Real-world use and perceptions of advanced combined therapies in treating inflammatory bowel disease

Hsin-Yun Wu; Zhi-Che Chen; Meng-Tzu Weng; Agnes Hiu Yan Ho; Joyce Wing Yan Mak; Rupert W Leong; Siew-Chien Ng; Uma Mahadevan; Fernando Magro; Deng-Chyang Wu; Shu-Chen Wei

doi:10.5217/ir.2025.00325

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Original Article Real-world use and perceptions of advanced combined therapies in treating inflammatory bowel disease: Hsin-Yun Wu^1,2, Zhi-Che Chen^1,2, Meng-Tzu Weng^2,3, Agnes Hiu Yan Ho⁴, Joyce Wing Yan Mak⁴, Rupert W Leong⁵, Siew-Chien Ng^6,7,8, Uma Mahadevan⁹, Fernando Magro¹⁰, Deng-Chyang Wu¹¹, Shu-Chen Wei²; DOI: https://doi.org/10.5217/ir.2025.00325
Published online: May 19, 2026

¹Department of Internal Medicine, National Taiwan University Hospital Jinshan Branch, New Taipei City, Taiwan

²Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

³Department of Medical Research, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan

⁴Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China

⁵Department of Gastroenterology, Concord Repatriation General Hospital, Sydney, Australia

⁶Microbiota I-Center (MagIC), Hong Kong, China

⁷Department of Medicine and Therapeutics, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China

⁸New Cornerstone Science Laboratory, The Chinese University of Hong Kong, Hong Kong, China

⁹Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA

¹⁰Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal

¹¹Division of Gastroenterology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

Correspondence to Shu-Chen Wei, Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, No.7, Zhongshan S. Rd., Zhongzheng Dist., Taipei City 100225, Taiwan. E-mail: shuchenwei@ntu.edu.tw

• Received: December 18, 2025 • Revised: February 26, 2026 • Accepted: March 17, 2026

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
Graphical abstract
INTRODUCTION
METHODS
RESULTS
DISCUSSION
NOTES
Supplementary Material
REFERENCES

Abstract

Background/Aims
Combining therapies targeting distinct pathways shows promise in breaking the therapeutic ceiling for inflammatory bowel disease. The study explored real-world experiences and gaps between current evidence and clinical practice regarding advanced combined therapies.
Methods
A cross-sectional online survey was conducted via QR code during meetings or email invitation. The survey covered participant demographics, experiences with advanced combined therapies for ulcerative colitis, Crohn’s disease, and knowledge of these therapies.
Results
Between March and October of 2024, 234 participants from 20 countries replied and 51.7% had adopted advanced combined therapies (86.0% had treated ulcerative colitis, 66.9% Crohn’s disease, and 52.9% both). Among the 48.3% who had no experience, 76.1% would try if indicated. Refractory diseases were the most common indications. For combined therapies duration, 52.8% were time-oriented, favoring limited use within 6 months. Physicians reported no adverse events in 59.5% of cases. Of the events, infections (69.8%) were most common. Add-on strategy was the most commonly adopted, particularly the Janus kinase inhibitor added on anti-integrin for ulcerative colitis and anti-tumor necrosis factor alpha added on anti-interleukin 12/23 for Crohn’s disease. Concomitant strategy followed, while sequential strategy was the least used. More non-Asian experts were experienced (82.4%) compared to Asian participants (46.5%). Both inexperienced and non-Asian physicians preferred add-on strategy, but prioritized goal-oriented use, targeting clinical and endoscopic remission.
Conclusions
In real-world practice, advanced combined therapies were primarily used for refractory inflammatory bowel disease with limited duration. Add-on use was the most adopted. Differences in treatment approaches reflect varying levels of physician experience and geographical locations.
Keywords: Inflammatory bowel diseases; Advanced combined therapies; Real-world evidence

Graphical abstract

INTRODUCTION

Inflammatory bowel disease (IBD) encompasses a heterogeneous disease spectrum. Although multiple monoclonal antibodies and targeted small molecules have been developed, the therapeutic ceiling remains. Landmark studies of the widely used biological agents report 1-year clinical remission rates of only 36% to 53% [1-4], and many patients experience secondary loss of response. Therefore, advanced combined therapies (ACT) of distinct pathogenic pathways serve as a reasonable practice to achieve additive or even synergistic effects.

Currently, most evidence for ACT was derived from retrospective cohort studies treating refractory cases, severe extraintestinal manifestations (EIMs), or coexisting autoimmune disorders. An earlier randomized controlled trial of natalizumab plus infliximab in Crohn’s disease (CD) showed good tolerance and signals for efficacy [5], but risks of progressive multifocal leukoencephalopathy limited uptake. In response to the clinical need, the VEGA trial was conducted. It revealed that golimumab plus guselkumab improved clinical response rate in ulcerative colitis (UC), without an apparent increase in adverse events versus either monotherapy [6]. This prompted the ongoing trials for moderate to severe UC (DUET-UC, NCT05242484) and CD (DUET-CD, NCT05242471). To further address safety, co-induction of vedolizumab, adalimumab, and methotrexate, followed by vedolizumab maintenance, was evaluated in the EXPLORER trial [7]. Furthermore, pairing small molecules with biologic agents is promising, supported by the recent VETO study (vedolizumab with tofacitinib) [8], alongside ongoing trials (BI 706321 with ustekinumab, NCT04978493; and upadacitinib with vedolizumab, NCT06227910).

