Outcomes in Patients With IBD Stratified by Risk of Disease Progression

ABSTRACT

Objectives: Risk stratification of patients with Crohn disease (CD) and ulcerative colitis (UC) may improve outcomes and health care resource utilization (HCRU). We characterized patients with CD or UC as being at high or low risk of disease progression and estimated rates of CD-related and UC-related HCRU.

Study Design: This retrospective study used claims data from a US health care payer database from January 1, 2017, to December 31, 2019.

Methods: Included patients were fully insured, were 18 years or older, had a diagnosis of CD or UC, and were naive to biologic treatment. Patients were stratified as being at high or low risk of disease progression and associated HCRU using a priori definitions based on American Gastroenterological Association criteria.

Results: For CD, 1459 (39.1%) patients were high risk and 2272 (60.9%) patients were low risk. High-risk patients had higher mean hospitalizations (0.35 vs 0.28; P = .03) and surgeries (0.04 vs 0.01; P < .0001) per patient than low-risk patients. During follow-up, 13.8% of patients with CD at high risk received advanced therapy vs 4.8% of low-risk patients. For UC, 2215 (40.4%) patients were high risk and 3270 (59.6%) patients were low risk. High-risk patients had higher mean hospitalizations (0.33 vs 0.10; P < .0001) and surgeries (0.01 vs 0.00; P < .0001) per patient than low-risk patients. During follow-up, 7.7% of patients with UC at high risk received advanced therapy vs 1.8% of low-risk patients.

Conclusions: Health care claims data may be used for prognostic risk stratification in CD and UC and to identify patients who may benefit from early treatment with advanced therapies.

Am J Manag Care. 2025;31(5):In Press

Takeaway Points

• Risk stratification of patients with Crohn disease (CD) and ulcerative colitis (UC) may improve outcomes and health care resource utilization (HCRU).
• Using claims data from a US health care payer database, this retrospective study shows that patients with UC and CD who were at high risk of disease progression, according to definitions based on American Gastroenterological Association criteria, had higher HCRU and were more likely to receive an advanced therapy compared with low-risk patients.
• Prognostic risk stratification based on health care claims data may be used to identify patients with UC and CD who may benefit from early treatment with advanced therapies.

Crohn disease (CD) and ulcerative colitis (UC) are chronic, progressive, debilitating inflammatory bowel diseases (IBDs) that have a relapsing-remitting course and a significant negative impact on patients’ health-related quality of life.^1-3 CD and UC also have a substantial societal and economic impact; estimates suggest that in 2014, approximately 1.6 million people in the US had IBD, with annual direct costs between $11 billion and $28 billion.⁴ Traditionally, mild to moderate CD and UC are treated with 5-aminosalicylates, corticosteroids, or immunomodulator therapies.^1-3 For moderate to severe disease, biologics, including anti–tumor necrosis factor α (TNF-α) treatments, the α₄β₇ integrin receptor antagonist vedolizumab (Entyvio), and anticytokines, are effective^1-3 and recommended by most clinical guidelines, including those from the American Gastroenterological Association (AGA).^5,6

Management of CD and UC remains difficult because a high proportion of patients receiving biologics experience a primary nonresponse to treatment or a secondary loss of response following initial success.^7-11 Therefore, according to AGA guidelines,^5,6 an important goal of disease management is to ensure that patients receive the most appropriate treatments at the optimal time according to their risk for disease progression. This is crucial because disease management strategies, such as treat-to-target approaches, shift from aiming to control disease symptoms toward disease modification, with the goal of achieving long-term mucosal healing.^5,6 Disease progression in both CD and UC is heterogeneous and unpredictable, with some patients having more rapid progression to severe disease and experiencing poorer outcomes, including the need for hospitalization and surgery.^12,13 In CD, the annual incidence of hospital admissions is approximately 20%, and approximately half of all patients with CD will require surgery within 10 years of diagnosis.³ For UC, approximately 15% of patients experience an aggressive disease course; the 10-year cumulative probability for hospitalization is estimated to range from 39% to 66%, and the 5- and 10-year risks of colectomy are estimated at 10% to 15%.¹³

