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Comparative real-world outcomes between ustekinumab, infliximab, and adalimumab in bio-naïve and bio-experienced Crohn’s disease patients: a retrospective multicenter study

BMC Gastroenterology volume 24, Article number: 306 (2024) Cite this article

Abstract

Background

Numerous studies have compared the efficacy of ustekinumab (UST) and anti-TNF agents [infliximab (IFX) or adalimumab(ADA)] in moderate to severe Crohn’s disease (CD) patients. This study aims to compare the efficacy of UST, IFX, and ADA while differentiating between bio-naïve and bio-experienced patients, which is an underexplored aspect, particularly in Asia.

Methods

We conducted a retrospective multi-center study from 2012 to 2023, categorizing patients into bio-naïve and bio-experienced groups. We evaluated clinical remission rates after induction therapy and clinical outcomes, including CD-related hospitalization, intestinal resection, and drug discontinuation during maintenance therapy.

Results

Among the 214 bio-naïve CD patients, 60 received UST, 108 received IFX, and 46 received ADA. After 1:1 propensity score matching between UST and anti-TNF agents groups, 59 patients were analyzed in each group (45 in the IFX group and 14 in the ADA group). We found no significant differences in clinical remission rates (P = 0.071), CD-related hospitalization (P = 0.800), intestinal resection (P = 0.390), or drug discontinuation (P = 0.052) between the UST, IFX, and ADA groups in bio-naïve CD patients. In bio-experienced CD patients, with 35 in the UST group and 13 in the anti-TNF agents group, the UST group showed a lower risk of drug discontinuation (P = 0.004) than the anti-TNF agents group.

Conclusions

This study suggests that UST, IFX, and ADA are equally effective in bio-naïve CD patients, while in bio-experienced patients, mostly with previous exposure to anti-TNF agents, UST may offer superior drug durability.

Peer Review reports

Introduction

In patients with moderate to severe Crohn’s disease (CD), anti-tumor necrosis factor (TNF) agents, such as infliximab (IFX) and adalimumab (ADA), have been reported to have a high clinical response rate at four weeks, reaching up to 81%. However, the clinical remission rate at approximately one year falls short of 40% [1, 2]. Additionally, the discontinuation of anti-TNF agents due to the loss of response is reported to occur in about 10% per patient-year follow-up [3, 4]. In the case of ustekinumab (UST), a clinical trial reported a clinical response rate of 34% at week 6, with a clinical remission rate of approximately 53% at week 44 [5]. Clinical trials comparing the efficacy of anti-TNF agents and UST in bio-naïve CD patients showed no significant difference in clinical response rates at week 6 (44.9% for IFX and 37.9% for UST) [6]. Similarly, clinical remission rates at week 52 for adalimumab (ADA) and UST were 61% and 65%, respectively, with no significant differences [7]. A recent network meta-analysis comparing anti-TNF agents and UST in bio-naïve and experienced CD patients did not show significant differences in clinical remission after induction and during maintenance [8].

A recent retrospective study comparing the efficacy of IFX and UST in bio-naïve CD patients reported clinical response rates at 3 months of 86% for infliximab and 64% for UST, indicating superior results for IFX. However, the drug persistency showed no significant difference between IFX and UST [9]. Another retrospective study comparing ADA and UST in bio-naïve CD patients revealed that the clinical remission rate and drug persistency at 56 weeks showed no significant differences [10]. For bio-experienced CD patients, clinical remission rates after induction therapy were 60.6% for anti-TNF agents and 58.8% for UST, without significant difference [11].

So far, limited studies in Asia have compared the efficacy and clinical outcomes of UST and anti-TNF agents in both bio-naïve and experienced CD patients [12]. To address this gap, we have planned a multi-center study using propensity score matching to compare the efficacy and clinical outcomes between UST, IFX, and ADA.

Methods

Patients

This retrospective cohort study was conducted at three referral centers and included adult patients aged 18 or older with moderate-to-severe CD who had been receiving UST, IFX, or ADA and could be tracked for a minimum of three months from January 2012 to July 2023. Patients were categorized into two subgroups: bio-naïve and bio-experienced. The bio-experienced group consisted of patients who had previously received anti-TNF agents, UST, or vedolizumab before initiating UST or anti-TNF agents. This study was conducted according to the guidelines of the Declaration of Helsinki. The Institutional Review Board of Inje University Haeundae Paik Hospital approved our protocol (File number. 2023-04-012-003). Patients’ informed consent requirement was waived because only de-identified data were collected.