In this new frontier of IBD management, significant gaps remain regarding patient selection, optimal regimen and modes (concomitant, add-on, or sequential), treatment duration, and long-term safety. Additionally, the cost-effectiveness of ACT requires dedicated studies. In the interim, we aim to investigate and understand the differences in practice and perceptions toward ACT by conducting a global survey

METHODS

1. Ethical Considerations

The study did not involve patient-level data; therefore, the approval of the National Taiwan University Hospital Institutional Review Board (No. 202508008W) and written informed consent were waived. The study conformed to the Consensus for Reporting of Survey Studies (CROSS) guidelines [9].

2. Study Design and Participant Selection

We conducted a single-stage, cross-sectional online survey targeting clinicians involved in caring for IBD patients worldwide. The survey consisted of 4 domains, the demographics of the participants (5 questions), personal experiences of ACT for UC and CD (both up to 22 questions, based on experiences), and knowledge of ACT for inexperienced physicians (up to 14 questions, based on responses) (see Supplementary Table 1 with complete questionnaire). This study involved an international panel of IBD experts from the United States, Europe, Australia, Hong Kong, and Taiwan. All members of the panel had evaluated the contents within the questionnaire and confirmed the clarity and relevance internally. The survey link was distributed via emails, personal invitations, and QR codes shared at meetings held from March to October 2024. Participation was anonymous, and the survey was in English. Aside from the question about the responder’s practice location, all other questions were formatted as either single- or multiple-choice

3. Data Collection and Definition

The definition of ACT is the combination of different classes of biological agents and/or small molecules. Biological agents included anti-tumor necrosis factor alpha (anti-TNFα) agents, integrin antagonist (anti-integrin), and anti-interleukin 12/23 (anti-IL12/23) while small molecules included Janus kinase inhibitor (JAKi) and sphingosine-1 phosphate (S1P) receptor agonist. These classes of medications were included due to their broader clinical accessibility. High-risk phenotypes were generally perceived when patients have extensive bowel involvement, stricturing or fistulizing disease [10]. Treatment duration determinants were classified into time, goal, and cost oriented. We defined “time-oriented” as limited ACT use because of concerns for the exposure time and “goal-oriented” as ACT use until either clinical or endoscopic remission is achieved. Severe adverse events were defined as those leading to ACT discontinuation, surgery, hospitalization, or death.

4. Statistical Analysis

Descriptive analyses were conducted using Microsoft Excel (version 16.90.2; Microsoft Corp., Redmond, WA, USA). Differences between the groups were evaluated using chi-square test. Statistical analyses and visualizations were created using Python in Google Colaboratory. The statistical significance was set at P<0.05.

RESULTS

1. Participant Demographics

A total of 234 participants from 20 countries across all continents (Asia 85.5%, America 5.6%, Oceania 4.7%, Europe 2.1%, Africa 0.4%) completed the survey (Fig. 1). Most participants were gastroenterologists (95.3%), with 3% pediatricians, and the remainder comprising internal medicine specialists and other related disciplines. The majority were affiliated with academic centers (76.5%), while others practiced in tertiary centers (11.5%), secondary (5.1%) or primary (5.6%) practices, and others (1.3%). The experiences involved in IBD care were < 5 years (33.3%), 6–10 years (24.8%), 11–15 years (20.1%), 16–20 years (11.1%) and > 20 years (10.7%). Institutional IBD volume was evenly distributed between 0–100 cases/year (32.1%), 101–500 cases/year (38%), and > 500 cases/year (29.9%).

A total of 121 responders (51.7%) had previously adopted ACT. Of these, 104 (86.0%) had treated UC with ACT. The most common ACT experiences in patient numbers for UC were 1–5 patients (50%), followed by 6–10 patients (21.2%), and over 30 patients (12.5%). On the other hand, 81 (66.9%) had treated CD with ACT. The most common ACT experiences in patient numbers for CD were 1–5 patients (54.3%), 6–10 patients (18.5%), and 11–15 patients (13.6%). Sixty-four (52.9%) had experiences for both conditions. In contrast, 113 physicians (48.3%) had no prior experience, but 76.1% of them were willing to adopt ACT if indicated and available. Geographic distribution differed significantly between the experienced and inexperienced physicians (P<0.001).

2. Experienced Physicians

The most common indication for ACT was refractory disease for both UC and CD (44.1% and 48.7%, respectively) (Fig. 2). Other indications for UC were acute severe diseases in 25.0%, EIM in 21.6%, and high-risk phenotypes in 9.3%. For CD, EIM accounted for 22.2%, acute severe disease 16.5%, and high-risk phenotypes 12.7%, respectively. There was no statistical difference in the indications between UC and CD (P=0.221).

