Dual-targeted Therapy for the Management of Refractory Crohn’s Disease: A Retrospective Cohort Study

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Dual-targeted therapy (DTT) has been proven effective and safe in refractory inflammatory bowel disease (IBD), especially the combination of ustekinumab with vedolizumab (UST+VDZ). However, the efficacy and safety of DTT on refractory CD are still limited or insufficient. Aims: We aim to evaluate the efficacy and safety of DTT including ustekinumab combined with adalimumab (UST+ADA) and UST + VDZ in refractory CD patients. Methods: Refractory CD patients who failed at least two biologics from Xijing IBD Center were included. Clinical evaluation was performed by Crohn's Disease Activity Index (CDAI). Endoscopic data were assessed using Simple Endoscopic Score-Crohn's Disease (SES-CD). Other clinical indicators were also collected. Results: Totally, 23 patients were enrolled, and 20 completed 4-27 months of follow-up. Among these patients, there were significant post-treatment reductions in median SES-CD [14.5 to 5 (p＜0.005)] and CDAI [326.25 to 94.75 (p＜0.005)]. For UST + ADA (n=16), 68.75% reached endoscopic response, 56.25% achieved endoscopic remission, 75% clinical response occurred and 68.75% of patients achieved clinical remission. For UST + VDZ (n=4), 25% had endoscopic response, 50% had clinical response, and one achieved clinical remission. The regime of UST + ADA exhibited a more favorable performance during follow-up. 7 patients discontinued DTT due to no significant improvement or exacerbation, and no severe adverse events were observed. Conclusion: The study supports the effectiveness and safety of ACT for refractory CD, especially UST + ADA. Larger sample and randomized controlled trial (RCT) studies are needed for confirmation. Refractory Crohn’s disease Dual-targeted therapy Adalimumab Ustekinumab Vedolizumab Endoscopy Figures Figure 1 Figure 2 Introduction Crohn's disease (CD), which belongs to inflammatory bowel disease (IBD), is a chronic inflammatory condition of the gastrointestinal system resulting from a dysregulated immune response and has seen an increasing global prevalence.( 1 , 2 ) It can affect any part of the gastrointestinal tract, with the terminal ileum and proximal colon being the most commonly involved areas.( 1 ) Additionally, 50% of patients will have stenosis, fistulas, and abscesses, and up to 50% may have extra-intestinal symptoms, most commonly in the joints, skin, and eyes.( 1 , 3 ) Traditional treatment options include aminosalicylates, corticosteroids, and immunomodulators.( 4 ) Effective biological agents include TNF-α antagonists (Infliximab, Adalimumab, Certolizumab pegol) and antibodies inhibiting IL-12/23 p40 subunit (Ustekinumab) and targeting leukocyte α4β7 integrins (Vedolizumab).( 5 ) Currently, biological therapies are widely used in patients with moderate to severe early-stage CD; however, the remission rates are only approximately 40% after one year.( 6 , 7 ) Additionally, a retrospective study indicated that patients who required surgery had a recurrence rate of nearly 50% within 10 years.( 8 ) With the emergence of newer biological agents targeting different molecular pathways and small-molecule drugs, the medical treatment options for CD have further expanded.( 9 ) Nevertheless, some patients still have persistent symptoms and disease activity. They are defined as refractory CD according to the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) .( 10 ) The utilization of at least two biologic agents, or the concurrent use of one biologic agent and one small-molecule drug, might be a promising strategy for patients with refractory CD.( 11 ) A 2007-year randomized controlled trial first observed that combining natalizumab with infliximab in patients with refractory Crohn's disease did not result in more adverse events than Infliximab alone.( 12 ) Since then, the efficacy and safety of dual-targeted therapy (DTT) have been progressively explored. In a meta-analysis of 30 cohort studies, Ahmed et al. summarized pooled clinical and endoscopic remission rates of 58.8% (95% CI 42–74%) and 34.3% (95% CI 23–46%) on 288 IBD patients who received dual biologic or small molecule therapy, and they observed 31% (95% CI 13–54%) of adverse events, but only 7% (95% CI 2–13%) were severe event.( 13 ) Although limited data, ustekinumab plus vedolizumab (UST + VDZ) seems to be the most promising in all DTT trials reported.( 14 ) Studies have demonstrated that the inhibition of IL-23 is especially efficacious among patients who show no response to anti-TNF-α, and the most prevalent combination is Ustekinumab combined with anti-TNF-a antibodies.( 15 , 16 )Adalimumab, being a widely utilized anti-TNF-α agent, exhibits superior efficacy in patients with moderate-to-severe CD in comparison to infliximab.( 17 , 18 )It is possible that the combination of ustekinumab and adalimumab (UST + ADA) yields a better outcome. However, in the prior exploration of the application of dual biologic agents in patients with IBD, only four cases were treated with UST + ADA, and all patients achieved a clinical response without any adverse effects.( 15 ) Its efficacy and safety in treating refractory CD also need to be further explored. This study aims to further assess the efficacy and safety of DTT, including UST + ADA and UST + VDZ, after treatment of patients with refractory CD. Materials and Methods Study design and patient population This was a single-center retrospective study with the following inclusion criteria: (i) age ≥ 18 years; (ii) diagnosed with CD according to the Chinese guidelines for the diagnosis and treatment of CD.( 19 );(iii) patients met with refractory CD criteria according to the consensus of IOIBD.( 10 ); (iv) patients had previously experienced treatment failures with at least two biological agents. (v) patients were proactively willing to undergo treatment for long-term observation. Exclusion criteria: (i) patients who failed to satisfy refractory CD criteria; (ii) refractory CD patients were receiving surgery. (iii) refractory CD patients were receiving treatment with small molecule drugs. (iv) patients who were not willing to be engaged in this study. Outcome assessment Baseline demographic data, including sex, age, Montreal classification, duration of disease, prior therapies, surgical history, EIM (Extra-Intestinal Manifestations), and comorbidity, were collected for all the patients. The primary endpoint of this study is endoscopic response, which is defined as a ≥ 50% decrease in the Simple Endoscopic Score-Crohn's Disease (SES-CD).( 20 ) The secondary endpoint is clinical response, characterized by either a 70-point decrease in the Crohn's Disease Activity Index (CDAI) or a decrease of less than 70 points but with a total score of ≤ 150.( 21 ) Other outcome measures include endoscopic remission (SES-CD ≤ 2) and clinical remission (CDAI ≤ 150). During the treatment process, ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), BMI (body mass index), and stool frequency were recorded. Statistical Analysis Percentages were used for categorical variables. Between-group comparisons were performed using Wilcoxon rank. Continuous variables are indicated as the median (interquartile range). P-values ≤ 0.05 were considered significant. All results should be considered as exploratory. Data were explored using IBM SPSS Statistics version 27. Results A total of 23 patients were enrolled in the study, 3 patients haven’t finished the follow-up, while 20 patients finished 4-27months follow-up and then were evaluated within this study, and the median time to endoscopic and clinical assessment was 7 months ( 5 , 12 ) (Fig. 1). Of the 20 patients, 75%(n = 15)of patients were male. The median medical history was 4.5 years (2.55, 10.38). 18 patients were diagnosed before the age of 40 (90%),12 patients were involved with the ileocolonic (60%). 