Outcomes and assessment

The primary outcome was to compare the efficacy between UST, IFX, and ADA in terms of clinical remission after induction therapy and to assess the occurrence of CD-related hospitalization, intestinal resection, and drug discontinuation during maintenance therapy in both bio-naïve and bio-experienced patient groups. Clinical remission was defined as a Crohn’s Disease Activity Index (CDAI) score of less than 150 during the response evaluation after induction therapy. The secondary outcome was identifying factors associated with CD-related hospitalization, intestinal resection, and drug discontinuation.

The index date was when the patient initiated the first, second, or subsequent biological therapy. Separate definitions were applied for bio-naïve patients and bio-experienced patients. The schedule for induction and maintenance therapy, as well as the assessment of response after induction therapy, was as follows: (1) UST: administered intravenously at week 0, with the dose adjusted based on body weight (260 mg for ≤ 55 kg, 390 mg for > 55 kg to ≤ 85 kg, or 520 mg for > 85 kg), followed by subcutaneous UST 90 mg at week 8, and then maintained every 12 weeks. The response evaluation after induction therapy was performed before the 3rd dose; (2) IFX: administered intravenously at a quantity of 5 mg/kg at weeks 0, 2, and 6, followed by every eight weeks. The response evaluation after induction therapy was performed before the 2nd dose; (3) ADA: administered subcutaneously with an initial dose of 160 mg at week 0, followed by 80 mg at week 2, and then 40 mg every 2 weeks. The response evaluation after induction therapy was performed before the 3rd dose. In South Korea, based on insurance policies, the maintenance therapy for each biological therapy is determined according to the clinical response assessed using the Crohn’s Disease Activity Index (CDAI) before and after induction therapy. Therefore, the evaluation of CDAI before and after induction therapy is mandatory and can be obtained from the medical records. Dose intensification for all biologics was possible at the discretion of the physicians. The patients included in the study were followed up until the date of the last biological therapy or the last outpatient visit.

Covariates

We retrospectively gathered data from medical records, including the following variables: gender, age at diagnosis, age at starting biological therapy, disease duration, location, behavior, perianal disease, history of intestinal resection, CDAI before and after biological therapy, concomitant treatments [5-aminosalicylic acid (5-ASA), steroids, immunomodulators], laboratory data [c-reactive protein (CRP), hemoglobin, albumin], and the duration of follow-up.

Statistical analysis

Continuous variables were presented as mean ± standard deviation and compared using a one-way analysis of variance or the Kruskal-Wallis test. Categorical variables were expressed as n (%) and compared using the chi-squared or Fisher’s exact test. The comparison between UST, IFX, and ADA involved multiple comparisons, and we applied Bonferroni’s method. In this context, we considered P values less than 0.0167 statistically significant.

For the comparison between UST and anti-TNF agents, we utilized propensity score matching with a 1:1 ratio using the MatchIt package in the R program [13], employing optimal matching. The matching variables were determined based on differences observed in baseline characteristics between the UST and anti-TNF agents groups. To analyze primary outcomes, including the rate and cumulative survival of clinical remission after induction therapy, CD-related hospitalization, intestinal resection, and drug discontinuation among the three groups (UST, IFX, and ADA), we used the chi-squared or Fisher’s exact test, as well as Kaplan-Meier survival curves. To identify the factors associated with each clinical outcome, Cox proportional hazard analysis was employed. In the multivariate analysis, only the factors with a P value < 0.05 in the univariate analysis were included. A P value < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS Statistics 25.0 and R-4.2.2.

