https://orcid.org/0000-0003-3369-5059
Abstract
The efficacy of 5-aminosalicylic acid (5-ASA) in combination with advanced therapies (ADTs), particularly ustekinumab (UST), for the treatment of inflammatory bowel disease (IBD) remains unclear.
This retrospective cohort analysis used data from the Medical Data Vision database, including patients with ulcerative colitis (UC) and Crohn’s disease (CD) who had initiated UST therapy. Cumulative UST continuation rates and factors associated with UST failure were analyzed, and post hoc subgroup analyses based on prior ADT use were conducted.
A total of 1971 patients with CD and 1284 patients with UC were included. Overall, the concomitant use of 5-ASA did not significantly affect UST failure in either CD or UC. Post hoc subgroup analysis suggested a protective effect of 5-ASA in ADT-naïve patients with CD or UC who had been previously exposed to ADT.
5-ASA did not provide a significant overall benefit when used in combination with UST for CD or UC. However, post hoc subgroup analyses indicated a potential role for 5-ASA in specific subgroups. Further studies are necessary to confirm these findings and explore personalized treatment strategies.
Lay Summary
The use of 5-aminosalicylic acid with ustekinumab shows no significant overall benefits in inflammatory bowel disease. However, post hoc subgroup analyses suggest potential benefits in specific patient groups, emphasizing the importance of tailoring treatment based on individual therapy history.
• 5-aminosalicylic acid is generally not recommended in combination with advanced therapies for Crohn’s disease and ulcerative colitis; however, evidence supporting this recommendation, particularly regarding its use with ustekinumab, is limited.
• Overall, concomitant 5-aminosalicylic acid use did not significantly contribute to the failure of ustekinumab in Crohn’s disease or ulcerative colitis; however, post hoc subgroup analyses revealed a protective effect of 5-aminosalicylic acid in advanced, therapy-naïve, patients with Crohn’s disease, and patients with ulcerative colitis with prior exposure to advanced therapy.
• This study suggests that 5-aminosalicylic acid does not provide significant overall benefits when used in combination with ustekinumab for inflammatory bowel disease; however, subgroup analyses indicated potential benefits in specific patient groups, such as advanced therapy-naïve patients with Crohn’s disease or patients with ulcerative colitis with prior exposure to advanced therapy. These findings emphasize the importance of personalized treatment strategies tailored to a patient’s treatment history.
Introduction
Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are characterized by chronic immune-mediated inflammation of the gastrointestinal tract.1 The treatment landscape for IBD has evolved significantly with the introduction of targeted biological therapies and other advanced therapies (ADT), such as Janus kinase (JAK) inhibitors.2 Ustekinumab (UST), a monoclonal antibody targeting interleukin-12/23 p40, has demonstrated efficacy in treating both CD and UC in randomized controlled trials.3–5 In Japan, UST has been approved since March 2017 for CD and March 2020 for UC, providing a novel treatment option for these conditions. The standard UST regimen involves an intravenous induction dose followed by a subcutaneous maintenance dose of 90 mg every 8 or 12 weeks. Despite advancements in IBD treatment, many patients in Japan continue to use oral 5-aminosalicylic acid (5-ASA) during UST therapy.6–9 However, there is limited evidence supporting the efficacy of combination therapy of 5-ASA with newer biologics or JAK inhibitors in both UC and CD patients.10–15 Notably, studies specifically evaluating the concomitant use of 5-ASA with UST are scarce. To address this gap, this study aimed to assess the impact of concomitant 5-ASA therapy during UST treatment in patients with UC and CD.
Materials and Methods
Study Design and Data Sources
This retrospective cohort study used data from the Medical Data Vision (MDV) database, a comprehensive real-world database of Japanese healthcare claims. As of March 2022, the MDV database included approximately 39.4 million cases from both inpatients and outpatients across 463 hospitals in Japan that used the Diagnosis Procedure Combination (DPC) system, representing approximately 26% of all Japanese DPC hospitals. The database contains detailed information on patient demographics, diagnostic categories, medication prescriptions, and medical procedures, with diagnoses coded using the International Classification of Diseases, 10th Revision (ICD-10), as well as codes specific to the Japanese healthcare system.