Several factors have been identified for CD and UC that place patients at higher risk of more complicated disease, greater health care resource utilization (HCRU), and poorer clinical outcomes.³ For CD, these include ileal or ileocolonic disease location, extensive small bowel disease, perianal or rectal disease, early stricturing, and young age at diagnosis.³ In patients with UC, predictors of a more aggressive disease course include extensive colitis, presence of extraintestinal manifestations, early use of corticosteroids, and young age at diagnosis.⁵ However, limited data are available on the role that these risk factors play in the longitudinal management of disease and clinical decisions in the real world. For example, it remains unclear whether those patients who are at higher risk of disease progression are more likely to receive an advanced therapy early in the disease course than low-risk patients.

To optimize HCRU at the population level and achieve optimal clinical outcomes, stratification of patients by their risk of disease progression and associated HCRU may be a valuable tool to enable health care providers and payers to offer and cover targeted IBD treatment programs and policies.

METHODS

Objectives

The primary objectives of this study were to quantify the proportion of patients at high or low risk of disease progression according to AGA criteria in separate populations of biologic-naive patients with CD and UC, to describe their respective demographic and clinical characteristics, and to estimate the rates of IBD-related hospitalization and surgery in each group. The key secondary objective was to estimate the proportions of patients with CD and UC who were treated with conventional and advanced therapies in the high- and low-risk cohorts.

Study Design and Patient Population

Real World IBD Population Risk Stratification and Outcomes (RADAR-1) was a retrospective observational analysis of administrative claims data over a 3-year period between January 1, 2017, and December 31, 2019, from a large US commercially insured and Medicare Advantage database (Aetna) with 15 million covered individuals.

The study design, including definitions of the first and second index dates, is shown in Figure 1. We selected patients for the study based on a 2-step selection process. Patients were first categorized into separate CD and UC risk-stratification cohorts (primary objectives) to identify high- and low-risk patients and then categorized into subgroups based on previous treatments (secondary objectives). Full details of inclusion and exclusion criteria are shown in eAppendix Methods (eAppendix available at ajmc.com).

Included patients in the CD and UC disease groups were stratified according to their risk of disease progression and associated HCRU using a set of a priori definitions based on AGA criteria. The definitions used to classify patients with high-risk CD or UC are shown in Table 1. Patients were identified using International Statistical Classification of Diseases, Tenth Revision (ICD-10) or Current Procedural Terminology codes corresponding to each of the definitions in Table 1 (see eAppendix Table 1). Full attrition tables for the selection of patients with CD and UC are shown in eAppendix Tables 2 and 3, respectively. The treatment subgroups included risk-stratified patients who had evidence of treatment after the first index date. For patients with evidence of treatment with conventional therapies after the first index date, the second index date was defined as the date of the first medical or pharmacy claim for a conventional therapy. For patients with evidence of treatment with an advanced therapy after the first index date, the second index date was defined as the date of the first medical or pharmacy claim for an advanced therapy (Figure 1). Conventional therapies included 5-aminosalicylic acid, immunotherapy, immunomodulators, and topical or rectal steroids. Advanced therapies included integrin receptor antagonists (eg, vedolizumab) and anticytokines, such as anti–TNF-α treatments and IL-12/23 inhibitors (eg, ustekinumab [Stelara]), and the Janus kinase inhibitor tofacitinib (Xeljanz).

Outcomes

The primary outcomes were the proportion of patients with CD or UC classified as having a high or low risk of disease progression, the number of IBD-related hospitalizations in patients with CD or UC overall and stratified by risk, and the number of IBD-related surgeries in patients with CD and UC overall and stratified by risk. IBD-related hospitalizations were defined as an inpatient hospitalization event in Aetna’s Medical Case database with a diagnosis of CD or UC in the primary, secondary, or tertiary diagnostic position and the admission date occurring within the follow-up period. IBD-related surgeries were defined as a medical claim with a procedure code for surgery and a diagnosis of CD or UC in the primary diagnostic position with a date occurring within the follow-up period. The secondary outcome was the proportions of patients receiving conventional therapy or advanced therapy in the high- and low-risk CD and UC cohorts.