Result

Baseline characteristics

In this study, a total of 214 bio-naïve CD patients and 48 bio-experienced CD patients were included. All patients received UST, IFX, and ADA at standard dosages. Among the 214 bio-naïve CD patients, 60 received UST, 108 received IFX, and 46 received ADA (Table 1). The age at diagnosis and the age at the first biological therapy were higher in the UST, with mean ages of 29 years and 35 years, respectively, compared to 26 years and 30 years for IFX and 24 years and 28 years for ADA. There were no significant differences in disease duration, location, behavior, perianal disease, or history of intestinal resection among the groups. The CDAI before starting biological therapy was higher in the UST group, with a mean of 288.6, compared to 276.8 for IFX and 273.2 for ADA. Approximately half of the patients in all three groups were on steroid therapy, and about 85% were concurrently taking immunomodulators. The CRP values were lower in the UST group, with a mean of 1.8 mg/dL, compared to 3.2 mg/dL for IFX and 3.1 mg/dL for ADA. Albumin levels were higher in the UST group, with a mean of 4.1 g/dL, compared to 3.8 g/dL for IFX and 3.7 g/dL for ADA.

Table 1 Baseline characteristics of the bio-naïve Crohn’s disease patients
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After performing 1:1 propensity score matching for variables showing differences between the UST and the anti-TNF agents groups, including gender, age at diagnosis, age at first biological therapy, CDAI, CRP, and albumin, 59 patients were selected for each group, with 45 patients in the IFX group and 14 patients in the ADA group (Table 2). Following propensity score matching, no statistically significant differences existed in any of the variables between the UST, IFX, and ADA groups, except for the follow-up duration.

Table 2 Baseline characteristics of the bio-naïve Crohn’s disease patients after propensity score matching
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Among the bio-experienced CD patients, there were 35 patients in the UST group and 13 patients in the anti-TNF agents group (Table 3). Since no significant differences were observed in variables between the two groups, propensity score matching was not conducted. The disease duration for bio-experienced CD patients in each group had a relatively long mean period of 7.8 and 7.6 years, respectively. The history of intestinal resection was observed at rates of 25.7% for the UST group and 38.5% for the anti-TNF agents group. The co-administration rate of immunomodulators was 45.7% and 38.5% in the respective groups.

Table 3 Baseline characteristics of the bio-experienced Crohn’s disease patients
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Clinical outcomes of bio-naïve patients after propensity score matching

In bio-naïve CD patients after propensity score matching, the rates of clinical remission after induction therapy in the UST, IFX, and ADA groups were 55 (93.2%) of 59, 39 (86.7%) of 45, and 10 (71.4%) of 14, respectively, showing no statistically significant differences (Table 4). For CD-related hospitalization during the maintenance period, the rates in the UST, IFX, and ADA groups were 8 (13.6%) of 59, 6 (13.3%) of 45, and 1 (7.1%) of 14, respectively. Intestinal resection rates were 1 (1.7%) of 59, 3 (6.7%) of 45, and 1 (7.1%) of 14, respectively, and drug discontinuation rates were 1 (1.7%) of 59, 6 (13.3%) of 45, and 2 of 14 (14.3%), respectively, with no statistically significant differences observed. When comparing cumulative survivals, CD-related hospitalization, intestinal resection, and drug discontinuation showed no significant differences among the three groups (Fig. 1).

Table 4 Major clinical outcome rates after induction and maintenance therapy of ustekinumab and anti-tumor necrosis factor agents after propensity score matching only in bio-naïve patients
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Fig. 1
figure 1

Clinical outcomes during maintenance therapy in bio-naïve Crohn’s disease patients after propensity score matching. A CD-related hospitalization, B Intestinal resection, C Drug discontinuation

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Clinical outcomes of bio-experienced patients

Among bio-experienced CD patients, the rates of clinical remission after induction therapy in the UST and anti-TNF agents groups were 27 (77.1%) of 35 and 10 (one missing value, 83.3%) of 12, respectively, showing no statistically significant difference (Table 4). For CD-related hospitalization during the maintenance period, the rates in the UST and anti-TNF agents groups were 12 (34.3%) of 35 and 4 (30.8%) of 13, respectively. Intestinal resection rates were 6 (17.1%) of 35 in the UST group and 2 (15.4%) of 13 in the anti-TNF agents group, with no statistically significant difference. However, drug discontinuation was significantly higher in the anti-TNF agents group, with 7 (53.8%) of 13 compared to 4 (11.4%) of 35 in the UST group. The cumulative survival of CD-related hospitalization and intestinal resection showed no significant difference between the UST and anti-TNF agents groups (Fig. 2). However, the cumulative risk of drug discontinuation was higher in the anti-TNF agents group compared to the UST group.