Study Population
We analyzed data from patients diagnosed with CD or UC who received UST identified in the MDV database using ICD-10 codes K-50 for CD and K-51 for UC. The study included CD patients who initiated UST therapy between March 2017 and April 2022, following its approval in Japan, and UC patients who started UST therapy between March 2020 and April 2022, corresponding to the post-approval period. The extracted data included age, sex, prescription details, and prescription dates. The concomitant use of 5-ASA or immunomodulators (IM) (ie, azathioprine and mercaptopurine) was assessed based on the presence of prescriptions within 90 days before or after the initial UST administration, as well as within 90 days before or after the UST failure date, or the last UST administration for patients without UST failure. Patients with prescriptions during both periods were classified as receiving concomitant therapy, whereas those without prescriptions in both periods were classified as not receiving concomitant therapy. Patients who initiated or discontinued concomitant therapy during the study period were excluded from the analysis. Corticosteroid use prior to UST administration was defined as the prescription of prednisolone within 90 days before the initiation of UST.
Primary Endpoint
The primary outcome measure in this study was UST failure.
Definition
UST failure was defined as either hospitalization because of CD or UC or a switch from UST to an alternative medication, including intravenous corticosteroids, biologics, or JAK inhibitors, after the initial administration of UST. Intravenous corticosteroids were specifically included to simplify the definition of UST failure and to avoid potential confounding by oral corticosteroid use, which may have been prescribed concomitantly with UST initiation. Biologics and JAK inhibitors are collectively referred to as ADT. The dosing interval for UST was classified on the basis of the average interval during the observation period, defined as a 3-month interval if it exceeded 2.5 months, and a 2-month interval if it was less than 2.5 months. Patients without a history of ADT before UST administration were classified as ADT-naive, whereas those with a history of at least 1 ADT were classified as ADT-exposed.
Duration of Follow-Up
The duration of UST therapy was calculated from the date of the first prescription to either the last prescription date or UST failure.
Statistical Analysis
Clinical characteristics were summarized using medians and interquartile ranges for continuous variables and counts and percentages for categorical variables. Continuous variables were compared using the Wilcoxon rank-sum test, while categorical variables were evaluated using the Chi-square test.
Survival analysis was conducted using the Kaplan–Meier method to assess UST failure following UST administration, stratified by concomitant 5-ASA use. The log-rank test was used to compare survival curves between the groups. A multivariable Cox proportional hazards regression model was constructed to assess the effect of predefined covariates on UST failure, with the results presented as adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Baseline covariates, including patient age, sex, UST dosing intervals, concomitant use of IM (ie, azathioprine and mercaptopurine), concomitant 5-ASA use, prior corticosteroid use before UST administration, and prior biologic therapy, were adjusted as time-fixed covariates. These covariates were also included in the inverse probability of treatment weighting (IPTW) analysis to ensure balanced comparisons between the groups.
Subgroup analyses were performed post hoc to evaluate the risk factors for UST failure and assess the significance of concomitant 5-ASA therapy in each subgroup, given the significant differences in patient characteristics based on the previous use of ADTs.
A P-value of <.05 was considered statistically significant. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University), a graphical user interface for R (The R Foundation for Statistical Computing, version 4.1.1). EZR is a modified version of R Commander (version 2.7-1), which includes statistical functions frequently used in biostatistics.
Results
Patients With CD
Study population
In this retrospective database study, we analyzed a cohort of 2378 patients diagnosed with CD who initiated treatment with a UST between March 2017 and April 2022. A total of 331 patients were excluded because of treatment adjustments, comprising 29 patients who initiated 5-ASA therapy during UST treatment, 154 who discontinued 5-ASA, 108 who initiated IMs, and 116 who discontinued IMs. This resulted in a final sample size of 1971 patients (Supplementary Figure S1). Among them, the majority (78.7%) received concomitant 5-ASA therapy. Comprehensive demographic data, including age, sex, and prior ADT exposure, were collated, and comparisons were made between patients receiving 5-ASA in combination with UST and those who were not. The demographic details, presented in Table 1, indicate a notably higher proportion of males and a greater percentage of ADT-naïve patients in the combination group.