9 patients (45%) had a structuring phenotype, and 1 patient had a penetrating phenotype. Two patients had EIM of oral ulcers, and one had a comorbidity of rheumatoid arthritis (Table 1 ). Table 1 Baseline characteristics of 20 patients Case Sex Age Montreal classification Duration (Years) Previous therapy Combination EIM/ Comorbidity Surgical history 1 M 26 A2L3B1 3.4 5-ASA、ADA、UST UST + ADA -- -- 2 M 21 A1L2B2 5 5-ASA、IFX、UST UST + ADA -- -- 3 F 19 A2L3B1 2.4 5-ASA、GC、IM、IFX、ADA UST + ADA -- -- 4 M 30 A2L2B1 2.2 5-ASA、GC、ADA、UST UST + ADA Oral ulcer -- 5 M 35 A2L3B2 15 5-ASA、IFX、ADA UST + ADA -- Colectomy 6 F 22 A2L3B1 5 5-ASA、IM、ADA、UST UST + ADA -- -- 7 F 26 A2L3B2 2 5-ASA、IFX、UST UST + ADA -- -- 8 F 56 A3L3B1 0.5 5-ASA、IFX、UST UST + ADA Rheumatoid arthritis -- 9 M 32 A2L1B2 10 5-ASA、ADA、UST UST + ADA -- Colectomy 10 M 51 A2L1B3 12.4 5-ASA、GC、IM、IFX、ADA、UST UST + ADA Oral ulcer Colectomy 11 M 37 A2L3B2 11.2 5-ASA、GC、IFX、ADA UST + ADA -- -- 12 M 24 A2L3B1 3 5-ASA、ADA、UST UST + ADA -- -- 13 M 37 A2L1BI 10 5-ASA、GC、IFX、UST UST + ADA -- -- 14 M 26 A2L3B1 9.2 5-ASA、ADA、UST UST + ADA -- -- 15 M 44 A2L2B2 3 5-ASA、IM、IFX、UST UST + ADA -- -- 16 M 42 A3L2B2 0.5 5-ASA、GC、IFX、UST UST + ADA -- -- 17 F 24 A2L3B2 10.8 5-ASA、IM、IFX、VDZ、UST UST + VDZ -- -- 18 M 39 A2L1B1 4 5-ASA、GC、IM、IFX、UST UST + VDZ -- -- 19 M 25 A2L3B1 3.4 5-ASA、ADA、UST UST + VDZ -- -- 20 M 32 A2L1B2 10.5 5-ASA、ADA、UST UST + VDZ -- Colectomy Note: 5-ASA: 5-aminosalicylic acid; GC: Corticosteroid ; IM: immunomodulator; IFX: Infliximab; ADA: Adalimumab; UST: Ustekinumab; VDZ: Vedolizumab; EIM: Extra-Intestinal Manifestation. All 20 patients used 5-aminosalicylic acid (5-ASA), 6 patients used Immunomodulators, 6 patients used Corticosteroids before, and moreover all patients received at least 2 biological monotherapies. 20% (4/20) of patients had a history of colectomy. In this study, the DTT includes UST + ADA (n = 16), and UST + VDZ (n = 4) (Table 1 ). All patients were followed up for 4–27 months, the median SES-CD score reduced from 14.5 (12, 18.75) to 5 (0.5, 11.5) (p<0.005) and the median CDAI score decreased from 326.25 (273.3, 385.77) to 94.75 (37.8, 241.5) (p<0.005) (Fig. 2). Endoscopic response occurred in 60% of treatments, and endoscopic remission was achieved in 45% of patients. Clinical response occurred in 70% of treatments, and clinical remission was achieved in 60% of patients. (Table 2 ). Table 2 Response and remission rates on clinical and endoscopic of two DTT regimens Endoscopic response Endoscopic remission Clinical response Clinical remission UST + ADA 68.75% (11/16) 56.25% (9/16) 75% (12/16) 68.75% (11/16) UST་VDZ 25% (1/4) 0 50% (2/4) 25% (1/4) All DTT 60% (12/20) 45% (9/20) 70% (14/20) 60% (12/20) Note: UST: Ustekinumab; ADA: Adalimumab; VDZ: Vedolizumab; DTT: Dual-targeted Therapy In the regimen of UST་ADA, clinical scores and endoscopic scores were significantly reduced (Fig. 2). Endoscopic response occurred in 68.75% (11/16) of trials, 56.25% (9/16) achieved endoscopic remission, and the mean SES-CD score reduced from 14.5 (12, 18.75) to 2 (0, 11.25). Clinical response occurred in 75% (12/16) of treatments, 68.75% (11/16) of patients achieved clinical remission, and the mean CDAI score decreased from 319.5 (241.35, 380.50) to 83 (36.73, 225.50) (Table 2 ). Patients’ clinical indicators were also significantly improved. The mean stool frequency decreased from 5.62 times to 2 times, the mean ESR level decreased from 28.99 mm/h to 9.06 mm/h, and the mean CRP concentration declined from 34.28 mg/L to 8.54 mg/L. Overall patients’ BMI level also increased, with the mean BMI level increasing from 20.95 kg/m2 to 22.13 kg/m2 (Table 3 ). Two patients initially combined with enteral nutrition therapy and ultimately achieved endoscopic remission. For the patients with concomitant oral ulcers, the symptoms also disappeared after treatment. Table 3 Paired sample Wilcoxon signed rank test for the mean changes in in the regimen of ustekinumab combined with adalimumab Pre-treatment Post-treatment Z value P Value SES-CD score 15.62 (12, 18.75) 5.5 (0, 11.25) -3.099 0.002 CDAI score 318.31 (241.35, 380.50) 120.85 (36.73, 225.5) -3.361 <0.001 ESR 28.99 (6.40, 43.35) 9.06 (4.00, 11.90) -2.999 0.003 C-reactive protein 34.28 (5.99, 69.55) 8.54 (1.29, 15.04) -2.982 0.003 Stool frequency 5.62 ( 4 , 8 ) 2 (1, 2.75) -3.159 0.002 BMI 20.95 (19.30, 22.78) 22.13 (21.32, 23.48) -2.379 0.017 Platelet 307.81 (222.25, 397.75) 242.25 (194.25, 236.25) -2.637 0.008 In the regimen of UST + VDZ. During the follow-up, 25% (1/4) of patients reached endoscopic response with no endoscopic remission occurring, and the mean SES-CD score decreased from 15.25 (9, 22.75) to 8.75 (6.25, 11.5). 50% (2/4) of patients reached clinical response, one of them achieved clinical remission, and the mean CDAI score reduced from 358.7 (301.25, 401.2) to 219.25 (117, 32.25). (Table 2 ). Compared with the regimen of UST + ADA, the improvement of the four patients' other clinical indicators' mean values is not significant (Table 4 ). Table 4 Paired sample Wilcoxon signed rank test for the mean changes in in the regimen of ustekinumab combined with vedolizumab Pre-treatment Post-treatment Z value P Value SES-CD score 15.25 (9, 22.75) 8.75 (6.25, 11.5) -1.826 0.068 CDAI score 358.7 (301.25, 401.2) 219.25 (117, 320.25) -1.826 0.068 ESR 41.25 (10.25, 83) 16.17 (6.83, 22.35) -1.826 0.068 C-reactive protein 23.77 (5.48, 44.28) 12.16 (3.89, 20.63) -2.599 0.068 Stool frequency 5.5 (3.25, 7.75) 3 (2.25, 3.75) -1.604 0.109 BMI 19.9 (16.87, 22.18) 20.35 (18.43, 21.73) -0.816 0.414 Platelet 478.5 (252, 783.5) 248.75 (214, 298.75) -1.461 0.144 In total, 7 patients discontinued the treatment. Four patients were UST + ADA, among them, three patients showed exacerbated diarrhea after 5 months of treatment and one patient showed a slight improvement in endoscopy after 4 months of initial treatment. The other three were treated with UST + VDZ, they chose to discontinue the treatment due to no significant benefit in the endoscopic examination during the 5 months’ treatment. No major adverse events such as serious infection, malignancy, major adverse cardiovascular events, or venous thromboembolism were recorded. Discussion Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin 12 and 23, has shown efficacy and long-term safety in patients with moderately-to-severely active CD.( 22 , 23 ) Adalimumab, a -widely used traditional anti-TNF-α agent, is more effective for CD than Infliximab and has similar efficacy to Ustekinumab in treating moderate - severe CD.( 18 , 24 ) Vedolizumab, an integrin antagonist, binds to α4β7 integrins to prevent the migration from the bloodstream to the intestinal mucosa, thus reducing the influx of leukocytes into inflamed tissue, and exhibited good effectiveness and safety for CD patients in clinical trials and the real-world settings.( 25 , 26 ) In this study, 12 patients were administered UST + ADA, while 4 patients received UST + VDZ. In a retrospective study, Edward Yang, MD, et al. reported that endoscopic and clinical responses were observed in 43% and 50% of refractory CD patients treated with dual biological therapy, respectively.( 27 ) In our study, endoscopic response and clinical response rates reached 60% (12/20) and 70% (14/20), respectively, which is better than previous studies. Among the patients who received UST + VDZ in Yang et al.'s study, 63% (5/8) of the patients achieved endoscopic improvement and 71% (5/7) achieved clinical improvement. However, 25% (1/4) of the patients who received UST + VDZ in our study had an endoscopic response, and 50% (2/4) achieved clinical response. It is possible that bias occurred due to the small volume of patients in this type of combination. Nonetheless, 68.75% (11/16) of patients with UST + ADA achieved endoscopic response, and 75% (12/16) of the patients achieved Clinical response and clinical indicators significantly reduced, indicating that UST + ADA is more effective than UST + VDZ in this study. According to Privitera et al., adverse effects of dual-biological therapy involving UST + VDZ were identified in 13–30% of patients, with infections being the most prevalent.( 28 ) Yang et al. noted adverse events in 13% of the trials (3/22).( 27 ) Among patients who were reported to have received UST + ADA, no adverse events were reported( 15 ). In our study, after careful screening and timely monitoring, no adverse events were observed in either of the DTT regimens. For the combinations of different drugs, besides efficacy and safety of a single drug, the mechanisms of action (MOAs) are also needed to be considered.( 11 ) Based on the MOAs of various effective molecules, it is theoretically believed the combination of anti-TNF or anti-12/13 or anti-23 with anti-integrin, having some overlap in the MOAs, may possess good efficacy in enhancing activity over a single agent and low additional risks; however, the combination of anti-TNF and IL-12/13 or anti-23, which have similar MOAs, might exhibit low efficacy in enhancing activity over a single agent and exhibit an increase in additional risks.