Regarding the major determinant for ACT duration, there were also no differences between UC and CD (P=0.276). More physicians (55.6% for UC and 48.7% for CD) adopted time-oriented approaches, mostly favoring a limited duration of 6 months (Fig. 3). At the same time, 39.1% and 47.9% of physicians were goal-oriented while treating UC and CD, respectively. This included 17.8% of clinical remission and 21.3% of endoscopic remission in the UC group and 26.4% of clinical remission and 21.5% of endoscopic remission in the CD group. Cost was the determining factor in only 5.3% of ACT cases in UC and 3.3% in CD.

Safety-wise, 59.5% of ACT use did not encounter adverse events (Fig. 4). The most frequently reported adverse events were infections (69.8%), including herpes zoster (14.4%), tuberculosis (TB; 6.5%), hepatitis B reactivation (5.8%), and other infections (43.2%). The second most reported adverse events were worsening of IBD (18.7%). Among all events, 48.2% were graded as non-severe, while 25.5% led to ACT discontinuation, 19.1% required hospitalizations, 7.1% resulted in surgeries, but fortunately, 0% mortality. Furthermore, we investigated the etiologies of infectious adverse events in detail. Of the 20 cases of herpes zoster, 14 occurred in Asian countries (13 in China and 1 in Taiwan), and 6 from the other continents (4 in Australia, 1 in the United States, and 1 in Brazil). All TB (7 in China and 2 in Malaysia) and hepatitis B reactivation (6 in China and 2 in Malaysia) cases were reported from Asia. Pooled reported frequency of specified infections (herpes zoster, TB, and hepatitis B reactivation) between the Asian and non-Asian groups were 33.3% (31/93) and 21.4% (6/28), respectively. It was numerically higher in Asian group but without statistical differences (P=0.335).

ACT strategies were classified into concomitant, add-on, and sequential approaches (Fig. 5). The strategies used were not mutually exclusive, and participants could choose from whichever applied based on their experiences. The most common strategy was add-on use for both UC (78.8%) and CD (71.6%). The most frequent combinations for UC were JAKi added on anti-integrin (18.6%), and anti-TNFα added on anti-IL12/23 (14.0%) for CD (Table 1). The second frequently used strategy was concomitant use for both UC (51%) and CD (48.1%). The most common combinations were anti-integrin plus JAKi (21.7%) for UC and anti-IL12/23 plus anti-TNFα (23.1%) for CD. Additionally, sequential strategy was not uncommon in UC (33%) and CD (29.6%). The most common sequences were anti-integrin plus JAKi then anti-integrin alone (10.9%) for UC and anti-IL12/23 plus anti-TNFα then antiIL12/23 alone (12.5%) for CD. Statistically, the strategies of ACT being employed by physicians for UC and CD were similar (P=0.988).

Regarding the sources of payment, 35.8% of ACT usage was reimbursed by government-based insurances, while 25.4% were covered by private insurances. However, still a portion of the usages required partial (21.2%) or even full (7.2%) self-financing. Additionally, 10.4% of cases were paid by charitable funds. Cost considerations contributed to the discontinuation of ACT in 26.5% of cases. Looking at future perspectives, physicians emphasized the need for more real-world evidence (44.2%), head-to-head randomized controlled studies (42.2%), and preclinical studies (13.6%) to guide the use of ACT in clinical practice.

3. Inexperienced Physicians

Responses from the inexperienced group were not further stratified for UC or CD. Among those willing to adopt ACT, the top indications (Fig. 2) were also refractory diseases (39.4%). These were followed by acute severe diseases (26%), high-risk phenotypes (18.3%), and EIM (16.3%). The significantly higher proportion of high-risk phenotypes in the inexperienced group accounted for the overall statistical difference in indications applied (P=0.018). Regarding the major determinant for ACT duration (Fig. 3), unlike the experienced physicians, a greater proportion (57.8%) were goal-oriented, targeting clinical remission (27.6%) or even endoscopic remission (30.2%). A smaller percentage (30.7%) favored time-oriented use. Cost considerations had a greater influence on determining the ACT duration (11.6%) compared to the experienced group (4.5%). The treatment duration determinants were significantly distinct from the experienced group (P<0.001).

The inclinations for how inexperienced doctors would adopt the ACT strategies (Fig. 5) were similar to the experienced group (P=0.131), with add-on strategy being the most favored (87.2%), followed by concomitant use (80.2%), then sequential use (64.0%). However, drug selections were more uniform, with fewer considerations for JAKi. The most favored combinations were anti-integrin added on anti-TNFα (9.1%) for add-on strategy, anti-integrin plus anti-TNFα (14.1%) for concomitant use, and anti-integrin plus anti-TNFα, followed by anti-integrin alone (9.5%) for sequential use (Table 1).

Inexperienced physicians perceived current ACT evidence to rely heavily on expert opinions (29.4%) and retrospective cohort studies (25.8%). This was reflected in their concerns for adopting ACT. Safety was the primary concern (54.2%), followed by inadequate evidence (23.1%). Therefore, inexperienced physicians were also eager for more real-world evidence (48.5%), head-to-head randomized controlled studies (40.3%), and preclinical studies (11.2%) to be conducted.