Baseline characteristics of patients with CD.
| All patients | Without 5-ASA | With 5-ASA | P-value | |
|---|---|---|---|---|
| Number of patients | 1971 | 420 | 1551 | |
| Sex: male/female | 1291 (65.5%)/680 (34.5%) | 247 (58.8%)/173 (41.2%) | 1044 (67.3%)/507 (32.7%) | <.001 |
| Age at initiation of UST, median (IQR) | 40.0 (29.0-50.0) | 39.0 (28.75-51.0) | 40.0 (29.0-50.0) | .846 |
| Concomitant 5-ASA | 1551 (78.7%) | 0 (0%) | 1551 (100%) | NA |
| Concomitant IM | 569 (28.9%) | 112 (26.7%) | 457 (29.5%) | .275 |
| Prior PSL use | 288 (14.6%) | 61 (14.5%) | 227 (14.6%) | 1 |
| ADT-naïve/ADT exposure | 837 (42.5%)/1134 (57.5%) | 151 (36.0%)/269 (64.0% | 686 (44.2%)/865 (55.8%) | .003 |
| UST intervals: 8 weeks/12 weeks | 1843 (93.5%)/128 (6.5%) | 392 (93.3%)/28(6.7%) | 1451 (93.6%)/100 (6.4%) | .911 |
| All patients | Without 5-ASA | With 5-ASA | P-value | |
|---|---|---|---|---|
| Number of patients | 1971 | 420 | 1551 | |
| Sex: male/female | 1291 (65.5%)/680 (34.5%) | 247 (58.8%)/173 (41.2%) | 1044 (67.3%)/507 (32.7%) | <.001 |
| Age at initiation of UST, median (IQR) | 40.0 (29.0-50.0) | 39.0 (28.75-51.0) | 40.0 (29.0-50.0) | .846 |
| Concomitant 5-ASA | 1551 (78.7%) | 0 (0%) | 1551 (100%) | NA |
| Concomitant IM | 569 (28.9%) | 112 (26.7%) | 457 (29.5%) | .275 |
| Prior PSL use | 288 (14.6%) | 61 (14.5%) | 227 (14.6%) | 1 |
| ADT-naïve/ADT exposure | 837 (42.5%)/1134 (57.5%) | 151 (36.0%)/269 (64.0% | 686 (44.2%)/865 (55.8%) | .003 |
| UST intervals: 8 weeks/12 weeks | 1843 (93.5%)/128 (6.5%) | 392 (93.3%)/28(6.7%) | 1451 (93.6%)/100 (6.4%) | .911 |
Abbreviation: 5-ASA, 5-aminosalicylic acid; ADT, advanced therapy; CD, Crohn’s disease; IMs, immunomodulators; IQR, interquartile range; PSL, predonisolone; UST, ustekinumab.
Baseline characteristics of patients with CD.
| All patients | Without 5-ASA | With 5-ASA | P-value | |
|---|---|---|---|---|
| Number of patients | 1971 | 420 | 1551 | |
| Sex: male/female | 1291 (65.5%)/680 (34.5%) | 247 (58.8%)/173 (41.2%) | 1044 (67.3%)/507 (32.7%) | <.001 |
| Age at initiation of UST, median (IQR) | 40.0 (29.0-50.0) | 39.0 (28.75-51.0) | 40.0 (29.0-50.0) | .846 |
| Concomitant 5-ASA | 1551 (78.7%) | 0 (0%) | 1551 (100%) | NA |
| Concomitant IM | 569 (28.9%) | 112 (26.7%) | 457 (29.5%) | .275 |
| Prior PSL use | 288 (14.6%) | 61 (14.5%) | 227 (14.6%) | 1 |
| ADT-naïve/ADT exposure | 837 (42.5%)/1134 (57.5%) | 151 (36.0%)/269 (64.0% | 686 (44.2%)/865 (55.8%) | .003 |
| UST intervals: 8 weeks/12 weeks | 1843 (93.5%)/128 (6.5%) | 392 (93.3%)/28(6.7%) | 1451 (93.6%)/100 (6.4%) | .911 |
| All patients | Without 5-ASA | With 5-ASA | P-value | |
|---|---|---|---|---|
| Number of patients | 1971 | 420 | 1551 | |
| Sex: male/female | 1291 (65.5%)/680 (34.5%) | 247 (58.8%)/173 (41.2%) | 1044 (67.3%)/507 (32.7%) | <.001 |
| Age at initiation of UST, median (IQR) | 40.0 (29.0-50.0) | 39.0 (28.75-51.0) | 40.0 (29.0-50.0) | .846 |
| Concomitant 5-ASA | 1551 (78.7%) | 0 (0%) | 1551 (100%) | NA |
| Concomitant IM | 569 (28.9%) | 112 (26.7%) | 457 (29.5%) | .275 |
| Prior PSL use | 288 (14.6%) | 61 (14.5%) | 227 (14.6%) | 1 |
| ADT-naïve/ADT exposure | 837 (42.5%)/1134 (57.5%) | 151 (36.0%)/269 (64.0% | 686 (44.2%)/865 (55.8%) | .003 |
| UST intervals: 8 weeks/12 weeks | 1843 (93.5%)/128 (6.5%) | 392 (93.3%)/28(6.7%) | 1451 (93.6%)/100 (6.4%) | .911 |
Abbreviation: 5-ASA, 5-aminosalicylic acid; ADT, advanced therapy; CD, Crohn’s disease; IMs, immunomodulators; IQR, interquartile range; PSL, predonisolone; UST, ustekinumab.