( 29 ) The findings of our study do not fully align with the theory, the results of our study and the previous four cases all demonstrated the efficacy and safety of UST + ADA, which indicates that there may be other underlying mechanisms. However, the overall sample size of this combination is limited, and it is necessary to further enlarge the sample size to explore its latent mechanisms. The strengths of this study are presented as follows: ( 1 ). Firstly, this study emphasized UST + ADA as well as that of UST + VDZ. ( 2 ). Secondly, all patients were assessed with objective endoscopic and clinical endpoints. ( 3 ). Thirdly, our study encompassed the largest number of patients receiving UST + ADA and meticulously analyzed its efficacy and safety. However, this study still had the following limitations. ( 1 ). Firstly, it's a single-center respective study with a small number of patients. ( 2 ). Secondly, since there are significant differences in follow-up time, the long-term efficacy of both DTT regimes can’t be established. ( 3 ). Thirdly, 4 patients haven’t finished the follow-up and were not included in the evaluation. In conclusion, our study adds to the evidence for the efficacy and safety of clinically applying DTT in the treatment of refractory patients, especially UST + ADA. However, more extended investigation needs to be carried out on long-term effectiveness and safety. Declarations Data availability The original contributions presented in the study are included in the article material. Further inquiries can be directed to the corresponding authors. Statement of Conflict All the authors confirmed no conflicts of interest statement. Ethical Considerations This study was conducted following the guidelines of the Declaration of Helsinki and proved by the Medical Ethics Committee of the First Affiliated Hospital of the Air Force Medical University (reference number: KY20222333-C-1). Informed consent was obtained from all patients. Permission to reproduce material from other sources This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Authors’ contributions Jindan He and Jiaqi Zhang: Design and conception overall project; Data curation; Statistical analyses; Writing - original draft. Yanting Shi: Data curation; Formal analysis, Interpretation of results; Writing - review & editing. Jie Liang: Conceptualization; Funding acquisition; Supervision; Writing - review & editing. All authors reviewed and approved the final draft of the article before submission. Funding: This work was supported by the National Natural Science Foundation of China (82370588); Natural Science Foundation of Shaanxi Province, Key Industrial Innovation Project Fund (2023-ZDLSF-44); Medical Personnel Training and Promotion Program of Xijing Hospital (XJZT24QN41); National Natural Science Foundation of China Major Research Program Integration Project (92259302); Independent Funds of the Key Laboratory (CBSKL2022ZZ34). References Dolinger M, Torres J, Vermeire S. Crohn's disease. Lancet. 2024;403(10432):1177–91. Dou Z, Zheng H, Shi Y, Li Y, Jia J. Analysis of global prevalence, DALY and trends of inflammatory bowel disease and their correlations with sociodemographic index: Data from 1990 to 2019. Autoimmun Rev. 2024;23(11):103655. Rogler G, Singh A, Kavanaugh A, Rubin DT. Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management. Gastroenterology. 2021;161(4):1118–32. Di Rienzo A, Marinelli L, Dimmito MP, Toto EC, Di Stefano A, Cacciatore I. Advancements in Inflammatory Bowel Disease Management: From Traditional Treatments to Monoclonal Antibodies and Future Drug Delivery Systems. Pharmaceutics. 2024;16(9). Duijvestein M, Battat R, Vande Casteele N, D'Haens GR, Sandborn WJ, Khanna R, et al. Novel Therapies and Treatment Strategies for Patients with Inflammatory Bowel Disease. Curr Treat Options Gastroenterol. 2018;16(1):129–46. Berg DR, Colombel JF, Ungaro R. The Role of Early Biologic Therapy in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2019;25(12):1896–905. Hirten RP, Iacucci M, Shah S, Ghosh S, Colombel JF. Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders. Clin Gastroenterol Hepatol. 2018;16(9):1374–84. Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn's disease. Ann Surg. 2000;231(1):38–45. Higashiyama M, Hokari R. New and Emerging Treatments for Inflammatory Bowel Disease. Digestion. 2023;104(1):74–81. Parigi TL, D'Amico F, Abreu MT, Dignass A, Dotan I, Magro F, et al. Difficult-to-treat inflammatory bowel disease: results from an international consensus meeting. Lancet Gastroenterol Hepatol. 2023;8(9):853–9. Danese S, Solitano V, Jairath V, Peyrin-Biroulet L. The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment). Gut. 2022;71(12):2380–7. Sands BE, Kozarek R, Spainhour J, Barish CF, Becker S, Goldberg L, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab. Inflamm Bowel Dis. 2007;13(1):2–11. Ahmed W, Galati J, Kumar A, Christos PJ, Longman R, Lukin DJ, et al. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2022;20(3):e361-e79. Triantafillidis JK, Zografos CG, Konstadoulakis MM, Papalois AE. Combination treatment of inflammatory bowel disease: Present status and future perspectives. World J Gastroenterol. 2024;30(15):2068–80. Feng Z, Kang G, Wang J, Gao X, Wang X, Ye Y, et al. Breaking through the therapeutic ceiling of inflammatory bowel disease: Dual-targeted therapies. Biomed Pharmacother. 2023;158:114174. Schmitt H, Billmeier U, Dieterich W, Rath T, Sonnewald S, Reid S, 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. Bouhnik Y, Carbonnel F, Laharie D, Stefanescu C, Hébuterne X, Abitbol V, et al. Efficacy of adalimumab in patients with Crohn's disease and symptomatic small bowel stricture: a multicentre, prospective, observational cohort (CREOLE) study. Gut. 2018;67(1):53–60. Kamal ME, Werida RH, Radwan MA, Askar SR, Omran GA, El-Mohamdy MA, et al. Efficacy and safety of infliximab and adalimumab in inflammatory bowel disease patients. Inflammopharmacology. 2024;32(5):3259–69. 中华医学会消化病学分会炎症性肠病学组, 中国炎症性肠病诊疗质量控制评估中心. 中国克罗恩病诊治指南(2023年·广州). 中华炎性肠病杂志༈中英文༉. 2024(01):2–32. Daperno M, D'Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest Endosc. 2004;60(4):505–12. Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology. 1976;70(3):439–44. Ghosh S, Gensler LS, Yang Z, Gasink C, Chakravarty SD, Farahi K, et al. Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn's Disease: An Integrated Analysis of Phase II/III Clinical Development Programs. Drug Saf. 2019;42(6):751–68. Sandborn WJ, Rebuck R, Wang Y, Zou B, Adedokun OJ, Gasink C, et al. Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn's Disease: The IM-UNITI Trial. Clin Gastroenterol Hepatol. 2022;20(3):578 – 90.e4. Sands BE, Irving PM, Hoops T, Izanec JL, Gao LL, Gasink C, 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. 2022;399(10342):2200–11. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013;369(8):711–21. Schreiber S, Dignass A, Peyrin-Biroulet L, Hather G, Demuth D, Mosli M, et al. Systematic review with meta-analysis: real-world effectiveness and safety of vedolizumab in patients with inflammatory bowel disease. J Gastroenterol. 2018;53(9):1048–64. Yang E, Panaccione N, Whitmire N, Dulai PS, Vande Casteele N, Singh S, et al. Efficacy and safety of simultaneous treatment with two biologic medications in refractory Crohn's disease. Aliment Pharmacol Ther. 2020;51(11):1031–8. Privitera G, Pugliese D, Onali S, Petito V, Scaldaferri F, Gasbarrini A, et al. Combination therapy in inflammatory bowel disease - from traditional immunosuppressors towards the new paradigm of dual targeted therapy. Autoimmun Rev. 2021;20(6):102832. Stalgis C, Deepak P, Mehandru S, Colombel JF. Rational Combination Therapy to Overcome the Plateau of Drug Efficacy in Inflammatory Bowel Disease. Gastroenterology. 2021;161(2):394–9. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 21 Jul, 2025 Read the published version in Clinical and Experimental Medicine → Version 1 posted Editorial decision: Revision requested 26 Apr, 2025 Reviews received at journal 25 Apr, 2025 Reviews received at journal 24 Apr, 2025 Reviewers agreed at journal 22 Apr, 2025 Reviewers agreed at journal 22 Apr, 2025 Reviews received at journal 07 Apr, 2025 Reviewers agreed at journal 29 Mar, 2025 Reviewers agreed at journal 24 Mar, 2025 Reviewers invited by journal 24 Mar, 2025 Editor assigned by journal 14 Mar, 2025 Submission checks completed at journal 13 Mar, 2025 First submitted to journal 10 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6199348","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":435786373,"identity":"35ea25cc-625b-4d9a-a3b8-0ca95ed6d856","order_by":0,"name":"Jindan He","email":"","orcid":"","institution":"Fourth Military Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jindan","middleName":"","lastName":"He","suffix":""},{"id":435786374,"identity":"2ba9bd45-0326-4312-bd89-f30d0ed406f5","order_by":1,"name":"Jiaqi Zhang","email":"","orcid":"","institution":"Fourth Military Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jiaqi","middleName":"","lastName":"Zhang","suffix":""},{"id":435786375,"identity":"df2958bd-b65b-44b2-9ab0-1cac9e4a5f86","order_by":2,"name":"He Zhou","email":"","orcid":"","institution":"Fourth Military Medical University","correspondingAuthor":false,"prefix":"","firstName":"He","middleName":"","lastName":"Zhou","suffix":""},{"id":435786376,"identity":"ddcff788-c716-4ada-8e00-61a014191d7a","order_by":3,"name":"Yu Da","email":"","orcid":"","institution":"Fourth Military Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Da","suffix":""},{"id":435786377,"identity":"3c07e7e3-17cf-4d18-bbea-b7d1d85c6124","order_by":4,"name":"Xiaoning Liu","email":"","orcid":"","institution":"Fourth Military Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoning","middleName":"","lastName":"Liu","suffix":""},{"id":435786378,"identity":"2a6693e4-6a0c-4678-9c4b-f614dd9c36f4","order_by":5,"name":"Tiantian Zhang","email":"","orcid":"","institution":"Fourth Military Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tiantian","middleName":"","lastName":"Zhang","suffix":""},{"id":435786379,"identity":"d608da16-65ff-4c86-bfc4-0709ce1aa3f0","order_by":6,"name":"Zhenzhen Fan","email":"","orcid":"","institution":"Fourth Military Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhenzhen","middleName":"","lastName":"Fan","suffix":""},{"id":435786380,"identity":"090a01bb-f76d-4daf-a339-153cec35c958","order_by":7,"name":"Tong Wu","email":"","orcid":"","institution":"Fourth Military Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tong","middleName":"","lastName":"Wu","suffix":""},{"id":435786381,"identity":"456ad4b0-9c2e-45e3-bc32-fcd688076613","order_by":8,"name":"Yanting Shi","email":"","orcid":"","institution":"Fourth Military Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yanting","middleName":"","lastName":"Shi","suffix":""},{"id":435786382,"identity":"4d10fc93-6cf8-4523-96d9-731c61504fc9","order_by":9,"name":"Jie Liang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYBACPmYQySPBwM98ACzA2EBICxtMi2RbArFaYAyDY0RrYWd+9vCLjIWc8THu1M08DDayGw4wP3uA32Fs5sYyPBLGZsd4t93mYUgz3nCAzdwAvxYGM2kJHonEbfd7QVoOJ244wMMmgV8L+zeQlvrNbWBb/hOjhcdM8gOPRIIBG1jLAaK0lEkDA9lwBtAvN+cYJBvPPMxmhlcLP//xbZI/e+rk+YEOu/Gmwk6273jzM7xaQICZtwfGBAUVMyH1QMD44wcRqkbBKBgFo2DkAgBHzz4UMkx8EgAAAABJRU5ErkJggg==","orcid":"","institution":"Fourth Military Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jie","middleName":"","lastName":"Liang","suffix":""}],"badges":[],"createdAt":"2025-03-11 02:08:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6199348/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6199348/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10238-025-01731-x","type":"published","date":"2025-07-21T15:57:57+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79756634,"identity":"cf27e83c-6b7e-4369-99f4-d40f8c20cad3","added_by":"auto","created_at":"2025-04-02 10:36:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":92759,"visible":true,"origin":"","legend":"\u003cp\u003ePatient inclusion flowchart.\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6199348/v1/36ea0ec8733f85dae07bb133.png"},{"id":79756633,"identity":"30024389-bc74-4149-8a5e-fb735749ed3f","added_by":"auto","created_at":"2025-04-02 10:36:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":135010,"visible":true,"origin":"","legend":"\u003cp\u003e(A) (B): Changes in CDAI and SES-CD in all patients. (C) (D): Changes in CDAI and SES-CD in patients who received UST+ADA. CDAI: Crohn’s Disease Activity Index; SES-CD: Simplified Endoscopic Score–Crohn’s Disease.\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6199348/v1/befda7bfaa331725de96d0c4.png"},{"id":87756747,"identity":"3356d08f-9c38-495a-95a7-cc34c25c88a7","added_by":"auto","created_at":"2025-07-28 16:08:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1193684,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6199348/v1/b259cf08-3306-463f-a6e2-691e1b2e3cc1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eDual-targeted Therapy for the Management of Refractory Crohn’s Disease: A Retrospective Cohort Study \u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCrohn's disease (CD), which belongs to inflammatory bowel disease (IBD), is a chronic inflammatory condition of the gastrointestinal system resulting from a dysregulated immune response and has seen an increasing global prevalence.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) It can affect any part of the gastrointestinal tract, with the terminal ileum and proximal colon being the most commonly involved areas.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Additionally, 50% of patients will have stenosis, fistulas, and abscesses, and up to 50% may have extra-intestinal symptoms, most commonly in the joints, skin, and eyes.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Traditional treatment options include aminosalicylates, corticosteroids, and immunomodulators.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Effective biological agents include TNF-α antagonists (Infliximab, Adalimumab, Certolizumab pegol) and antibodies inhibiting IL-12/23 p40 subunit (Ustekinumab) and targeting leukocyte α4β7 integrins (Vedolizumab).(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Currently, biological therapies are widely used in patients with moderate to severe early-stage CD; however, the remission rates are only approximately 40% after one year.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Additionally, a retrospective study indicated that patients who required surgery had a recurrence rate of nearly 50% within 10 years.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) With the emergence of newer biological agents targeting different molecular pathways and small-molecule drugs, the medical treatment options for CD have further expanded.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) Nevertheless, some patients still have persistent symptoms and disease activity. They are defined as refractory CD according to the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) .(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) The utilization of at least two biologic agents, or the concurrent use of one biologic agent and one small-molecule drug, might be a promising strategy for patients with refractory CD.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) A 2007-year randomized controlled trial first observed that combining natalizumab with infliximab in patients with refractory Crohn's disease did not result in more adverse events than Infliximab alone.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) Since then, the efficacy and safety of dual-targeted therapy (DTT) have been progressively explored. In a meta-analysis of 30 cohort studies, Ahmed et al. summarized pooled clinical and endoscopic remission rates of 58.8% (95% CI 42\u0026ndash;74%) and 34.3% (95% CI 23\u0026ndash;46%) on 288 IBD patients who received dual biologic or small molecule therapy, and they observed 31% (95% CI 13\u0026ndash;54%) of adverse events, but only 7% (95% CI 2\u0026ndash;13%) were severe event.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) Although limited data, ustekinumab plus vedolizumab (UST\u0026thinsp;+\u0026thinsp;VDZ) seems to be the most promising in all DTT trials reported.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) Studies have demonstrated that the inhibition of IL-23 is especially efficacious among patients who show no response to anti-TNF-α, and the most prevalent combination is Ustekinumab combined with anti-TNF-a antibodies.(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)Adalimumab, being a widely utilized anti-TNF-α agent, exhibits superior efficacy in patients with moderate-to-severe CD in comparison to infliximab.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)It is possible that the combination of ustekinumab and adalimumab (UST\u0026thinsp;+\u0026thinsp;ADA) yields a better outcome. However, in the prior exploration of the application of dual biologic agents in patients with IBD, only four cases were treated with UST\u0026thinsp;+\u0026thinsp;ADA, and all patients achieved a clinical response without any adverse effects.(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) Its efficacy and safety in treating refractory CD also need to be further explored. This study aims to further assess the efficacy and safety of DTT, including UST\u0026thinsp;+\u0026thinsp;ADA and UST\u0026thinsp;+\u0026thinsp;VDZ, after treatment of patients with refractory CD.