Statistical Analysis

The baseline demographics and disease characteristics for high- and low-risk patients in the CD and UC cohorts are reported using appropriate descriptive statistics. Baseline and follow-up variables were compared between high- and low-risk patients for each disease using a Student t test or Wilcoxon rank sum test for continuous variables and a χ² test for categorical variables.

Ethical Considerations

This study was carried out in accordance with Guidelines for Good Pharmacoepidemiology Practices. The retrospective, observational study did not involve patient recruitment or consent. The study protocol was approved by the Sterling Institutional Review Board. Takeda Pharmaceuticals USA, Inc, funded this research and was involved in the collection of data, their analysis and interpretation, and the decision to approve the manuscript for publication.

Data Availability Statement

The data sets generated during and/or analyzed during the current study are not publicly available due to executed data use agreements.

RESULTS

Baseline Demographics, Clinical Characteristics, and All-Cause HCRU

For the risk-stratification cohorts, 3731 patients with CD and 5485 patients with UC met the eligibility criteria (eAppendix Tables 2 and 3). Among the patients with CD, 1459 (39.1%) were classified as having a high risk of disease progression and 2272 (60.9%) were classified as having a low risk (eAppendixTable 4 and Figure 2) according to the predefined risk-stratification criteria (Table 1). For patients with UC, 2215 (40.4%) were classified as having a high risk of disease progression and 3270 (59.6%) were classified as having a low risk (eAppendix Table 5 and Figure 2). The baseline demographics, clinical characteristics, and baseline all-cause HCRU for high- and low-risk patients with CD and UC are shown in eAppendix Tables 4 and 5, respectively. In patients with either disease, there was a significant difference in age between high- and low-risk patients as well as significant differences in disease location, age-adjusted Charlson Comorbidity Index scores, and baseline hospitalizations.

Of the predefined risk factors used to stratify patients, the most commonly occurring in high-risk patients with CD was a diagnosis of perianal or severe rectal disease. The most common risk factor in high-risk patients with UC was a diagnosis of extensive colitis (Figure 2). Young age during the baseline period prior to the first index date was also a major risk factor, with 17.5% of high-risk patients with CD younger than 30 years and 34.7% of high-risk patients with UC younger than 40 years.

HCRU in Risk-Stratified Patients With CD and UC

During the follow-up period of the study, the mean numbers of IBD-related hospitalizations and surgeries for patients with CD and UC were significantly higher in high-risk patients than low-risk patients (Table 2). In particular, the proportion of patients with CD with at least 1 IBD-related surgery was 3.4% in the high-risk group vs 0.9% in the low-risk group; in patients with UC, the proportion of high-risk patients with 1 or more surgeries (1.1%) was approximately 2 to 3 times that of the low-risk patients (0.4%).

Treatment Patterns in Risk-Stratified Patients With CD and UC

Of the 3731 patients in the CD risk-stratification cohort, 2016 (54.0%) had evidence of receiving a conventional therapy or advanced therapy during the index period and were eligible for inclusion in the treatment identification subgroup (eAppendix Table 2). For UC, 3706 (67.6%) of 5485 patients in the risk-stratification cohort had evidence of treatment during the index period (eAppendix Table 3). The treatments received by all patients included in the CD (n = 3731) and UC (n = 5485) risk-stratification cohorts in the 12-month period following their first index date are shown in Figure 3. In patients with CD who were treated within 12 months of the first index date (n = 2016), the proportions who received a conventional therapy only were equal between high-risk and low-risk patients (45.8%). However, a greater proportion of high-risk patients received an advanced therapy, either alone (6.4% vs 2.2% in the low-risk group) or in combination with a conventional therapy (7.4% vs 2.6% in the low-risk group). In patients with UC who were treated within 12 months of the first index date (n = 3706), a greater proportion of patients in the high-risk group received a conventional therapy (66.5% vs 61.3% in the low-risk group). For advanced therapies, their use was higher in the high-risk group in patients with UC, whether administered alone (0.8% vs 0.3% in the low-risk group) or in combination with conventional therapies (6.9% vs 1.5% in the low-risk group). For CD and UC, 46.0% and 32.4% of all patients, respectively, did not receive treatment in the 12 months after the first index date.