UST failure after UST administration in CD
The median follow-up period after UST initiation was 322 days (interquartile range [IQR]: 116-707). During this period, 726 of the 1971 patients (36.8%) experienced UST failure. UST failure occurred in 36.2% of patients not receiving concomitant 5-ASA therapy compared to 37.0% of those on 5-ASA therapy. Kaplan–Meier survival analysis revealed no significant difference in the cumulative rate of UST continuity between the 2 cohorts (P = .359) (Figure 1). To further assess the factors associated with the risk of UST failure, Cox proportional hazards analysis was performed. The analysis identified concurrent IM use (adjusted HR: 1.24; 95% CI: 1.07-1.46), prior corticosteroid use (adjusted HR: 1.48; 95% CI: 1.23-1.78), and prior ADT exposure (adjusted HR: 1.31; 95% CI: 1.12-1.57) as significant predictors of UST failure. However, the use of 5-ASA (adjusted HR: 0.96; 95% CI: 0.80-1.17) was not identified as a risk factor for UST failure (Figure 2). The IPTW-adjusted Cox proportional hazards model for 5-ASA use showed no significant effect on UST failure, with an adjusted HR of 0.93 (95% CI: 0.78-1.13).
Kaplan–Meier analysis of time to ustekinumab (UST) failure after UST administration. A, Kaplan–Meier curve depicting the cumulative rate of UST continuity in all patients with CD after UST administration. B, Comparison of the cumulative rate of UST continuity between CD patients with and without concomitant 5-ASA therapy. No significant differences were observed between the 2 groups (P = .359). Abbreviation: 5-ASA, 5-aminosalicylic acid; CD, Crohn’s disease; UST, ustekinumab.
Multivariable Cox proportional hazards analysis of risk factors for UST failure in patients with CD. Hazard ratios of various covariates influencing the risk of UST failure in patients with CD undergoing UST treatment. Concomitant use of IMs and previous ADT exposure are identified as significant risk factors. Abbreviation: 5-ASA, 5-aminosalicylic acid; ADT, advanced therapy; CD, Crohn’s disease; IMs, immunomodulators; UST, ustekinumab.
Subgroup analysis based on previous use of ADT in CD
A post hoc subgroup analysis was performed on a cohort of 1971 patients with CD, of whom 57.5% had previously been treated with ADT. This analysis aimed to explore the differences in patient characteristics based on prior ADT exposure. Significant differences in demographic and clinical characteristics were observed between the ADT-naïve group and those with prior ADT exposure (Supplementary Table S1). Kaplan–Meier analysis revealed no significant differences in the cumulative rate of UST continuity between patients with and without concomitant 5-ASA use in the ADT-exposed group (P = .341). Furthermore, when stratifying patients by the number of prior ADTs used (1, 2, or 3 or more types), Kaplan–Meier analysis was conducted to evaluate the cumulative rate of UST continuity for each group. The results showed no significant differences in the cumulative rate of UST continuity between those with, and without concomitant 5-ASA use across all groups, and patients with prior exposure to 1 ADT (P = .15), 2 ADTs (P = .85), and 3 or more ADTs (P = .954). However, in the ADT-naïve group, the cumulative rate of UST continuity was significantly higher in patients who received concomitant 5-ASA therapy (P = .0121) (Supplementary Figure S2). Additionally, multivariate Cox analysis within each subgroup revealed that, in the ADT-naïve group, the concomitant use of IMs (adjusted HR: 1.36; 95% CI: 1.02-1.80) was a significant risk factor for UST failure. Conversely, concomitant 5-ASA use was identified as a protective factor for UST failure (adjusted HR: 0.69; 95% CI: 0.51-0.94), indicating a significant therapeutic potential for 5-ASA in this specific patient population. In contrast, only prior corticosteroid use (adjusted HR: 1.52; 95% CI: 1.21-1.91) was identified as a risk factor in the ADT-exposed group (Supplementary Figure S3). These findings from the post hoc analysis should be interpreted with caution, as they were not prespecified in the study design.