4. Comparisons on ACT Approaches Between Non-Asian and Asian Experts

Overall, more non-Asian experts had experience of applying ACT (82.4%) compared to Asian participants (46.5%). When comparing ACT strategies, the use of concomitant strategies was comparable for both UC and CD. However, more non-Asian physicians favored the add-on strategies (UC: Asian vs. non-Asian, 62.4% vs. 85.7%, P=0.037; CD: Asian vs. non-Asian, 41.9% vs. 67.9%, P=0.028) and sequential use (UC: Asian vs. non-Asian, 19.4% vs. 57.1%, P<0.001; CD: Asian vs. non-Asian, 12.9% vs. 42.9%, P=0.001) (Table 2). Furthermore, we investigated the factors which determined the ACT duration. We found that for the add-on approach, significantly more Asian physicians adopted time-oriented use while more non-Asian physicians favored goal-oriented use (P=0.008 in UC and P=0.009 in CD).

DISCUSSION

This study bridged the gap between current evidence and real-world practice in the emerging field of ACT for IBD. There have been multiple retrospective reports for ACT; however, these may be subjected to publication biases–favoring positive outcomes and underreporting adverse events. Our study offered a comprehensive overview for how physicians adopted ACT and reflected key concerns. In real-world practice, ACT was mostly used for refractory IBD with a limited duration, favoring add-on strategies. JAKi added on anti-integrin for UC and anti-TNFα added on anti-IL12/23 for CD were the most common combinations.

The strengths of our study included the exploration of the less discussed aspects regarding ACT, such as the strategies adopted (add-on, concomitant, and sequential) and determinants of ACT duration (time, goal, and cost issues). Notably, this result reflected the current practice pattern and physician comfort instead of a validated clinical superiority over other methods. Additionally, we involved the ACT inexperienced physicians and further compared them to the experienced physicians. Through the comparison, we noticed the biggest difference lay in the ACT duration determinants–experienced physicians favoring a time-oriented approach while the inexperienced group favoring goal-oriented approach. The reasoning behind this observation may be because experienced physicians had deeper knowledge of the topic and had possibly encountered prior adverse events. Thus, the experienced doctors may be more realistic, taking safety into account. In contrast, inexperienced physicians may be driven more by an idealistic focus on achieving optimal outcomes while possibly underestimating the associated risks. Also, they may be less experienced with the cost perspective. On the other hand, through the responses of inexperienced physicians, we may infer that more ACT-related evidence and trials should be promoted to enhance their understanding.

The COMBIO study from European centers was the largest retrospective cohort study of ACT with patient-level data [11]. Among the 104 combinations for 98 patients, the most common combination was anti-TNFα plus anti-integrin. The adverse events rate of 42% was comparable to our results. Since Caucasians accounted 94% of the cases in the COMBIO study, our Asian-predominant survey offers a valuable complement to existing ACT research. This contrasted with another highlight of our study–the comparison between Asian and non-Asian physicians. Yet such comparisons are likely underpowered due to the limited non-Asian sample size (n=28) and should be viewed as exploratory results pending future studies with balanced global distribution to validate.

We especially examined the infectious adverse events etiologies. The pooled rate for herpes zoster, TB, and hepatitis B reactivation was numerically higher in the Asian cohort (33.3%), as compared to non-Asian groups (21.4%), although the differences were not statistically significant. Seventy percent of herpes zoster cases occurred in Asian countries. The differences in herpes zoster vaccination access and coverage around the world may contribute [12]. All TB and hepatitis B reactivation cases were reported from Asian countries, which was not surprising since both diseases are highly prevalent in East Asia [13,14]. From this closer examination, we know that although the reported frequency of adverse events was similar to previous studies [11], these findings highlight regional variations in the infectious risks.

Beyond epidemiological differences, regional differences in screening and prophylaxis policies may also shape these safety patterns. Prior multinational survey by the Asian Organization of Crohn’s and Colitis suggested that screening of TB and hepatitis B prior to anti-TNFα therapies were well executed (> 70%) in Asia [15]. However, screening statuses before other advanced therapies or ACT were unknown. Different policies on latent TB treatment may also contribute. Since the Chinese guideline suggested chemoprophylaxis for latent TB only before anti-TNFα initiation [16], a real-world evidence study revealed 52.8% of the latent TB infection patients did not receive chemoprophylaxis prior to ustekinumab [17]. In Taiwan on the other hand, it is recommended to screen for and treat hepatitis B and latent TB prior to all advanced therapies [18,19].

Regarding the geographical comparison for ACT approach, it is noteworthy that more non-Asian experts adopted the addon and sequential strategies for both UC and CD. Asian experts were more time-oriented while the non-Asian experts were more goal-oriented. In Asian regions, the concerns for infections, especially TB, herpes zoster, and hepatitis B reactivation, may greatly affect the physicians’ decision on ACT duration. However, the cost of advanced therapies and even regulations from national health insurance may play more important roles in Asian countries, potentially contributing to the regional differences instead of physicians’ preferences alone. The most recent meta-analysis by Ahmed et al. [20] included 30 studies with 279 patients (76% with CD). Aligned with our results, refractory diseases were the main indications for applying ACT. The most common combinations were anti-TNFα plus anti-integrin, followed by anti-integrin with anti-IL12/23. However, our study provided additional insights by stratifying the usage based on disease subtypes (UC and CD) and ACT strategies. Furthermore, we observed that JAKi is among the most frequently used medications for combination, including for CD. Since tofacitinib is not approved for CD, many of the JAKi usages in our study might be upadacitinib. In contrast, the meta-analysis was published in 2022 and included only tofacitinib as the small molecule medication. With broader availability and expanding indications of small molecules, our study provided more updated real-world results.