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patient population\u003c/h2\u003e \u003cp\u003e This was a single-center retrospective study with the following inclusion criteria: (i) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years; (ii) diagnosed with CD according to the Chinese guidelines for the diagnosis and treatment of CD.(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e);(iii) patients met with refractory CD criteria according to the consensus of IOIBD.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e); (iv) patients had previously experienced treatment failures with at least two biological agents. (v) patients were proactively willing to undergo treatment for long-term observation. Exclusion criteria: (i) patients who failed to satisfy refractory CD criteria; (ii) refractory CD patients were receiving surgery. (iii) refractory CD patients were receiving treatment with small molecule drugs. (iv) patients who were not willing to be engaged in this study.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcome assessment\u003c/h3\u003e\n\u003cp\u003eBaseline demographic data, including sex, age, Montreal classification, duration of disease, prior therapies, surgical history, EIM (Extra-Intestinal Manifestations), and comorbidity, were collected for all the patients.\u003c/p\u003e \u003cp\u003eThe primary endpoint of this study is endoscopic response, which is defined as a\u0026thinsp;\u0026ge;\u0026thinsp;50% decrease in the Simple Endoscopic Score-Crohn's Disease (SES-CD).(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) The secondary endpoint is clinical response, characterized by either a 70-point decrease in the Crohn's Disease Activity Index (CDAI) or a decrease of less than 70 points but with a total score of \u0026le;\u0026thinsp;150.(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) Other outcome measures include endoscopic remission (SES-CD\u0026thinsp;\u0026le;\u0026thinsp;2) and clinical remission (CDAI\u0026thinsp;\u0026le;\u0026thinsp;150). During the treatment process, ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), BMI (body mass index), and stool frequency were recorded.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003ePercentages were used for categorical variables. Between-group comparisons were performed using Wilcoxon rank. Continuous variables are indicated as the median (interquartile range). P-values\u0026thinsp;\u0026le;\u0026thinsp;0.05 were considered significant. All results should be considered as exploratory. Data were explored using IBM SPSS Statistics version 27.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 23 patients were enrolled in the study, 3 patients haven\u0026rsquo;t finished the follow-up, while 20 patients finished 4-27months follow-up and then were evaluated within this study, and the median time to endoscopic and clinical assessment was 7 months (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) (Fig.\u0026nbsp;1). Of the 20 patients, 75%(n\u0026thinsp;=\u0026thinsp;15)of patients were male. The median medical history was 4.5 years (2.55, 10.38). 18 patients were diagnosed before the age of 40 (90%),12 patients were involved with the ileocolonic (60%). 9 patients (45%) had a structuring phenotype, and 1 patient had a penetrating phenotype. Two patients had EIM of oral ulcers, and one had a comorbidity of rheumatoid arthritis (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of 20 patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMontreal classification\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDuration (Years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePrevious therapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eEIM/\u003c/p\u003e \u003cp\u003eComorbidity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSurgical history\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L3B1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、ADA、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA1L2B2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、IFX、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L3B1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、GC、IM、IFX、ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L2B1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、GC、ADA、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOral ulcer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L3B2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、IFX、ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eColectomy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L3B1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、IM、ADA、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L3B2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、IFX、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA3L3B1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、IFX、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eRheumatoid arthritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L1B2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、ADA、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eColectomy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L1B3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、GC、IM、IFX、ADA、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOral ulcer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eColectomy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L3B2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、GC、IFX、ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L3B1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、ADA、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L1BI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、GC、IFX、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L3B1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、ADA、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L2B2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、IM、IFX、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA3L2B2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、GC、IFX、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L3B2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、IM、IFX、VDZ、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;VDZ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L1B1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、GC、IM、IFX、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;VDZ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L3B1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、ADA、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;VDZ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA2L1B2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-ASA、ADA、UST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;VDZ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eColectomy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eNote: 5-ASA: 5-aminosalicylic acid; GC: Corticosteroid ; IM: immunomodulator; IFX: Infliximab; ADA: Adalimumab; UST: Ustekinumab; VDZ: Vedolizumab; EIM: Extra-Intestinal Manifestation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAll 20 patients used 5-aminosalicylic acid (5-ASA), 6 patients used Immunomodulators, 6 patients used Corticosteroids before, and moreover all patients received at least 2 biological monotherapies. 20% (4/20) of patients had a history of colectomy. In this study, the DTT includes UST\u0026thinsp;+\u0026thinsp;ADA (n\u0026thinsp;=\u0026thinsp;16), and UST\u0026thinsp;+\u0026thinsp;VDZ (n\u0026thinsp;=\u0026thinsp;4) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAll patients were followed up for 4\u0026ndash;27 months, the median SES-CD score reduced from 14.5 (12, 18.75) to 5 (0.5, 11.5) (p\u0026lt;0.005) and the median CDAI score decreased from 326.25 (273.3, 385.77) to 94.75 (37.8, 241.5) (p\u0026lt;0.005) (Fig.\u0026nbsp;2). Endoscopic response occurred in 60% of treatments, and endoscopic remission was achieved in 45% of patients. Clinical response occurred in 70% of treatments, and clinical remission was achieved in 60% of patients. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResponse and remission rates on clinical and endoscopic of two DTT regimens\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndoscopic response\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEndoscopic remission\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClinical response\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClinical remission\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUST\u0026thinsp;+\u0026thinsp;ADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.75% (11/16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56.25% (9/16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75% (12/16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68.75% (11/16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUST་VDZ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25% (1/4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50% (2/4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25% (1/4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll DTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60% (12/20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45% (9/20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70% (14/20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60% (12/20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: UST: Ustekinumab; ADA: Adalimumab; VDZ: Vedolizumab; DTT: Dual-targeted Therapy\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the regimen of UST་ADA, clinical scores and endoscopic scores were significantly reduced (Fig.\u0026nbsp;2). Endoscopic response occurred in 68.75% (11/16) of trials, 56.25% (9/16) achieved endoscopic remission, and the mean SES-CD score reduced from 14.5 (12, 18.75) to 2 (0, 11.25). Clinical response occurred in 75% (12/16) of treatments, 68.75% (11/16) of patients achieved clinical remission, and the mean CDAI score decreased from 319.5 (241.35, 380.50) to 83 (36.73, 225.50) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Patients\u0026rsquo; clinical indicators were also significantly improved. The mean stool frequency decreased from 5.62 times to 2 times, the mean ESR level decreased from 28.99 mm/h to 9.06 mm/h, and the mean CRP concentration declined from 34.28 mg/L to 8.54 mg/L. Overall patients\u0026rsquo; BMI level also increased, with the mean BMI level increasing from 20.95 kg/m2 to 22.13 kg/m2 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Two patients initially combined with enteral nutrition therapy and ultimately achieved endoscopic remission. For the patients with concomitant oral ulcers, the symptoms also disappeared after treatment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePaired sample Wilcoxon signed rank test for the mean changes in in the regimen of ustekinumab combined with adalimumab\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePre-treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePost-treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSES-CD score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.62 (12, 18.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.5 (0, 11.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.099\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCDAI score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e318.31 (241.35, 380.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e120.85 (36.73, 225.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.361\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.99 (6.40, 43.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.06 (4.00, 11.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.28 (5.99, 69.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.54 (1.29, 15.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.982\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStool frequency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.62 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (1, 2.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20.95 (19.30, 22.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22.13 (21.32, 23.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.379\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e307.81 (222.25, 397.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e242.25 (194.25, 236.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.637\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the regimen of UST\u0026thinsp;+\u0026thinsp;VDZ. During the follow-up, 25% (1/4) of patients reached endoscopic response with no endoscopic remission occurring, and the mean SES-CD score decreased from 15.25 (9, 22.75) to 8.75 (6.25, 11.5). 50% (2/4) of patients reached clinical response, one of them achieved clinical remission, and the mean CDAI score reduced from 358.7 (301.25, 401.2) to 219.25 (117, 32.25). (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Compared with the regimen of UST\u0026thinsp;+\u0026thinsp;ADA, the improvement of the four patients' other clinical indicators' mean values is not significant (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePaired sample Wilcoxon signed rank test for the mean changes in in the regimen of ustekinumab combined with vedolizumab\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePre-treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePost-treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSES-CD score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15.25 (9, 22.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.75 (6.25, 11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.826\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCDAI score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e358.7 (301.25, 401.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e219.25 (117, 320.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.826\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41.25 (10.25, 83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16.17 (6.83, 22.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.826\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.77 (5.48, 44.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.16 (3.89, 20.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.599\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStool frequency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.5 (3.25, 7.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (2.25, 3.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.604\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.109\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19.9 (16.87, 22.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20.35 (18.43, 21.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.816\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.414\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e478.5 (252, 783.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e248.75 (214, 298.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.144\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn total, 7 patients discontinued the treatment. Four patients were UST\u0026thinsp;+\u0026thinsp;ADA, among them, three patients showed exacerbated diarrhea after 5 months of treatment and one patient showed a slight improvement in endoscopy after 4 months of initial treatment. The other three were treated with UST\u0026thinsp;+\u0026thinsp;VDZ, they chose to discontinue the treatment due to no significant benefit in the endoscopic examination during the 5 months\u0026rsquo; treatment. No major adverse events such as serious infection, malignancy, major adverse cardiovascular events, or venous thromboembolism were recorded.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eUstekinumab, a monoclonal antibody targeting the p40 subunit of interleukin 12 and 23, has shown efficacy and long-term safety in patients with moderately-to-severely active CD.(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) Adalimumab, a -widely used traditional anti-TNF-α agent, is more effective for CD than Infliximab and has similar efficacy to Ustekinumab in treating moderate - severe CD.(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) Vedolizumab, an integrin antagonist, binds to α4β7 integrins to prevent the migration from the bloodstream to the intestinal mucosa, thus reducing the influx of leukocytes into inflamed tissue, and exhibited good effectiveness and safety for CD patients in clinical trials and the real-world settings.(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) In this study, 12 patients were administered UST\u0026thinsp;+\u0026thinsp;ADA, while 4 patients received UST\u0026thinsp;+\u0026thinsp;VDZ.\u003c/p\u003e \u003cp\u003eIn a retrospective study, Edward Yang, MD, et al. reported that endoscopic and clinical responses were observed in 43% and 50% of refractory CD patients treated with dual biological therapy, respectively.