Patients With UC
Study population in patients with UC
This study identified 1500 patients with UC who underwent UST therapy between March 2020 and April 2022. After applying exclusion criteria similar to those used in the CD cohort, 5 patients who initiated 5-ASA during UST treatment, 59 who discontinued 5-ASA, 35 who started IMs, and 117 who discontinued IMs were excluded, resulting in a total of 1284 patients included in the analysis (Supplementary Figure S1). Of these, 82.6% received combination therapy with 5-ASA. The demographic characteristics of these patients, along with comparisons between those using and those not using 5-ASA, are presented in Table 2.
Baseline characteristics of the patients with UC.
| All patients | Without 5-ASA | With 5-ASA | P-value | |
|---|---|---|---|---|
| Number of patients | 1284 | 223 | 1061 | |
| Sex: male/female | 752 (58.6%)/532 (41.4%) | 130 (58.3%)/93 (41.7%) | 622 (58.6%)/439 (41.4%) | .94 |
| Age at initiation of UST, median (IQR) | 43.0 (30.0-57.0) | 42.0 (27.0-56.0) | 44.0 (31.0-58.0) | .145 |
| Concomitant 5-ASA | 1061 (82.6%) | 0 (0%) | 1061 (100%) | NA |
| Concomitant IM | 492 (38.3%) | 80 (35.9%) | 412 (38.8%) | .449 |
| Prior PSL use | 930 (72.4%)/354 (27.6%) | |||
| ADT-naïve/ADT exposure | 480 (37.4%)/804 (62.6%) | 68 (30.5%)/155 (69.5%) | 412 (38.8%)/649 (61.2%) | .022 |
| UST intervals: 8 weeks/12 weeks | 1264 (98.4%)/20 (1.6%) | 220 (98.7%)/3 (1.3%) | 1044 (98.4%)/17 (1.6%) | 1.000 |
| All patients | Without 5-ASA | With 5-ASA | P-value | |
|---|---|---|---|---|
| Number of patients | 1284 | 223 | 1061 | |
| Sex: male/female | 752 (58.6%)/532 (41.4%) | 130 (58.3%)/93 (41.7%) | 622 (58.6%)/439 (41.4%) | .94 |
| Age at initiation of UST, median (IQR) | 43.0 (30.0-57.0) | 42.0 (27.0-56.0) | 44.0 (31.0-58.0) | .145 |
| Concomitant 5-ASA | 1061 (82.6%) | 0 (0%) | 1061 (100%) | NA |
| Concomitant IM | 492 (38.3%) | 80 (35.9%) | 412 (38.8%) | .449 |
| Prior PSL use | 930 (72.4%)/354 (27.6%) | |||
| ADT-naïve/ADT exposure | 480 (37.4%)/804 (62.6%) | 68 (30.5%)/155 (69.5%) | 412 (38.8%)/649 (61.2%) | .022 |
| UST intervals: 8 weeks/12 weeks | 1264 (98.4%)/20 (1.6%) | 220 (98.7%)/3 (1.3%) | 1044 (98.4%)/17 (1.6%) | 1.000 |
Abbreviation: 5-ASA, 5-aminosalicylic acid; ADT, advanced therapy; IMs, immunomodulators; IQR, interquartile range; PSL, predonisolone; UC, ulcerative colitis; UST, ustekinumab.
Baseline characteristics of the patients with UC.