The most recent meta-analysis by Ahmed et al. [20] included 30 studies with 279 patients (76% with CD). Aligned with our results, refractory diseases were the main indications for applying ACT. The most common combinations were anti-TNFα plus anti-integrin, followed by anti-integrin with anti-IL12/23. However, our study provided additional insights by stratifying the usage based on disease subtypes (UC and CD) and ACT strategies. Furthermore, we observed that JAKi is among the most frequently used medications for combination, including for CD. Since tofacitinib is not approved for CD, many of the JAKi usages in our study might be upadacitinib. In contrast, the meta-analysis was published in 2022 and included only tofacitinib as the small molecule medication. With broader availability and expanding indications of small molecules, our study provided more updated real-world results.

There were also some studies on the pediatric group, the biggest cohort being the DOUBLE-PIBD cohort [21], which included 62 children. Similarly, the most common combination was anti-TNFα plus vedolizumab and the adverse event rate was 47%. However, pediatricians accounted for only 3% of our respondents, limiting the generalizability of our findings to the pediatric population.

We acknowledged several limitations for our survey. First, we did not include questions regarding the clinical outcomes, limiting our ability to draw conclusions about ACT effectiveness. Second, the survey is in English only. Third, we were unable to determine the exact response rate due to the anonymous nature of the survey and its distribution through personal networks and public conferences. This may lead to potential nonresponse bias and limit the generalizability of the survey, as well as self-selection bias, where more enthusiastic physicians are more likely to respond. Fourth, selection bias may cause our data to skew towards Asian countries and academic centers. The results may benefit from more diverse global data, especially from countries with higher IBD prevalence and more ACT experiences. More respondents from academic centers may lead to overestimation of ACT usage. This institutional skew, along with indication bias, may be inevitable, since refractory IBD and high-risk cases usually are referred to these centers, with higher chances of receiving ACT. Furthermore, we included only the widely available medications, such as anti-TNFα, anti-integrin, anti-IL12/23, JAKi, and S1P. Although the inclusion of newer JAKi and S1P was broader than previous studies, newer agents, such as antibodies targeting p19 subunits, were not included. Recall bias may apply as well, making the 40.5% adverse event rate a conservative estimation, particularly for milder events. Finally, we lacked patient-level data to analyze disease severities, phenotypes, clinical outcomes, and follow-up after adverse events or ACT discontinuation.

A review by De Bernardi et al. [22] conducted a SWOT analysis which not only brought out the pros and cons of ACT, but also depicted the concerns in safety, regulations, and costs. The current study is the first global survey to highlight the real-world usage of ACT. It reinforced the challenges and barriers in the SWOT analysis.

In conclusion, we demonstrated that ACT was used particularly in refractory IBD, with a preference for limited duration and add-on use in real-world practice. JAKi added on anti-integrin for UC and anti-TNFα added on anti-IL12/23 for CD were the more preferred combinations. Determinants of ACT duration differed according to physician’s expertise and geographic locations. Infections were the most reported adverse events with regional variations. We look forward to future studies to provide the evidence and guide the treatment to break the therapeutic ceiling for IBD patients

NOTES

Funding Source

This study was supported by grants from National Taiwan University Hospital (grant number MS 507; Wei SC) and The Liver Disease Prevention and Treatment Research Foundation, Taiwan (HYW, MTW, and Wei SC).

Conflict of Interest

Leong RW has served as an advisory board member for AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, and Takeda; has received research grants from: Joanna Tiddy USYD, McCusker Charitable Foundation, Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, and Medical Research Future Fund of Australia. Ng SC has served as an advisory board member for Pfizer, Ferring, Janssen and AbbVie and received honoraria as a speaker for Ferring, Tillotts, Menarini, Janssen, AbbVie and Takeda; has received research grants through her affiliated institutions from Olympus, Ferring and AbbVie; is a founder member, non-executive director, non-executive scientific advisor and shareholder of GenieBiome Ltd. is a shareholder of MicroSigx Diagnostic Holding Limited; is a founder member, non-executive Board Director, non-executive scientific advisor and Honorary Chief Scientific Officer of MicroSigx Biotech Diagnostic Limited, which is non-remunerative; and receives patent royalties through her affiliated institutions. Mahadevan U has consulted for AbbVie, Abivax, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Enveda, Gilead, Janssen, Lilly, Merck, Pfizer, Protagonist, Roivant, Takeda, and Trex. Fernando Magro has served as a speaker for AbbVie, Arena, Biogen, Bristol Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, and Vifor. Wei SC has consulted and/or served on advisory boards for AbbVie, Bristol Myers Squibb, Celltrion, Everest Medicine, Ferring Pharmaceuticals Inc., Janssen, Pfizer, Sanofi, and Takeda; has received lecture fee from AbbVie, Bristol Myers Squibb, Celltrion, CornerStones, Excelsior, Ferring Pharmaceuticals Inc., Janssen, Pfizer, Takeda, and Thermo Fisher. Wu HY, Chen ZC, Weng MT, Ho AHY, Mak JWY, and Wu DC have no conflicts of interest to declare.