Fig. 2
figure 2

Clinical outcomes during maintenance therapy in bio-experienced Crohn’s disease patients. A CD-related hospitalization, B Intestinal resection, C Drug discontinuation

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Associating factors with clinical outcomes

Among the 262 CD patients, seven patients with missing values in CDAI before biological therapy were omitted (Table 5). Risk factors for experiencing CD-related hospitalization were determined for 54 of 255 patients. Bio-experienced CD patients were found to be at a higher risk compared to bio-naïve CD patients [hazard ratio (HR) 2.43; 95% confidence interval (CI) 1.32–4.48]. Female patients were at a higher risk than male patients (HR 1.87, 95% CI 1.02–3.41). Patients taking steroids concurrently were also at a higher risk (HR 2.32, 95% CI 1.30–4.13), while those with lower albumin levels were at a higher risk (HR 0.59, 95% CI 0.35–0.99).

For intestinal resection, which occurred in 18 of 255 patients, multivariate analysis identified bio-experienced CD patients as the only significant risk factor (HR 6.30, 95% CI 2.09–18.99).

Regarding drug discontinuation, which occurred in 49 of 255 patients, it was found to be more likely in patients receiving IFX (HR 2.67, 95% CI 1.00-7.12) or ADA (HR 3.75, 95% CI 1.37–10.22) compared to UST. Conversely, the concurrent use of immunomodulators (HR 0.54, 95% CI 0.29–0.98) and higher albumin levels (HR 0.50, 95% CI 0.33–0.77) were identified as protective factors.

Table 5 Risk factors associated with clinical outcomes in Crohn’s disease patients
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Discussion

This study conducted a comparative analysis of the effectiveness of UST, IFX, and ADA, stratifying patients into bio-naïve and bio-experienced groups based on real-world data. In bio-naïve CD patients, following propensity score matching, UST, IFX, and ADA demonstrated similar outcomes regarding clinical remission after induction therapy and clinical prognosis during maintenance therapy, encompassing CD-related hospitalization, intestinal resection, and drug discontinuation. Among bio-experienced patients, no significant differences were observed between UST and anti-TNF agents concerning clinical remission after induction therapy, CD-related hospitalization, and intestinal resection. However, there was a higher risk of drug discontinuation in the anti-TNF agent group compared to the UST group. When considering all patients, including bio-naïve and bio-experienced CD patients, the risk of drug discontinuation was higher in IFX and ADA compared to UST in multivariate analysis. In summary, in bio-naïve patients, UST, IFX, and ADA demonstrated equivalent efficacy. In bio-experienced patients, UST may offer superior durability compared to anti-TNF agents. Nevertheless, it is essential to note that most bio-experienced patients included in this study had prior exposure to anti-TNF agents, which should be considered when interpreting these results.

Previous clinical trials and meta-analyses that compared the efficacy of UST, IFX, and ADA in moderate to severe CD patients found no significant differences in clinical remission rates in both bio-naïve and bio-experienced groups [7, 8, 11, 14]. Ideally, conducting clinical trials to compare the long-term outcomes of these biologics would offer the highest level of reliability. However, in practice, there are challenges in conducting such trials to assess the long-term effectiveness of these treatments. Consequently, numerous retrospective studies have been undertaken to compare the efficacy of UST, IFX, and ADA. Among these studies, our research is distinctive. It is the first to differentiate between bio-naïve and experienced patients and includes all three biologics (UST, IFX, and ADA) to assess crucial clinical outcomes. Furthermore, the significance of our study is emphasized by the provision of real-world data, particularly in Asia, where such data is limited [12, 15, 16].

