Comparison of Endoscopic Healing and Durability between Combination Therapy with Infliximab and Azathioprine versus Infliximab Monotherapy in Pediatric Crohn's disease

Comparison of Endoscopic Healing and Durability between Combination Therapy with Infliximab and Azathioprine versus Infliximab Monotherapy in Pediatric Crohn's disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Comparison of Endoscopic Healing and Durability between Combination Therapy with Infliximab and Azathioprine versus Infliximab Monotherapy in Pediatric Crohn's disease Yoon Zi Kim, Eun Sil Kim, Yiyoung Kwon, Seon Young Kim, Hansol Kim, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4512921/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract This study aimed to evaluate endoscopic healing (EH) efficacy and the durability of infliximab (IFX) in combination therapy with IFX and AZA versus IFX monotherapy in pediatric patients with Crohn’s disease (CD). In this retrospective observational study, clinical remission (CR), biochemical remission (BR), EH, transmural healing (TH) after 1-year of treatment, IFX trough levels (TLs), antibodies-to-IFX (ATIs), and IFX durability of 108 patients receiving IFX therapy, who were grouped into AZA combo-therapy (combination therapy group) and IFX monotherapy (monotherapy group), were compared. Of 108 patients who received IFX therapy, 85 (78.7%) received AZA combo-therapy for ≥3 months, and 23 (21.3%) received IFX monotherapy. No significant differences were observed in CR and TH at 1-year between the groups. However, the BR (92.9% vs. 66.7%, p = 0.003) and EH (78.6% vs. 33.3%, p < 0.001) were higher in the combination therapy group than in the monotherapy group. Further, the proportion of patients with TLs above the therapeutic drug levels was significantly higher in the combination therapy group than in the monotherapy group ( p = 0.023). ATI formation was also significantly lower in the combination therapy group than in the monotherapy group (25.0% vs. 52.2%, p = 0.025). Multivariable Cox proportional hazard regression analysis showed that ATI positivity (hazard ratio [HR] 5.33, 95% CI [confidence interval] 1.61–17.60, p = 0.006) and combination therapy with IFX and AZA (HR 0.13, 95% CI 0.03–0.51, p = 0.004) were associated with IFX durability. Kaplan–Meier survival curves revealed significantly higher IFX durability in the combination therapy group (log-rank test, p = 0.0026) than in the monotherapy group. Compared with IFX monotherapy, combination therapy with IFX and AZA was associated with higher EH rates and longer IFX durability in pediatric patients with CD. Health sciences/Gastroenterology Health sciences/Medical research inflammatory bowel disease endoscopic healing infliximab durability pediatric Figures Figure 1 Figure 2 Introduction Crohn's disease (CD), a type of inflammatory bowel disease (IBD), is characterized by inflammation in the gastrointestinal tract 1 . With an increasing prevalence of CD, numerous studies are being conducted on its treatment 2 , 3 . Notably, the emergence of biologics is widely regarded as a pivotal development in the effective treatment of CD. A novel biologic therapy with anti-tumor necrosis factor alpha (anti-TNF α) agents, such as infliximab (IFX) or adalimumab (ADL), has revolutionized CD treatment. IFX, the first biologic agent, is highly effective in the induction and maintenance of remission in patients with moderate-to-severe CD, even pediatric patients 4 , 5 . However, a considerable number of patients with CD undergoing anti-TNF α treatment experience a loss of response (LOR) to anti-TNF induction therapy called primary LOR or a LOR to treatment over time after initially experiencing clinical improvement called secondary LOR 6 . Secondary LOR is mainly attributed to pharmacokinetic problems and subtherapeutic drug concentrations due to the formation of anti-drug antibodies (ADAs) that neutralize biologics 7 , 8 . The landmark SONIC trial for CD demonstrated superior effectiveness of IFX and azathioprine (AZA), which is known as a combination therapy, to IFX monotherapy for corticosteroid-free clinical remission (CR) in naïve patients with moderate-to-severe disease 9 . Further, compared with monotherapy, combination