Leong RW, Ng SC, and Wei SC are editorial board members of this journal but were not involved in the peer review process of this article.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author Contributions

Conceptualization: Wu DC, Wei SC. Data curation: Wu HY, Chen ZC, Weng MT, Ho AHY, Mak JWY. Formal analysis: Wu HY. Funding acquisition: Wu HY, Weng MT, Wei SC. Investigation: Wu HY, Chen ZC, Weng MT, Ho AHY, Mak JWY. Methodology: Leong RW, Ng SC, Mahadevan U, Magro F, Wu DC, Wei SC. Project administration: Wu HY. Resources: Wei SC. Software: Wu HY. Supervision: Leong RW, Ng SC, Mahadevan U, Magro F, Wu DC, Wei SC. Validation: Wei SC. Visualization: Wu HY, Leong RW, Wu DC, Wei SC. Writing–original draft: Wu HY. Writing–review & editing: all authors. Approval of final manuscript: all authors.

Additional Contributions

We are sincerely grateful to all physicians who participated in this study.

Supplementary Material

Supplementary materials are available at the Intestinal Research website (https://www.irjournal.org).

Supplementary Table 1.

Complete Questionnaire

ir-2025-00325-Supplementary-Table-1.pdf

Fig. 1.

The geographical distribution and the experiences of the physicians. The participating physicians were Asian predominant. ACT experiences of the responders varied across countries. ACT, advanced combined therapies.

Fig. 2.

Indications for advanced combined therapies. Refractory disease is the most common indication for both UC and CD. It was followed by acute severe UC and extraintestinal manifestation in CD. UC, ulcerative colitis; CD, Crohn’s disease.

Fig. 3.

Treatment duration determinants for ACT. Experienced physicians favored time-oriented approach for ACT, especially limiting within 6 months use. On the other hand, more inexperienced physicians preferred goal-oriented approach. UC, ulcerative colitis; CD, Crohn’s disease; ACT, advanced combined therapies.

Fig. 4.

Adverse events for ACT. Among ACT usage, the reported frequency of adverse events was 40.5%. Infection is the most common adverse events, followed by worsening of IBD. IBD, inflammatory bowel disease; ACT, advanced combined therapies.

Fig. 5.

Advanced combined therapies strategies. Add-on strategies were the most adopted, followed by concomitant, then sequential usages for UC, CD, and among inexperienced physicians. UC, ulcerative colitis; CD, Crohn’s disease.

Table 1.

Advanced Combined Therapy Strategies and Medication Selections

	Ulcerative colitis		Crohn’s disease		Inexperienced
	Medication	No. (%)	Medication	No. (%)	Medication	No. (%)
Add-on
1st	Anti-integrin → Anti-integrin + JAKi	41 (18.6)	Anti-IL12/23 → Anti-IL12/23 + Anti-TNFα	24 (14.0)	Anti-TNFα → Anti-TNFα + Anti-integrin	46 (9.1)
2nd	Anti-IL12/23 → Anti-IL12/23 + JAKi	25 (11.4)	Anti-IL12/23 → Anti-IL12/23 + JAKi	21 (12.2)	Anti-integrin → Anti-integrin + Anti-IL12/23	39 (7.6)
3rd	Anti-integrin → Anti-integrin + Anti-TNFα	22 (10.0)	Anti-TNFα → Anti-TNFα + Anti-IL12/23	18 (10.5)	Anti-TNFα → Anti-TNFα + Anti-IL12/23	38 (7.5)
Concomitant
1st	Anti-integrin + JAKi	25 (21.7)	Anti-IL12/23 + Anti-TNFα	21 (23.1)	Anti-TNFα + anti-integrin	49 (14.1)
2nd	Anti-IL12/23 + Anti-TNFα	16 (13.9)	Anti-IL12/23 + Anti-integrin	15 (16.5)	Anti-IL12/23 + Anti-TNFα	48 (13.8)
	Anti-IL12/23 + JAKi
	Anti-TNFα + JAKi
3rd	Anti-integrin + Anti-TNFα	12 (10.4)	Anti-integrin + JAKi	14 (15.4)	Anti-integrin + JAKi	37 (10.7)
3rd	Anti-integrin + Anti-TNFα	12 (10.4)	Anti-integrin + JAKi	14 (15.4)	Anti-TNFα + JAKi	37 (10.7)
Sequential
1st	Anti-integrin + JAKi → Anti-integrin	11 (10.9)	Anti-IL12/23 + Anti-TNFα → Anti-IL12/23	13 (12.5)	Anti-TNFα + anti-integrin → anti-integrin	36 (9.5)
2nd	Anti-IL12/23 + JAKi → Anti-IL12/23	9 (8.9)	Anti-IL12/23 + Anti-integrin → Anti-IL12/23	11 (10.6)	Anti-IL12/23 + Anti-TNFα → Anti-IL12/23	29 (7.7)
2nd	Anti-integrin + JAKi → JAKi	9 (8.9)	Anti-IL12/23 + Anti-integrin → Anti-IL12/23	11 (10.6)	Anti-IL12/23 + Anti-TNFα → Anti-IL12/23	29 (7.7)
3rd	Anti-TNFα + JAKi → JAKi	8 (7.9)	Anti-IL12/23 + JAKi → Anti-IL12/23	9 (8.7)	Anti-integrin + JAKi → JAKi	26 (6.9)
3rd	Anti-IL12/23 + Anti-integrin → Anti-IL12/23	8 (7.9)	Anti-IL12/23 + JAKi → JAKi	9 (8.7)	Anti-integrin + JAKi → JAKi	26 (6.9)