Among patients with CD who had at least 6 months of medical and pharmacy insurance coverage after the second index date (n = 1689), 578 (34.2%) were high risk and received conventional therapy, 930 (55.1%) were low risk and received conventional therapy, 116 (6.9%) were high risk and received an advanced therapy, and 65 (3.8%) were low risk and received an advanced therapy. Among patients with UC who had at least 6 months of medical and pharmacy coverage after the second index date (n = 3281), 1337 (40.7%) were high risk and received conventional therapy, 1861 (56.7%) were low risk and received conventional therapy, 57 (1.7%) were high risk and received an advanced therapy, and 26 (0.8%) were low risk and received an advanced therapy.

DISCUSSION

This study evaluated a set of a priori claims-based ICD-10 definitions based on AGA criteria and previously identified prognostic factors that can be used to stratify patients with CD or UC according to their risk of disease progression and associated HCRU. The results show that patients classified as high risk based on prognostic data from the 6-month period before their diagnosis go on to have higher HCRU, including hospitalizations and surgeries, in the 12-month period following diagnosis. Our claims data–based findings are similar to those of another recent study that included 2 cohorts of patients with CD. In contrast to the present study, which stratified patients as high or low risk according to AGA criteria, the study by Santiago and colleagues evaluated the association of individual risk criteria with risk of disease complication. They found that individual criteria, including younger age at diagnosis, were associated with increased risk of disease complications and that having 3 or more of the risk criteria led to the highest risk of complications.¹⁴

There is growing evidence demonstrating that prognostic factors, including symptoms and biomarkers, can be used to identify patients at risk and that adjusting their treatment early in the disease course can result in better disease control, improved outcomes, and efficient HCRU. For example, in the CALM study (NCT01235689), a greater proportion of patients with CD receiving the TNF-α antagonist adalimumab (Humira) whose treatment was escalated using an algorithm that incorporated information about symptoms (eg, Crohn’s Disease Activity Index score, prednisone use) and biomarkers (eg, fecal calprotectin, C-reactive protein) had mucosal healing at week 48 than patients who received symptomatic management alone.¹⁵ These data showed that making treatment decisions based on clinical symptoms and prognostic biomarkers in patients with early CD can result in better treatment outcomes than symptom-driven treatment decisions alone. Furthermore, not only did the incorporation of prognostic biomarkers lead to improvements in clinical outcomes vs clinical management alone, but this form of management also was more cost-effective, resulted in fewer CD-related hospitalizations, and improved quality of life.¹⁶ Nonetheless, the data from the present study show that baseline clinical characteristics at diagnosis can be successfully captured in claims data and that these alone are sufficient to risk stratify patients with CD or UC. These findings demonstrate the potential for risk stratification based on these AGA criteria to be used by payers to provide population health interventions, including care management, disease management, and decision support, to optimize patient treatment and achieve lower future HCRU and better treatment outcomes. Future prospective studies will be required to determine whether early identification of high-risk patients and any associated changes in disease management (eg, earlier introduction of biologics) can result in better outcomes and lower HCRU. These studies may include an assessment of whether combining the clinical and symptomatic risk factors used in the present study with prognostic biomarkers can improve the effectiveness of risk stratification for patients with CD or UC.

Management strategies for CD and UC are moving away from simply treating the symptoms of the diseases toward interventions that seek to modify the disease course and achieve long-term mucosal healing.^5,6 For example, in patients with early CD, post hoc analyses of clinical trials have identified that early intervention with an advanced therapy is associated with higher response and remission rates.¹⁷ Thus, the ability to stratify patients and identify those at high risk creates an opportunity to target those patients who may benefit most from the early initiation of an advanced therapy. In this situation, the AGA high-risk criteria used in this study could be applied to qualify patients for advanced therapy.

