment decisions but could not be extracted due to systemic data constraints. While this information might be available from medical center electronic health records, it was unavailable in our study. However, because the analysis focused on overall prescription patterns by dividing patients into catastrophic illness certificate and non-catastrophic illness certificate groups, the lack of detailed clinical categorization and perianal fistula data is unlikely to significantly impact the primary conclusions of this study. This is because most patients requiring surgery are classified into the catastrophic illness certificate group, ensuring that the overall trends observed remain valid. A potential limitation of this study is the lack of analysis on the requirement for surgery in the pre-biologics and post-biologics eras. While this aspect was explored in a separate analysis, this study primarily focused on medication use and its effects.
Conclusion
By including patients without a catastrophic illness certificate, this study provided a more accurate representation of the population of patients with CD in Taiwan. The study demonstrated that the incidence rate in Taiwan exhibits sustained stability. During the post-biologics era, steroid dependence decreased. Additionally, this study highlighted the notable influence of Taiwan’s National Health Insurance regulations on prescription patterns, particularly those of immunomodulators.
Acknowledgements
We are grateful to the Health Data Science Center, National Cheng Kung University Hospital, for their administrative and technical support during this study. Language editing for this manuscript was provided by Editage.
Declarations
Conflict of Interest
Nai-Yu Chen, Chiao-Hsiung Chuang, Yu-Ching Chang, Yea-Huei Kao Yang, and Ching-Lan Cheng disclose no relevant financial or personal relationships that could be perceived as a competing interest related to this work. Hua Hsu and Chieh-Min Chen are affiliated with Takeda Pharmaceuticals Taiwan, Ltd.
Ethics/Ethical Approval
This study was approved by the Institutional Review Board of National Cheng Kung University Hospital (approval number A-EX-108–049; the informed consent requirement was waived). All collaborating institutions involved in this study also received ethical approval from their respective ethics committees.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Unsere Produktempfehlungen
e.Med Interdisziplinär
Kombi-Abonnement
Für Ihren Erfolg in Klinik und Praxis - Die beste Hilfe in Ihrem Arbeitsalltag
Mit e.MedInterdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de.
Mit e.Med Innere Medizin erhalten Sie Zugang zu CME-Fortbildungen des Fachgebietes Innere Medizin, den Premium-Inhalten der internistischen Fachzeitschriften, inklusive einer gedruckten internistischen Zeitschrift Ihrer Wahl.
Mit e.Med Allgemeinmedizin erhalten Sie Zugang zu allen CME-Fortbildungen und Premium-Inhalten der allgemeinmedizinischen Zeitschriften, inklusive einer gedruckten Allgemeinmedizin-Zeitschrift Ihrer Wahl.
Wang R, Li Z, Liu S, Zhang D. Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: a systematic analysis based on the Global Burden of Disease Study 2019. BMJ Open. 2023;13(3): e065186. https://doi.org/10.1136/bmjopen-2022-065186.CrossRefPubMedPubMedCentral
Turner D, et al. STRIDE-II: an Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology. 2021;160(5):1570–83. https://doi.org/10.1053/j.gastro.2020.12.031.CrossRefPubMed
Chhaya V, et al. Steroid dependency and trends in prescribing for inflammatory bowel disease - a 20-year national population-based study. Aliment Pharmacol Ther. 2016;44(5):482–94. https://doi.org/10.1111/apt.13700.CrossRefPubMed
Elias ED, Targownik LE, Singh H, Bernstein CN. A population-based study of combination vs monotherapy of anti-TNF in persons with IBD (in Eng). Inflamm Bowel Dis. 2019. https://doi.org/10.1093/ibd/izz148.CrossRef
Chen NY, Chuang CH, Chang YC, Yang YK, Chen PH, Cheng CL. Suboptimal outcomes and retreatment rate of Crohn’s disease patients after forced discontinuation of biologics: a Nationwide Population-Based Study (in Eng). Clin Pharmacol Ther. 2023. https://doi.org/10.1002/cpt.3003.CrossRefPubMed
Feuerstein JD, et al. AGA clinical practice guidelines on the medical management of moderate to severe luminal and Perianal Fistulizing Crohn’s Disease (in Eng). Gastroenterology. 2021;160(7):2496–508. https://doi.org/10.1053/j.gastro.2021.04.022.CrossRefPubMed
33.
Chen G, Lissoos T, Dieyi C, Null KD. Development and validation of an inflammatory bowel disease severity index using US administrative claims data: a retrospective Cohort Study (in Eng). Inflamm Bowel Dis. 2021;27(8):1177–83. https://doi.org/10.1093/ibd/izaa263.CrossRefPubMed
Mit Hilfe der PSMA-PET/CT lassen sich Patienten mit Prostatakarzinomen identifizieren, bei denen eine lokale Therapie möglich ist und die z.B. von einer stereotaktischen Radiotherapie profitieren könnten. Die aktuelle Evidenz dazu wurde auf dem DGHO-Kongress vorgestellt.
IDH (Isocitrat-Dehydrogenase)-Mutationen sind bei Gliomen im Erwachsenenalter ein wichtiger prognostischer und prädiktiver Faktor und zugleich ein ideales Target für eine zielgerichtete Therapie. Mittlerweile gibt es mit Vorasidenib eine zugelassene Behandlungsoption.
Die Prognose von Patientinnen und Patienten mit nicht-kleinzelligem Lungenkarzinom (NSCLC) hat sich durch die Einführung von Immuntherapien enorm verbessert. Dennoch erreicht nur ein Teil der Betroffenen eine langfristige und stabile Krankheitsremission. Das hat verschiedene Gründe.
Chronische Schmerzen und therapieresistent: Botulinumtoxin A könnte dafür eine Lösung sein. Wie der Wirkstoff in der Orthopädie eingesetzt wird, welche Evidenz dafür spricht und wie es um die Kostenübernahme steht, erklärte Dr. Stephan Grüner auf dem Kongress für Orthopädie und Unfallchirurgie.