JAKi, Janus kinase inhibitor; anti-IL12/23, anti-interleukin 12/23; anti-TNFα, anti-tumor necrosis factor alpha.

Table 2.

Comparisons for Asian and Non-Asians Physicians on ACT Approaches

	Asian (n=93)	Non-Asians (n=28)	P-value
ACT strategies, UC
Add-on	58 (62.4)	24 (85.7)	0.037
Time-oriented	34 (58.6)	6 (25.0)	0.008^a
Goal-oriented	22 (37.9)	14 (58.3)
Cost-oriented	2 (3.5)	4 (16.7)
Concomitant	38 (40.9)	15 (53.6)	0.331
Time-oriented	29 (76.3)	7 (46.7)	0.114^a
Goal-oriented	8 (21.1)	7 (46.7)
Cost-oriented	1 (2.6)	1 (6.7)
Sequential	18 (19.4)	16 (57.1)	<0.001
Time-oriented	11 (61.1)	7 (43.8)	0.398^a
Goal-oriented	7 (38.9)	8 (50.0)
Cost-oriented	0	1 (6.3)
ACT strategies, CD
Add-on	39 (41.9)	19 (67.9)	0.028
Time-oriented	20 (51.3)	4 (21.1)	0.009^a
Goal-oriented	19 (48.7)	12 (63.2)
Cost-oriented	0	3 (15.8)
Concomitant	29 (31.2)	10 (35.7)	0.827
Time-oriented	20 (69.0)	4 (40.0)	0.213^a
Goal-oriented	9 (31.0)	6 (60.0)
Cost-oriented	0	0	NA^b
Sequential	12 (12.9)	12 (42.9)	0.001
Time-oriented	8 (66.7)	3 (25.0)	0.100^a
Goal-oriented	4 (33.3)	8 (66.7)
Cost-oriented	0	1 (8.3)

Values are presented as number (%).

^a P-values represent comparisons of the time-, goal-, and cost-oriented distributions within each ACT strategy.

^b Both Asians and non-Asian physicians were not cost-oriented while applying concomitant ACT for CD. Chi-square test was invalid in this situation and therefore, only time- and goal-oriented approaches were compared.

ACT, advanced combined therapies; UC, ulcerative colitis; CD, Crohn’s disease; NA, not available.

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Real-world use and perceptions of advanced combined therapies in treating inflammatory bowel disease

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Real-world use and perceptions of advanced combined therapies in treating inflammatory bowel disease

Fig. 1. The geographical distribution and the experiences of the physicians. The participating physicians were Asian predominant. ACT experiences of the responders varied across countries. ACT, advanced combined therapies.

Fig. 2. Indications for advanced combined therapies. Refractory disease is the most common indication for both UC and CD. It was followed by acute severe UC and extraintestinal manifestation in CD. UC, ulcerative colitis; CD, Crohn’s disease.

Fig. 3. Treatment duration determinants for ACT. Experienced physicians favored time-oriented approach for ACT, especially limiting within 6 months use. On the other hand, more inexperienced physicians preferred goal-oriented approach. UC, ulcerative colitis; CD, Crohn’s disease; ACT, advanced combined therapies.

Fig. 4. Adverse events for ACT. Among ACT usage, the reported frequency of adverse events was 40.5%. Infection is the most common adverse events, followed by worsening of IBD. IBD, inflammatory bowel disease; ACT, advanced combined therapies.

Fig. 5. Advanced combined therapies strategies. Add-on strategies were the most adopted, followed by concomitant, then sequential usages for UC, CD, and among inexperienced physicians. UC, ulcerative colitis; CD, Crohn’s disease.