| All patients | Without 5-ASA | With 5-ASA | P-value | |
|---|---|---|---|---|
| Number of patients | 1284 | 223 | 1061 | |
| Sex: male/female | 752 (58.6%)/532 (41.4%) | 130 (58.3%)/93 (41.7%) | 622 (58.6%)/439 (41.4%) | .94 |
| Age at initiation of UST, median (IQR) | 43.0 (30.0-57.0) | 42.0 (27.0-56.0) | 44.0 (31.0-58.0) | .145 |
| Concomitant 5-ASA | 1061 (82.6%) | 0 (0%) | 1061 (100%) | NA |
| Concomitant IM | 492 (38.3%) | 80 (35.9%) | 412 (38.8%) | .449 |
| Prior PSL use | 930 (72.4%)/354 (27.6%) | |||
| ADT-naïve/ADT exposure | 480 (37.4%)/804 (62.6%) | 68 (30.5%)/155 (69.5%) | 412 (38.8%)/649 (61.2%) | .022 |
| UST intervals: 8 weeks/12 weeks | 1264 (98.4%)/20 (1.6%) | 220 (98.7%)/3 (1.3%) | 1044 (98.4%)/17 (1.6%) | 1.000 |
| All patients | Without 5-ASA | With 5-ASA | P-value | |
|---|---|---|---|---|
| Number of patients | 1284 | 223 | 1061 | |
| Sex: male/female | 752 (58.6%)/532 (41.4%) | 130 (58.3%)/93 (41.7%) | 622 (58.6%)/439 (41.4%) | .94 |
| Age at initiation of UST, median (IQR) | 43.0 (30.0-57.0) | 42.0 (27.0-56.0) | 44.0 (31.0-58.0) | .145 |
| Concomitant 5-ASA | 1061 (82.6%) | 0 (0%) | 1061 (100%) | NA |
| Concomitant IM | 492 (38.3%) | 80 (35.9%) | 412 (38.8%) | .449 |
| Prior PSL use | 930 (72.4%)/354 (27.6%) | |||
| ADT-naïve/ADT exposure | 480 (37.4%)/804 (62.6%) | 68 (30.5%)/155 (69.5%) | 412 (38.8%)/649 (61.2%) | .022 |
| UST intervals: 8 weeks/12 weeks | 1264 (98.4%)/20 (1.6%) | 220 (98.7%)/3 (1.3%) | 1044 (98.4%)/17 (1.6%) | 1.000 |
Abbreviation: 5-ASA, 5-aminosalicylic acid; ADT, advanced therapy; IMs, immunomodulators; IQR, interquartile range; PSL, predonisolone; UC, ulcerative colitis; UST, ustekinumab.
UST failure after UST administration in UC
The median follow-up period after UST initiation was 224 days (IQR, 63-406 days). During the follow-up period, 236 of 1284 patients (18.4%) experienced UST failure. Among these, 21.1% (47 of 223) of patients without concomitant 5-ASA therapy experienced UST failure compared to 17.8% (189 of 1061) of those on 5-ASA. Kaplan–Meier analysis showed no significant difference in the cumulative rate of UST continuity between the 2 groups (P = .0892) (Figure 3). To further assess the associations between UST failure and demographic or clinical factors, Cox proportional hazards analysis was performed (Figure 4). This analysis identified concomitant use of IMs (adjusted HR: 1.45; 95% CI: 1.12-1.89), prior corticosteroid use (adjusted HR: 2.23; 95% CI: 1.71-2.90), and previous ADT use (adjusted HR: 1.37; 95% CI: 1.04-1.81) as significant predictors of UST failure. However, the use of 5-ASA (adjusted HR: 0.78; 95% CI: 0.57-1.08) was not identified as a risk factor for UST failure. Furthermore, the IPTW-adjusted Cox proportional hazards model for 5-ASA use showed no significant effect on UST failure, with an adjusted HR of 0.78 (95% CI: 0.56-1.08).
Kaplan–Meier analysis of cumulative rate of UST continuity for patients with UC post-UST administration. A, Cumulative rate of UST continuity in patients with UC post-UST administration. B, Comparison of the cumulative rate of UST continuity between UC patients with and without concomitant 5-ASA therapy. No significant differences were observed between the 2 groups (P = .0892). Abbreviation: 5-ASA, 5-aminosalicylic acid; UC, ulcerative colitis; UST, ustekinumab.
Multivariable Cox proportional hazards analysis of risk factors for UST failure in patients with UC. Hazard ratios of various covariates influencing the risk of UST failure in patients with UC undergoing UST treatment. Concomitant use of IMs is identified as a significant risk factor, while the use of 5-ASA appears to be a protective factor against UST failure. Abbreviation: 5-ASA, 5-aminosalicylic acid; IMs, immunomodulators; UC, ulcerative colitis; UST, ustekinumab.