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) In our study, endoscopic response and clinical response rates reached 60% (12/20) and 70% (14/20), respectively, which is better than previous studies. Among the patients who received UST\u0026thinsp;+\u0026thinsp;VDZ in Yang et al.'s study, 63% (5/8) of the patients achieved endoscopic improvement and 71% (5/7) achieved clinical improvement. However, 25% (1/4) of the patients who received UST\u0026thinsp;+\u0026thinsp;VDZ in our study had an endoscopic response, and 50% (2/4) achieved clinical response. It is possible that bias occurred due to the small volume of patients in this type of combination. Nonetheless, 68.75% (11/16) of patients with UST\u0026thinsp;+\u0026thinsp;ADA achieved endoscopic response, and 75% (12/16) of the patients achieved Clinical response and clinical indicators significantly reduced, indicating that UST\u0026thinsp;+\u0026thinsp;ADA is more effective than UST\u0026thinsp;+\u0026thinsp;VDZ in this study.\u003c/p\u003e \u003cp\u003eAccording to Privitera et al., adverse effects of dual-biological therapy involving UST\u0026thinsp;+\u0026thinsp;VDZ were identified in 13\u0026ndash;30% of patients, with infections being the most prevalent.(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) Yang et al. noted adverse events in 13% of the trials (3/22).(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) Among patients who were reported to have received UST\u0026thinsp;+\u0026thinsp;ADA, no adverse events were reported(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). In our study, after careful screening and timely monitoring, no adverse events were observed in either of the DTT regimens.\u003c/p\u003e \u003cp\u003eFor the combinations of different drugs, besides efficacy and safety of a single drug, the mechanisms of action (MOAs) are also needed to be considered.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) Based on the MOAs of various effective molecules, it is theoretically believed the combination of anti-TNF or anti-12/13 or anti-23 with anti-integrin, having some overlap in the MOAs, may possess good efficacy in enhancing activity over a single agent and low additional risks; however, the combination of anti-TNF and IL-12/13 or anti-23, which have similar MOAs, might exhibit low efficacy in enhancing activity over a single agent and exhibit an increase in additional risks.(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) The findings of our study do not fully align with the theory, the results of our study and the previous four cases all demonstrated the efficacy and safety of UST\u0026thinsp;+\u0026thinsp;ADA, which indicates that there may be other underlying mechanisms. However, the overall sample size of this combination is limited, and it is necessary to further enlarge the sample size to explore its latent mechanisms.\u003c/p\u003e \u003cp\u003eThe strengths of this study are presented as follows: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Firstly, this study emphasized UST\u0026thinsp;+\u0026thinsp;ADA as well as that of UST\u0026thinsp;+\u0026thinsp;VDZ. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Secondly, all patients were assessed with objective endoscopic and clinical endpoints. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Thirdly, our study encompassed the largest number of patients receiving UST\u0026thinsp;+\u0026thinsp;ADA and meticulously analyzed its efficacy and safety. However, this study still had the following limitations. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Firstly, it's a single-center respective study with a small number of patients. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Secondly, since there are significant differences in follow-up time, the long-term efficacy of both DTT regimes can\u0026rsquo;t be established. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Thirdly, 4 patients haven\u0026rsquo;t finished the follow-up and were not included in the evaluation.\u003c/p\u003e \u003cp\u003eIn conclusion, our study adds to the evidence for the efficacy and safety of clinically applying DTT in the treatment of refractory patients, especially UST\u0026thinsp;+\u0026thinsp;ADA. However, more extended investigation needs to be carried out on long-term effectiveness and safety.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article material. Further inquiries can be directed to the corresponding authors.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of Conflict\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors confirmed no conflicts of interest statement.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted following the guidelines of the Declaration of Helsinki and proved by the Medical Ethics Committee of the First Affiliated Hospital of the Air Force Medical University (reference number: KY20222333-C-1). Informed consent was obtained from all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePermission to reproduce material from other sources\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJindan He and Jiaqi Zhang: Design and conception overall project; Data curation; Statistical analyses; Writing - original draft. Yanting Shi: Data curation; Formal analysis, Interpretation of results; Writing - review \u0026amp; editing. Jie Liang: Conceptualization; Funding acquisition; Supervision; Writing - review \u0026amp; editing. All authors reviewed and approved the final draft of the article before submission. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work was supported by the National Natural Science Foundation of China (82370588); Natural Science Foundation of Shaanxi Province, Key Industrial Innovation Project Fund (2023-ZDLSF-44); Medical Personnel Training and Promotion Program of Xijing Hospital (XJZT24QN41); National Natural Science Foundation of China Major Research Program Integration Project (92259302); Independent Funds of the Key Laboratory (CBSKL2022ZZ34).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDolinger M, Torres J, Vermeire S. Crohn's disease. Lancet. 2024;403(10432):1177\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDou Z, Zheng H, Shi Y, Li Y, Jia J. Analysis of global prevalence, DALY and trends of inflammatory bowel disease and their correlations with sociodemographic index: Data from 1990 to 2019. Autoimmun Rev. 2024;23(11):103655.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRogler G, Singh A, Kavanaugh A, Rubin DT. Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management. Gastroenterology. 2021;161(4):1118\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDi Rienzo A, Marinelli L, Dimmito MP, Toto EC, Di Stefano A, Cacciatore I. Advancements in Inflammatory Bowel Disease Management: From Traditional Treatments to Monoclonal Antibodies and Future Drug Delivery Systems. Pharmaceutics. 2024;16(9).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuijvestein M, Battat R, Vande Casteele N, D'Haens GR, Sandborn WJ, Khanna R, et al. Novel Therapies and Treatment Strategies for Patients with Inflammatory Bowel Disease. Curr Treat Options Gastroenterol. 2018;16(1):129\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerg DR, Colombel JF, Ungaro R. The Role of Early Biologic Therapy in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2019;25(12):1896\u0026ndash;905.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirten RP, Iacucci M, Shah S, Ghosh S, Colombel JF. Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders. Clin Gastroenterol Hepatol. 2018;16(9):1374\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn's disease. Ann Surg. 2000;231(1):38\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHigashiyama M, Hokari R. New and Emerging Treatments for Inflammatory Bowel Disease. Digestion. 2023;104(1):74\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParigi TL, D'Amico F, Abreu MT, Dignass A, Dotan I, Magro F, et al. Difficult-to-treat inflammatory bowel disease: results from an international consensus meeting. Lancet Gastroenterol Hepatol. 2023;8(9):853\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDanese S, Solitano V, Jairath V, Peyrin-Biroulet L. The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment). Gut. 2022;71(12):2380\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSands BE, Kozarek R, Spainhour J, Barish CF, Becker S, Goldberg L, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab. Inflamm Bowel Dis. 2007;13(1):2\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmed W, Galati J, Kumar A, Christos PJ, Longman R, Lukin DJ, et al. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2022;20(3):e361-e79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTriantafillidis JK, Zografos CG, Konstadoulakis MM, Papalois AE. Combination treatment of inflammatory bowel disease: Present status and future perspectives. World J Gastroenterol. 