Graphical abstract

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Graphical abstract

Real-world use and perceptions of advanced combined therapies in treating inflammatory bowel disease

	Ulcerative colitis		Crohn’s disease		Inexperienced
	Medication	No. (%)	Medication	No. (%)	Medication	No. (%)
Add-on
1st	Anti-integrin → Anti-integrin + JAKi	41 (18.6)	Anti-IL12/23 → Anti-IL12/23 + Anti-TNFα	24 (14.0)	Anti-TNFα → Anti-TNFα + Anti-integrin	46 (9.1)
2nd	Anti-IL12/23 → Anti-IL12/23 + JAKi	25 (11.4)	Anti-IL12/23 → Anti-IL12/23 + JAKi	21 (12.2)	Anti-integrin → Anti-integrin + Anti-IL12/23	39 (7.6)
3rd	Anti-integrin → Anti-integrin + Anti-TNFα	22 (10.0)	Anti-TNFα → Anti-TNFα + Anti-IL12/23	18 (10.5)	Anti-TNFα → Anti-TNFα + Anti-IL12/23	38 (7.5)
Concomitant
1st	Anti-integrin + JAKi	25 (21.7)	Anti-IL12/23 + Anti-TNFα	21 (23.1)	Anti-TNFα + anti-integrin	49 (14.1)
2nd	Anti-IL12/23 + Anti-TNFα	16 (13.9)	Anti-IL12/23 + Anti-integrin	15 (16.5)	Anti-IL12/23 + Anti-TNFα	48 (13.8)
	Anti-IL12/23 + JAKi
	Anti-TNFα + JAKi
3rd	Anti-integrin + Anti-TNFα	12 (10.4)	Anti-integrin + JAKi	14 (15.4)	Anti-integrin + JAKi	37 (10.7)
3rd	Anti-integrin + Anti-TNFα	12 (10.4)	Anti-integrin + JAKi	14 (15.4)	Anti-TNFα + JAKi	37 (10.7)
Sequential
1st	Anti-integrin + JAKi → Anti-integrin	11 (10.9)	Anti-IL12/23 + Anti-TNFα → Anti-IL12/23	13 (12.5)	Anti-TNFα + anti-integrin → anti-integrin	36 (9.5)
2nd	Anti-IL12/23 + JAKi → Anti-IL12/23	9 (8.9)	Anti-IL12/23 + Anti-integrin → Anti-IL12/23	11 (10.6)	Anti-IL12/23 + Anti-TNFα → Anti-IL12/23	29 (7.7)
2nd	Anti-integrin + JAKi → JAKi	9 (8.9)	Anti-IL12/23 + Anti-integrin → Anti-IL12/23	11 (10.6)	Anti-IL12/23 + Anti-TNFα → Anti-IL12/23	29 (7.7)
3rd	Anti-TNFα + JAKi → JAKi	8 (7.9)	Anti-IL12/23 + JAKi → Anti-IL12/23	9 (8.7)	Anti-integrin + JAKi → JAKi	26 (6.9)
3rd	Anti-IL12/23 + Anti-integrin → Anti-IL12/23	8 (7.9)	Anti-IL12/23 + JAKi → JAKi	9 (8.7)	Anti-integrin + JAKi → JAKi	26 (6.9)

	Asian (n=93)	Non-Asians (n=28)	P-value
ACT strategies, UC
Add-on	58 (62.4)	24 (85.7)	0.037
Time-oriented	34 (58.6)	6 (25.0)	0.008^a
Goal-oriented	22 (37.9)	14 (58.3)
Cost-oriented	2 (3.5)	4 (16.7)
Concomitant	38 (40.9)	15 (53.6)	0.331
Time-oriented	29 (76.3)	7 (46.7)	0.114^a
Goal-oriented	8 (21.1)	7 (46.7)
Cost-oriented	1 (2.6)	1 (6.7)
Sequential	18 (19.4)	16 (57.1)	<0.001
Time-oriented	11 (61.1)	7 (43.8)	0.398^a
Goal-oriented	7 (38.9)	8 (50.0)
Cost-oriented	0	1 (6.3)
ACT strategies, CD
Add-on	39 (41.9)	19 (67.9)	0.028
Time-oriented	20 (51.3)	4 (21.1)	0.009^a
Goal-oriented	19 (48.7)	12 (63.2)
Cost-oriented	0	3 (15.8)
Concomitant	29 (31.2)	10 (35.7)	0.827
Time-oriented	20 (69.0)	4 (40.0)	0.213^a
Goal-oriented	9 (31.0)	6 (60.0)
Cost-oriented	0	0	NA^b
Sequential	12 (12.9)	12 (42.9)	0.001
Time-oriented	8 (66.7)	3 (25.0)	0.100^a
Goal-oriented	4 (33.3)	8 (66.7)
Cost-oriented	0	1 (8.3)

Table 1. Advanced Combined Therapy Strategies and Medication Selections

JAKi, Janus kinase inhibitor; anti-IL12/23, anti-interleukin 12/23; anti-TNFα, anti-tumor necrosis factor alpha.

Table 2. Comparisons for Asian and Non-Asians Physicians on ACT Approaches

Values are presented as number (%).

P-values represent comparisons of the time-, goal-, and cost-oriented distributions within each ACT strategy.

Both Asians and non-Asian physicians were not cost-oriented while applying concomitant ACT for CD. Chi-square test was invalid in this situation and therefore, only time- and goal-oriented approaches were compared.

ACT, advanced combined therapies; UC, ulcerative colitis; CD, Crohn’s disease; NA, not available.