Subgroup analysis based on previous use of ADT in UC
A post hoc subgroup analysis was conducted to evaluate the effectiveness of 5-ASA based on the prior use of ADT. Among the UC patients, 62.6% had prior ADT exposure. A comparison of patient demographics based on previous ADT exposure revealed significant differences in sex and concomitant 5-ASA use between the ADT-naïve and ADT-exposed groups (Supplementary Table S2). Kaplan–Meier analysis within these subgroups demonstrated no significant difference in the cumulative rate of UST continuity between patients with and without 5-ASA use in the ADT-naïve group (P = .386). However, in the ADT-exposed group, patients who received concomitant 5-ASA therapy demonstrated significantly higher rates of continued UST therapy (P = .0173) (Supplementary Figure S4). Furthermore, when stratifying UC patients by the number of prior ADTs used (1, 2, or 3 or more types), Kaplan–Meier analysis showed that the cumulative rate of UST continuity was significantly higher in the group receiving concomitant 5-ASA therapy with prior exposure to only 1 ADT (P < .05). However, no significant differences were observed in the cumulative rate of UST continuity between those with and without concomitant 5-ASA use among patients with prior exposure to 2 (P = .387) or 3 or more ADTs (P = .398). Multivariate Cox analysis further revealed that in the ADT-naïve group, prior corticosteroid use (adjusted HR: 2.59; 95% CI: 1.64-4.11) was a significant risk factor against UST failure. In the ADT-exposed group, concomitant use of IMs (adjusted HR: 1.43; 95% CI: 1.04-1.97) and prior corticosteroid use (adjusted HR: 2.14; 95% CI: 1.55-2.96) were identified as risk factors for UST failure, while concomitant use of 5-ASA (adjusted HR: 0.63; 95% CI: 0.44-0.90) was a protective factor (Supplementary Figure S5). The results of the post hoc analysis highlight the need for further studies to validate these findings.
Discussion
This retrospective cohort study used a comprehensive, real-world medical database from Japan to evaluate the impact of concomitant 5-ASA therapy during UST treatment in patients with IBD. Our findings indicate that the use of 5-ASA in combination with UST does not provide significant overall benefits for either CD or UC.
For CD, our findings suggest that adding 5-ASA to UST therapy does not significantly alter the overall clinical outcomes. This is consistent with existing guidelines that question the benefits of 5-ASA in managing CD, especially in the era of more effective biologic agents.8,16,17 Oral 5-ASA has not consistently demonstrated efficacy over placebo in inducing remission and promoting mucosal healing in patients with CD.18–20 Moreover, some studies have reported no additional benefit when it is used in combination with antitumor necrosis factor agents11 or vedolizumab.12 Current guidelines do not recommend 5-ASA for CD treatment.16,17 This aligns with the findings of our study on the minimal overall impact of 5-ASA on clinical outcomes in patients with CD undergoing UST therapy. However, subgroup analyses, which were conducted post hoc, revealed that 5-ASA may have a protective effect in ADT-naïve patients. These exploratory findings suggest potential therapeutic value in specific clinical scenarios, but they should be interpreted cautiously owing to the post hoc nature of the analysis. Further research is required to confirm these observations.
In UC, the European Crohn’s and Colitis Organization recommends continuing 5-ASA therapy even after remission is achieved, although no explicit guidelines exist for its coadministration with biologics or JAK inhibitors.21 In contrast, the American College of Gastroenterology advises against using 5-ASA in conjunction with antitumor necrosis factor therapies,22 and the American Gastroenterological Association recommends discontinuing 5-ASA when transitioning to biological agents or tofacitinib.23 Our data support these recommendations, as no significant overall benefit of 5-ASA was observed in the UC population. However, subgroup analyses indicated a protective effect of 5-ASA in patients with prior exposure to ADT. Similar to the findings in CD, these results should be interpreted with caution, as the subgroup analyses were exploratory and not prespecified in the study design. When stratifying patients by the number of prior ADTs used, no significant differences in the cumulative rate of UST continuity were observed in CD patients between those with and without concomitant 5-ASA use across all groups (1, 2, or 3 types of ADTs). In UC patients, however, a significant benefit was observed in the group with prior exposure to 1 ADT, whereas no significant differences were observed in patients with prior exposure to 2, 3, or 4 ADTs. One possible reason for the lack of significant findings in the groups with prior exposure to 2, 3, or 4 ADTs is the insufficient sample size, which may have limited the statistical power to detect differences. These factors highlight the complexity of managing patients with extensive treatment histories and underscore the importance of individualized treatment approaches. Further studies with larger sample sizes are warranted to validate these findings and to better understand the role of 5-ASA in patient subgroups with different prior treatment histories.