2024;30(15):2068\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeng Z, Kang G, Wang J, Gao X, Wang X, Ye Y, et al. Breaking through the therapeutic ceiling of inflammatory bowel disease: Dual-targeted therapies. Biomed Pharmacother. 2023;158:114174.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmitt H, Billmeier U, Dieterich W, Rath T, Sonnewald S, Reid S, et al. Expansion of IL-23 receptor bearing TNFR2\u0026thinsp;+\u0026thinsp;T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease. Gut. 2019;68(5):814\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBouhnik Y, Carbonnel F, Laharie D, Stefanescu C, H\u0026eacute;buterne X, Abitbol V, et al. Efficacy of adalimumab in patients with Crohn's disease and symptomatic small bowel stricture: a multicentre, prospective, observational cohort (CREOLE) study. Gut. 2018;67(1):53\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamal ME, Werida RH, Radwan MA, Askar SR, Omran GA, El-Mohamdy MA, et al. Efficacy and safety of infliximab and adalimumab in inflammatory bowel disease patients. Inflammopharmacology. 2024;32(5):3259\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e中华医学会消化病学分会炎症性肠病学组, 中国炎症性肠病诊疗质量控制评估中心. 中国克罗恩病诊治指南(2023年\u0026middot;广州). 中华炎性肠病杂志༈中英文༉. 2024(01):2\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaperno M, D'Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest Endosc. 2004;60(4):505\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBest WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology. 1976;70(3):439\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhosh S, Gensler LS, Yang Z, Gasink C, Chakravarty SD, Farahi K, et al. Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn's Disease: An Integrated Analysis of Phase II/III Clinical Development Programs. Drug Saf. 2019;42(6):751\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSandborn WJ, Rebuck R, Wang Y, Zou B, Adedokun OJ, Gasink C, et al. Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn's Disease: The IM-UNITI Trial. Clin Gastroenterol Hepatol. 2022;20(3):578\u0026thinsp;\u0026ndash;\u0026thinsp;90.e4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSands BE, Irving PM, Hoops T, Izanec JL, Gao LL, Gasink C, 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. 2022;399(10342):2200\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013;369(8):711\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchreiber S, Dignass A, Peyrin-Biroulet L, Hather G, Demuth D, Mosli M, et al. Systematic review with meta-analysis: real-world effectiveness and safety of vedolizumab in patients with inflammatory bowel disease. J Gastroenterol. 2018;53(9):1048\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang E, Panaccione N, Whitmire N, Dulai PS, Vande Casteele N, Singh S, et al. Efficacy and safety of simultaneous treatment with two biologic medications in refractory Crohn's disease. Aliment Pharmacol Ther. 2020;51(11):1031\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrivitera G, Pugliese D, Onali S, Petito V, Scaldaferri F, Gasbarrini A, et al. Combination therapy in inflammatory bowel disease - from traditional immunosuppressors towards the new paradigm of dual targeted therapy. Autoimmun Rev. 2021;20(6):102832.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStalgis C, Deepak P, Mehandru S, Colombel JF. Rational Combination Therapy to Overcome the Plateau of Drug Efficacy in Inflammatory Bowel Disease. Gastroenterology. 2021;161(2):394\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-and-experimental-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clem","sideBox":"Learn more about [Clinical and Experimental Medicine](https://www.springer.com/journal/10238)","snPcode":"10238","submissionUrl":"https://submission.nature.com/new-submission/10238/3","title":"Clinical and Experimental Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Refractory Crohn’s disease, Dual-targeted therapy, Adalimumab, Ustekinumab, Vedolizumab, Endoscopy","lastPublishedDoi":"10.21203/rs.3.rs-6199348/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6199348/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eCrohn’s disease (CD) is a chronic relapsing autoimmune disease. Dual-targeted therapy (DTT) has been proven effective and safe in refractory inflammatory bowel disease (IBD), especially the combination of ustekinumab with vedolizumab (UST+VDZ). However, the efficacy and safety of DTT on refractory CD are still limited or insufficient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAims:\u003c/strong\u003eWe aim to evaluate the efficacy and safety of DTT including ustekinumab combined with adalimumab (UST+ADA) and UST + VDZ in refractory CD patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003eRefractory CD patients who failed at least two biologics from Xijing IBD Center were included. Clinical evaluation was performed by Crohn's Disease Activity Index (CDAI). Endoscopic data were assessed using Simple Endoscopic Score-Crohn's Disease (SES-CD). Other clinical indicators were also collected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003eTotally, 23 patients were enrolled, and 20 completed 4-27 months of follow-up. Among these patients, there were significant post-treatment reductions in median SES-CD [14.5 to 5 (p＜0.005)] and CDAI [326.25 to 94.75 (p＜0.005)]. For UST + ADA (n=16), 68.75% reached endoscopic response, 56.25% achieved endoscopic remission, 75% clinical response occurred and 68.75% of patients achieved clinical remission. For UST + VDZ (n=4), 25% had endoscopic response, 50% had clinical response, and one achieved clinical remission. The regime of UST + ADA exhibited a more favorable performance during follow-up. 7 patients discontinued DTT due to no significant improvement or exacerbation, and no severe adverse events were observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThe study supports the effectiveness and safety of ACT for refractory CD, especially UST + ADA. Larger sample and randomized controlled trial (RCT) studies are needed for confirmation.\u003c/p\u003e","manuscriptTitle":"Dual-targeted Therapy for the Management of Refractory Crohn’s Disease: A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-02 10:36:43","doi":"10.21203/rs.3.rs-6199348/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-26T08:39:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-25T05:24:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-25T00:50:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"256101742837560745733568514373783713688","date":"2025-04-22T13:03:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"248727277885218845420864718795058613012","date":"2025-04-22T12:44:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-07T16:47:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"339680906670131790016272512246430887868","date":"2025-03-29T19:20:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222589572691865896246448573398725230776","date":"2025-03-24T16:15:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-24T15:14:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-14T11:27:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-13T11:56:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical and Experimental Medicine","date":"2025-03-11T01:52:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-and-experimental-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clem","sideBox":"Learn more about [Clinical and Experimental Medicine](https://www.springer.com/journal/10238)","snPcode":"10238","submissionUrl":"https://submission.nature.com/new-submission/10238/3","title":"Clinical and Experimental Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4a083c42-402b-4356-9b53-339fb47fd391","owner":[],"postedDate":"April 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-28T16:02:56+00:00","versionOfRecord":{"articleIdentity":"rs-6199348","link":"https://doi.org/10.1007/s10238-025-01731-x","journal":{"identity":"clinical-and-experimental-medicine","isVorOnly":false,"title":"Clinical and Experimental Medicine"},"publishedOn":"2025-07-21 15:57:57","publishedOnDateReadable":"July 21st, 2025"},"versionCreatedAt":"2025-04-02 10:36:43","video":"","vorDoi":"10.1007/s10238-025-01731-x","vorDoiUrl":"https://doi.org/10.1007/s10238-025-01731-x","workflowStages":[]},"version":"v1","identity":"rs-6199348","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6199348","identity":"rs-6199348","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}