Summarizing the results of previous retrospective studies using real-world data, it was observed that in bio-naïve CD patients, anti-TNF agents exhibited higher clinical remission rates after induction therapy than UST [9, 10]. However, in terms of treatment persistence, the findings have been mixed. Some studies found no significant differences in treatment persistence between anti-TNF agents and UST in bio-naïve patients [9, 10, 15], while others reported UST as superior in this regard [12, 17]. In bio-experienced patients, primarily exposed to anti-TNF agents, UST has generally demonstrated better treatment persistence compared to anti-TNF agents [12, 16, 17], as well as vedolizumab [18,19,20]. Conversely, one study reported lower treatment persistence with UST than anti-TNF agents and vedolizumab in bio-experienced CD patients. However, it should be noted that this study did not conduct matching to account for differing baseline characteristics, which may limit the interpretation of the results due to potential bias [21]. Similarly, after completing propensity score matching, our study found no significant differences in clinical remission after induction therapy and clinical events during the maintenance period in bio-naïve CD patients, aligning with the comparable efficacy indicated in previous studies. However, for bio-experienced CD patients, most of whom had been exposed to anti-TNF agents, UST might be superior in drug persistence, depending on the reasons for discontinuing anti-TNF agents.

In the multivariate analysis, we found that the risk of drug discontinuation was higher for IFX and ADA compared to UST. This observation may be attributed to the retrospective nature of our study, which resulted in variations in follow-up duration between the UST and anti-TNF agent groups. Additionally, factors related to the initial choice of these treatments and the reasons for discontinuing anti-TNF agents likely influenced these results. Therefore, when interpreting the results of this study as a whole, it can be inferred that UST, blocking interleukin (IL)-12 and IL-23, may be a beneficial option for CD patients who do not respond to anti-TNF agents. This interpretation is supported by mechanistic evidence indicating an increase in IL23-positive T cells in CD patients who do not respond to anti-TNF agents [22]. This aligns with the treatment sequence previously suggested for CD patients who have failed anti-TNF agents, as supported by various studies [19, 20, 23, 24]. In our study, the concurrent use of immunomodulators was found to be a factor that reduces the risk of drug discontinuation. Recommendations regarding combination therapy for CD patients vary in recent guidelines, but some commonalities exist. Most guidelines recommend combination therapy during induction in bio-naïve CD patients treated with anti-TNF agents [25, 26] or IFX [27, 28]. For UST, the benefits of combination therapy have not been established [29,30,31,32]. When it comes to maintaining remission, the recommendations are somewhat limited. Nonetheless, one guideline suggests combination therapy with anti-TNF agents, particularly IFX [25], which is supported by meta-analysis [33]. It is important to note that combination therapy with anti-TNF agents has been associated with lower immunogenicity [34, 35], suggesting that combination therapy may benefit patients receiving it from a mechanical perspective. Notably, we observed that the proportion of patients receiving combination therapy in bio-experienced CD patients was approximately 40%, while it was around 85% in bio-naïve patients. This rate difference in the use of combination therapy between these two groups highlights the need for further research on the role of combination therapy in maintaining remission for both categories of patients.

This study has several limitations, primarily due to its retrospective nature. Firstly, it cannot eliminate the potential for selection bias. However, we attempted to mitigate this limitation by employing propensity score matching to ensure that variables were as similar as possible at baseline. This approach helps reduce the potential for bias when interpreting results in the bio-naïve group. Secondly, despite data being collected from three different institutions, the number of enrolled patients was similar to that in other studies. Particularly in the case of the bio-experienced CD patients, a comparison had to be made between UST and anti-TNF agents due to the small number. Thirdly, in bio-experienced CD patients, we could not compare clinical outcomes based on the types of prior biologics and reasons for discontinuation due to the lack of this information. Additionally, differences in follow-up duration between the UST and anti-TNF agent groups should be considered when interpreting the results, as these variations could influence the observed outcomes, where UST demonstrated superiority in drug persistency over anti-TNF agents in bio-experienced CD patients. Fourthly, information regarding treatment targets such as fecal calprotectin or endoscopic healing was lacking, preventing comparison on the effectiveness of different biologics based on these parameters. These limitations should be acknowledged when interpreting the study findings.

In conclusion, in bio-naïve CD patients, there was no observed difference in efficacy between UST, IFX, and ADA after propensity score matching. However, in bio-experienced CD patients, most of whom were exposed to anti-TNF agents, UST may have an advantage regarding drug durability depending on the reason for drug discontinuation. Further refined studies with long-term follow-up are warranted to address this issue.

Availability of data and materials

Data are available from the corresponding author upon reasonable request.

References

  1. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, Schreiber S, Byczkowski D, Li J, Kent JD, Pollack PF. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132(1):52–65.