Moreover, data from RADAR-1 may help identify patients who would benefit from early introduction of advanced therapies. In this study, only a small proportion of patients with high-risk CD or high-risk UC received an advanced therapy (CD, 13.8%; UC, 7.7%), whether alone or in combination with conventional therapy, in the 12 months following their diagnosis. This suggests that many patients who might benefit from the early introduction of advanced therapies are currently not being treated with them. Indeed, in the 12-month period following diagnosis, most patients in the high-risk and low-risk groups for both CD and UC received either no treatment or only conventional therapy. More than a quarter of all patients with CD or UC were untreated. This may suggest that some patients were asymptomatic and did not require treatment but could also indicate that some patients’ treatments were not fully captured in the claims data. Because reasons for not receiving treatment are not typically captured in claims data, it is difficult to know which of these scenarios is more likely. For both diseases, a higher proportion of high-risk patients received advanced therapy than low-risk patients. The routine adoption of a prognostic stratification approach, such as the one used in the present study, has the potential to identify high-risk patients more easily, aid clinical decision-making, and capture a higher proportion of patients who may benefit from early treatment with advanced therapies than at present.

Limitations

The data obtained by this study should not be interpreted without considering the study limitations. Some of these limitations relate to the use of claims data and are therefore shared by other observational studies that collect this type of data, which is associated with selection and information bias as well as an absence of some variables of interest. For example, claims data are collected for financial purposes rather than to obtain a thorough picture of a patient’s presentation and medical history. Useful information, such as disease severity, etiology, and symptomology, may therefore be missing from the database. In this study, the use of claims data limited risk stratification to the data that had been collected for insurance purposes. Additionally, patients included in the database were all insured by a single commercial carrier, so they may not be representative of the general US population, most of whom are insured by other providers or uninsured. Finally, a multivariable analysis to assess which of the risk-stratification factors had the most significant impact on outcomes was not specified in the study protocol or performed. In the future, such an analysis of claims data may help identify those most at risk of poor outcomes. Despite these limitations, this study suggests that risk stratification may be a useful tool to help guide population health management strategies for patients with IBD.

CONCLUSIONS

The results of RADAR-1 demonstrate that patients with CD who are at high risk of disease progression according to AGA criteria have higher HCRU than low-risk patients. High-risk patients also are more likely to receive an advanced therapy than low-risk patients, although the proportion of patients receiving advanced therapies was small. The present findings show that health care claims data obtained prior to disease diagnosis may be used to identify those who are at high risk of disease progression (according to AGA criteria) and predict future HCRU. Using this approach may enable health care providers and payers to implement the most effective treatment programs and care policies that are tailored to an individual patient’s risk. 

Author Affiliations: US Medical Economics and Outcomes Research (TF, CC, JW), Global Medical Evidence (JJ), and Clinical Science, GI (NC), Takeda Pharmaceuticals USA, Inc, Cambridge, MA; University of Illinois (KU), Chicago, IL (affiliated with Takeda Pharmaceuticals USA, Inc, at the time of the study); CVS Health (HC), Woonsocket, RI (now with Blue Health Intelligence, Chicago, IL).

Source of Funding: This work was supported by Takeda Pharmaceuticals USA, Inc. Medical writing support was provided by Adam Errington, PhD, of PharmaGenesis Cardiff in Cardiff, United Kingdom, and funded by Takeda Pharmaceuticals USA, Inc, in accordance with Good Publication Practice guidelines.

Author Disclosures: Dr Fan, Ms Jiang, Dr Chou, Dr Candela, and Dr Wagner are employees of Takeda Pharmaceuticals USA, Inc, and hold stock or stock options in Takeda. Takeda is a manufacturer of drugs for the treatment of patients with inflammatory bowel disease such as those described in the current work. Ms Umashankar is a former employee of the University of Illinois and was supported by a Takeda Pharmaceuticals USA, Inc, fellowship at the time of the study. Dr Coetzer reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (TF, HC, KU, NC); acquisition of data (HC, KU); analysis and interpretation of data (TF, CC, HC, KU, NC, JW); drafting of the manuscript (TF, JJ, KU); critical revision of the manuscript for important intellectual content (TF, CC, KU, NC, JW); statistical analysis (CC);administrative, technical, or logistic support (JJ, CC, HC, JW); and supervision (TF, JJ).

Address Correspondence to: Jeanne Jiang, MS, Global Medical Evidence, Takeda Pharmaceuticals USA, Inc, 500 Kendall St, Cambridge, MA 02142. Email: jeanne.jiang@takeda.com.

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