An additional potential advantage of long-term 5-ASA use is its possible chemopreventive effect against colorectal cancer. Some studies have suggested that UC patients treated with 5-ASA may have a lower risk of developing colorectal cancer,24,25 and various mechanisms for its chemopreventive action have been proposed.26,27 However, as effective inflammation control and sustained remission are also associated with reduced colorectal cancer risk, the unique chemopreventive effect of 5-ASA, beyond its anti-inflammatory properties, remains controversial.25,28 Furthermore, no studies have specifically evaluated the chemopreventive effects of 5-ASA during ADT. In this study, we were unable to assess the chemopreventive effect of concomitant 5-ASA owing to the low incidence of cancer and the relatively short follow-up period. Although the use of specific medications solely for the prevention of colorectal cancer is not recommended in patients with UC,22 the potential chemopreventive benefits of 5-ASA require further investigation.
Additionally, concomitant IM use has emerged as a risk factor for poor outcomes. Patients on IMs may have more severe disease activity, which might inherently reduce the efficacy of UST. However, because our study was retrospective and the MDV database had limitations, we were unable to assess the disease activity at treatment initiation. This limits our ability to conclusively attribute the poorer outcomes in IM users to disease severity, although this remains a plausible explanation.
Despite these insights, our study has several limitations that must be considered when interpreting the results. First, the retrospective nature of the study and reliance on the MDV database restricted our ability to assess critical variables such as disease severity, duration, age at onset, disease location, and serological markers such as C-reactive protein prior to UST administration. As we could not directly assess disease activity, we examined prior steroid use as a surrogate marker of disease activity. However, it is important to note that steroid use does not fully capture the complexity of disease activity and may not accurately reflect the overall clinical state of patients. Disease extension data were not available, and while disease duration could be estimated from the diagnosis date to UST initiation, the accuracy is uncertain because of potential interruptions in follow-up and patients visiting different hospitals. These limitations may have impacted our ability to fully explore the factors influencing treatment response. Second, the primary outcome of this study, UST failure, is based on surrogate measures such as hospitalization, treatment modification, or initiation of systemic corticosteroids, which reflect clinical decisions rather than direct assessments of disease activity or treatment response. Variability in clinical practice, including differences in adherence to treat-to-target recommendations, may introduce confounders, as clinicians prescribing 5-ASA with UST may have a lower threshold for modifying therapy. These factors limit the generalizability of the findings and underscore the need for future studies using objective measures, such as endoscopic or biomarker-based outcomes. Third, although corticosteroid use was included as one of the criteria for defining UST failure, the potential confounding effect of corticosteroid use at the time of UST initiation cannot be excluded. To minimize this issue, we focused on intravenous corticosteroid administration rather than oral corticosteroids, because oral corticosteroids may have been used concomitantly with UST initiation. However, this approach may not have fully eliminated the influence of baseline corticosteroid use on the outcome definition. Additionally, the definition of 5-ASA exposure used in this study had inherent limitations. Concomitant 5-ASA use was defined as the presence of 5-ASA prescriptions, both around the time of UST initiation and during the final observation period. Patients without 5-ASA prescriptions during these periods were categorized as having “no concomitant 5-ASA use.” However, this definition may result in misclassification, particularly in patients who temporarily discontinued or initiated 5-ASA therapy during the observation period. This limitation is compounded by the retrospective nature of the study and the heterogeneity of the patient population. Furthermore, a thorough evaluation of the side effects of 5-ASA is necessary to fully assess the impact of its concomitant use. However, our study design did not allow for this examination. Moreover, the inability to track patients who were transferred to other hospitals resulted in incomplete follow-up data, potentially introducing bias into our findings.
Nevertheless, the strength of this study is its large cohort size, which provides a robust data set for evaluating the impact of concomitant 5-ASA therapy during UST treatment. In conclusion, this study demonstrated that 5-ASA did not provide significant overall benefits when used in combination with UST for UC or CD. However, post hoc subgroup analyses suggested potential benefits in specific patient populations, such as ADT-naïve patients with CD and patients with UC with prior ADT exposure. These findings highlight the importance of tailoring treatment strategies based on individual patient histories and the necessity for further prospective studies to validate these observations and explore the underlying mechanisms.
Supplementary Data
Supplementary data are available at Inflammatory Bowel Diseases online.
Acknowledgments
We used OpenAI’s language models, ChatGPT-4 and ChatGPT-4o, for assistance in creating scripts for data and manuscript preparation. These tools significantly streamlined the development of this study. We express our gratitude for their support.
Author Contributions
All authors contributed to the study conception and design. Data collection and analysis were performed by Y.N. and S.H. The first draft of the manuscript was written by Y.N. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No specific funding was provided for this study.
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability
The data underlying this article will be shared at the aggregate/population level upon reasonable request to the corresponding author.