    Article  CAS  PubMed  Google Scholar 

  2. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet (London, England). 2002;359(9317):1541–9.

    Article  CAS  PubMed  Google Scholar 

  3. Schultheiss JPD, Mahmoud R, Louwers JM, van der Kaaij MT, van Hellemondt BP, van Boeckel PG, Mahmmod N, Jharap B, Fidder HH, Oldenburg B. Loss of response to anti-TNFα agents depends on treatment duration in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2021;54(10):1298–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Otake H, Matsumoto S, Mashima H. Long-term clinical and real-world experience with Crohn’s disease treated with anti-tumor necrosis factor-α antibodies. Intestinal research. 2022;20(4):464–74.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, Blank MA, Johanns J, Gao LL, Miao Y, et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016;375(20):1946–60.

    Article  CAS  PubMed  Google Scholar 

  6. Wong ECL, Dulai PS, Marshall JK, Jairath V, Reinisch W, Narula N. Comparative Efficacy of Infliximab vs Ustekinumab for Maintenance of Clinical Response in Biologic Naïve Crohn’s Disease. Inflamm Bowel Dis. 2023;29(7):1015–23.

    Article  PubMed  Google Scholar 

  7. Sands BE, Irving PM, Hoops T, Izanec JL, Gao LL, Gasink C, Greenspan A, Allez M, Danese S, Hanauer SB, et al. Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn’s disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial. Lancet (London, England). 2022;399(10342):2200–11.

    Article  CAS  PubMed  Google Scholar 

  8. Singh S, Murad MH, Fumery M, Sedano R, Jairath V, Panaccione R, Sandborn WJ, Ma C. Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn’s disease: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(12):1002–14.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Rivière P, Kanters C, Pellet G, Ni A, Hupé M, Aboulhamid N, Poullenot F, Bitton A, Zerbib F, Lakatos PL, et al. Comparative Effectiveness of Ustekinumab and Anti-TNF Agent as First-Line Biological Therapy in Luminal Crohn’s Disease: A Retrospective Study From 2 Referral Centers. Inflamm Bowel Dis. 2023;29(6):923–31.

    Article  PubMed  Google Scholar 

  10. Moens A, Alsoud D, Verstockt B, Sabino J, Ferrante M, Vermeire S. Adalimumab versus ustekinumab as first-line biological in moderate-to-severe Crohn’s disease: real-life cohort from a tertiary referral center. Eur J Gastroenterol Hepatol. 2022;34(10):1015–20.

    Article  CAS  PubMed  Google Scholar 

  11. Bokemeyer B, Plachta-Danielzik S, di Giuseppe R, Mohl W, Teich N, Hoffstadt M, Schweitzer A, von der Ohe M, Gauss A, Atreya R, et al. Real-world Comparative Effectiveness of Ustekinumab vs Anti-TNF in Crohn’s Disease With Propensity Score Adjustment: Induction Phase Results From the Prospective. Inflammatory bowel diseases: Observational RUN-CD Study; 2023.

    Google Scholar 

  12. Seo GH, Jung SH. Comparison of the Persistence of Anti-TNF Agents and Ustekinumab in Patients with Crohn's Disease: A Study Based on the Korean National Database. J Clin Med. 2023;12(6):2397. https://doi.org/10.3390/jcm12062397.

  13. Ho D, Imai K, King G, Stuart EA. MatchIt: Nonparametric Preprocessing for Parametric Causal Inference. J Stat Softw. 2011;42(8):1–28.

    Article  Google Scholar 

  14. Narula N, Wong ECL, Dulai PS, Sengupta NK, Marshall JK, Colombel JF, Reinisch W. Comparative Efficacy and Rapidity of Action for Infliximab vs Ustekinumab in Biologic Naïve Crohn’s Disease. Clin Gastroenterol Hepatol. 2022;20(7):1579-1587.e1572.

    Article  CAS  PubMed  Google Scholar 

  15. Shiga H, Tarasawa K, Moroi R, Makuuchi M, Takahashi T, Shimoyama Y, Kuroha M, Kakuta Y, Fushimi K, Fujimori K, et al. Long-term effectiveness of ustekinumab comparable to antitumor necrosis factor agents in patients with Crohn’s disease. J Gastroenterol Hepatol. 2022;37(11):2105–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Koo HM, Jun YK, Choi Y, Shin CM, Park YS, Kim N, Lee DH, Shin YK, Yoon H. 10 years of biologic use patterns in patients with inflammatory bowel disease: treatment persistence, switching and dose intensification – a nationwide population-based study. Therap Adv Gastroenterol. 2023;16:17562848231201728. https://doi.org/10.1177/17562848231201728.

  17. Ko Y, Paramsothy S, Yau Y, Leong RW. Superior treatment persistence with ustekinumab in Crohn’s disease and vedolizumab in ulcerative colitis compared with anti-TNF biological agents: real-world registry data from the Persistence Australian National IBD Cohort (PANIC) study. Aliment Pharmacol Ther. 2021;54(3):292–301.

    Article  CAS  PubMed  Google Scholar 

  18. Bacsur P, Matuz M, Resál T, Miheller P, Szamosi T, Schäfer E, Sarlós P, Iliás Á, Szántó K, Rutka M, et al. Ustekinumab is associated with superior treatment persistence but not with higher remission rates versus vedolizumab in patients with refractory Crohn’s disease: results from a multicentre cohort study. Therap Adv Gastroenterol. 2022;15:17562848221144348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Townsend T, Razanskaite V, Dodd S, Storey D, Michail S, Morgan J, Davies M, Penman D, Watters C, Swaminathan M, et al. Comparative effectiveness of ustekinumab or vedolizumab after one year in 130 patients with anti-TNF-refractory Crohn’s disease. Aliment Pharmacol Ther. 2020;52(8):1341–52.

    Article  CAS  PubMed  Google Scholar 

  20. Alric H, Amiot A, Kirchgesner J, Tréton X, Allez M, Bouhnik Y, Beaugerie L, Carbonnel F, Meyer A. The effectiveness of either ustekinumab or vedolizumab in 239 patients with Crohn’s disease refractory to anti-tumour necrosis factor. Aliment Pharmacol Ther. 2020;51(10):948–57.

    Article  CAS  PubMed  Google Scholar 

  21. Rayer C, Nachury M, Bourreille A, Roblin X, Peyrin-Biroulet L, Viennot S, Flamant M, Laharie D, Caron B, Dewitte M, et al. Efficacy of ustekinumab, vedolizumab, or a second anti-TNF agent after the failure of a first anti-TNF agent in patients with Crohn’s disease: a multicentre retrospective study. BMC Gastroenterol. 2022;22(1):498.

    Article  PubMed  Google Scholar 

  22. Schmitt H, Billmeier U, Dieterich W, Rath T, Sonnewald S, Reid S, Hirschmann S, Hildner K, Waldner MJ, Mudter J, et al. Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn’s disease. Gut. 2019;68(5):814–28.

    Article  CAS  PubMed  Google Scholar 

  23. Bressler B. Is there an optimal sequence of biologic therapies for inflammatory bowel disease? Therap Adv Gastroenterol. 2023;16:17562848231159452.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Garcia NM, Cohen NA, Rubin DT. Treat-to-target and sequencing therapies in Crohn’s disease. United European Gastroenterol J. 2022;10(10):1121–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Feuerstein JD, Ho EY, Shmidt E, Singh H, Falck-Ytter Y, Sultan S, Terdiman JP. AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Disease. Gastroenterology. 2021;160(7):2496–508.

    Article  PubMed  Google Scholar 

  26. Koh SJ, Hong SN, Park SK, Ye BD, Kim KO, Shin JE, Yoon YS, Lee HS, Jung SH, Choi M, et al. Korean clinical practice guidelines on biologics for moderate to severe Crohn’s disease. Intestinal research. 2023;21(1):43–60.

    Article  PubMed  Google Scholar 

  27. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4):481–517.

    Article  PubMed  Google Scholar 

  28. Torres J, Bonovas S, Doherty G, Kucharzik T, Gisbert JP, Raine T, Adamina M, Armuzzi A, Bachmann O, Bager P, et al. ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment. J Crohns Colitis. 2020;14(1):4–22.

    Article  PubMed  Google Scholar 

  29. Hanauer SB, Sandborn WJ, Feagan BG, Gasink C, Jacobstein D, Zou B, Johanns J, Adedokun OJ, Sands BE, Rutgeerts P, et al. IM-UNITI: Three-year Efficacy, Safety, and Immunogenicity of Ustekinumab Treatment of Crohn’s Disease. J Crohns Colitis. 2020;14(1):23–32.

    Article  PubMed  Google Scholar 

  30. Battat R, Kopylov U, Bessissow T, Bitton A, Cohen A, Jain A, Martel M, Seidman E, Afif W. Association Between Ustekinumab Trough Concentrations and Clinical, Biomarker, and Endoscopic Outcomes in Patients With Crohn’s Disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2017;15(9):1427-1434.e1422.

    Article  CAS  PubMed  Google Scholar 

  31. Adedokun OJ, Xu Z, Gasink C, Jacobstein D, Szapary P, Johanns J, Gao LL, Davis HM, Hanauer SB, Feagan BG, et al. Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn’s Disease. Gastroenterology. 2018;154(6):1660–71.

    Article  CAS  PubMed  Google Scholar 

  32. Hashash JG, Fadel CGA, Rimmani HH, Sharara AI. Biologic monotherapy versus combination therapy with immunomodulators in the induction and maintenance of remission of Crohn’s disease and ulcerative colitis. Ann Gastroenterol. 2021;34(5):612–24.

    PubMed  PubMed Central  Google Scholar 

  33. Hazlewood GS, Rezaie A, Borman M, Panaccione R, Ghosh S, Seow CH, Kuenzig E, Tomlinson G, Siegel CA, Melmed GY, Kaplan GG. Comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in Crohn’s disease: a network meta-analysis. Gastroenterology. 2015;148(2):344-354.e345 quiz e314–345.

    Article  CAS  PubMed  Google Scholar 

  34. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D’Haens G, Diamond RH, Broussard DL, et al. Infliximab. Azathioprine, or Combination Therapy for Crohn’s Disease. 2010;362(15):1383–95.

    CAS  PubMed  Google Scholar 

  35. Chalhoub JM, Rimmani HH, Gumaste VV, Sharara AI. Systematic Review and Meta-analysis: Adalimumab Monotherapy Versus Combination Therapy with Immunomodulators for Induction and Maintenance of Remission and Response in Patients with Crohn’s Disease. Inflamm Bowel Dis. 2017;23(8):1316–27.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, South Korea

    Ji Eun Na, Yong Eun Park, Jongha Park & Tae-Oh Kim

  2. Department of Internal Medicine, Dong-A University College of Medicine, Busan, South Korea

    Jong Hoon Lee

  3. Department of Internal Medicine, Pusan National University School of Medicine and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea

    Su Bum Park

  4. Department of Gastroenterology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea

    Soyoung Kim & Seung Bum Lee

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Busan Ulsan Gyeongnam Intestinal Study Group Society (BIGS)

Contributions

Author contributionsStudy concept and design: Ji Eun Na. Tae-Oh Kim. Acquisition, analysis, or interpretation of data: Ji Eun Na, Su Bum Park, Soyoung Kim, Seung Bum Lee. Writing and Drafting of the manuscript: Ji Eun Na, Tae-Oh Kim. Critical revision of the manuscript for important intellectual content: Yong Eun Park, Jong Ha Park, Tae-Oh Kim, Jong Hoon Lee, Su Bum Park, Soyoung Kim, Seung Bum Lee. Statistical analysis: Ji Eun Na. All authors approved the final submission.

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Correspondence to Tae-Oh Kim.

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Ethics approval and consent to participate

This study was conducted according to the guidelines of the Declaration of Helsinki. The Institutional Review Board of Inje University Haeundae Paik Hospital approved our protocol (File number. 2023-04-012-003). Patients’ informed consent requirement was waived because only de-identified data were collected.

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Na, J.E., Park, Y.E., Park, J. et al. Comparative real-world outcomes between ustekinumab, infliximab, and adalimumab in bio-naïve and bio-experienced Crohn’s disease patients: a retrospective multicenter study. BMC Gastroenterol 24, 306 (2024). https://doi.org/10.1186/s12876-024-03403-8

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Keywords

BMC Gastroenterology

ISSN: 1471-230X

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