therapy is also more effective for CR and reduces the LOR rate in pediatric patients with CD 10 , 11 . In addition, the combination therapy prevents ADA formation and maintains higher median IFX trough levels (TLs), improving the remission rate in CD 12 , 13 . In an update on the selection of therapeutic targets in IBD (STRIDE-Ⅱ), treatment of the target of endoscopic healing (EH) has been associated with improvements in long-term outcomes, as mucosal inflammation is associated with long-term disease-related complications, even in CR 14 – 16 . However, data on EH efficacy in combination therapy is limited compared with the monotherapy. Therefore, this study aimed to evaluate EH efficacy and the durability of IFX in combination therapy compared with monotherapy in pediatric patients with CD. Results Baseline characteristics A total of 108 patients were included in this study. Of these, 21.3% (23/108) and 78.7% (85/108) patients were assigned to the monotherapy and combination therapy groups, respectively. The mean age of the patients at diagnosis was 14.2 years, and 80.6% (87/108) were male. Four patients (3.7%) had a first-degree family history of IBD. No significant differences were observed in the baseline characteristics of the patients between the monotherapy and combination therapy groups. Disease phenotype, disease activity, and other baseline characteristics are presented in Table 1 . Table 1 Baseline characteristics Total ( n = 108) IFX monotherapy group ( n = 23) IFX + AZA combination therapy group ( n = 85) p -value Male sex, n (%) 87 (80.6) 19 (82.6) 68 (80.0) 0.2147 Age at diagnosis, years 14.2 ± 2.7 14.2 ± 3.1 14.2 ± 2.6 0.948 1st degree family history of IBD, n (%) 4 (3.7) 1 (4.4) 3 (3.5) > 0.99 Disease location, n (%) > 0.99 Ileal (L1) 11 (10.2) 2 (8.7) 9 (10.6) Colonic (L2) 5 (4.6) 1 (4.3) 4 (4.7) Ileocolonic (L3) 92 (85.2) 20 (87.0) 72 (84.7) UGI involvement, n (%) 0.971 None 15 (13.9) 5 (21.7) 10 (11.8) Proximal to the ligament of Treitz (L4a) 31 (28.7) 7 (30.5) 24 (28.2) Distal to the ligament of Treitz and proximal to the distal 1/3 ileum (L4b) 24 (22.2) 5 (21.7) 19 (22.4) Both (L4ab) 38 (35.2) 6 (26.1) 32 (37.6) Luminal disease behavior 0.804 Nonstricturing nonpenetrating (B1) 99 (91.7) 21 (91.2) 78 (91.8) Stricturing (B2) 6 (5.5) 1 (4.4) 5 (5.9) Penetrating (B3) 3 (2.8) 1 (4.4) 2 (2.3) Perianal disease, n (%) 67 (62.0) 14 (60.9) 53 (62.4) 0.614 Growth retardation, n (%) 28 (25.9) 6 (26.1) 22 (25.9) 0.970 PCDAI 32.5 (23.8, 40.0) 32.5 (30.0, 40.0) 32.5 (22.5, 40) 0.645 WBC count, × 10 3 /uL 8.9 (7.1, 10.7) 8.6 (7.6, 9.4) 9.1 (7.0, 10.8) 0.685 Hematocrit, % 37.9 ± 4.5 38.2 ± 5.1 37.8 ± 4.3 0.756 Platelet count, × 10 3 /uL 377.0 (308.5, 480.5) 364.0 (320.0, 453.5) 379.0 (322.0, 478.0) 0.696 ESR, mm/h 37.5 (19.5, 62.0) 38.0 (25.5, 58.5) 37.0 (18.0, 64.0) 0.813 Albumin, g/dL 4.1 ± 0.5 4.2 ± 0.4 4.1 ± 0.5 0.259 CRP, mg/dL 1.3 (0.3, 2.9) 1.1 (0.3, 2.5) 1.3 (0.3, 3.0) 0.626 SES-CD 15.0 (10.0, 22.0) 14.0 (10.0, 22.0) 15.0 (10.0, 22.0) 0.801 Continuous variables are expressed as the median (interquartile range) or mean ± standard deviation. Abbreviations: IBD, inflammatory bowel disease; UGI, upper gastrointestinal; PCDAI, Pediatric Crohn's Disease Activity Index; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; SES-CD, Simple Endoscopic Score for Crohn's Disease. Comparison of treatment outcomes between monotherapy and combination therapy groups No significant differences in the proportion of patients with CR and TH at 1 year (CR: 95.8% vs. 96.4%, p > 0.99; TH: 13.6% vs. 27.4%, p = 0.291) were observed between the monotherapy and combination therapy groups. The laboratory results and SES-CDs were also comparable between the two groups (SES-CD: 1.0 vs. 0.0, p = 0.083). However, the proportion of patients with BR and EH at 1 year was significantly lower in the monotherapy group than in the combination therapy group (BR: 66.7% vs. 92.9%, p = 0.003; EH: 33.3% vs. 78.6%, p < 0.001). Median IFX TLs were significantly lower in the monotherapy group compared with the combination therapy group (3.9 µg/mL vs. 4.6 µg/mL, p = 0.016; Fig. 1 ). Further, the proportion of patients with minimal maintenance of IFX threshold TLs for EH (5 µg/mL) 17 was lower in the monotherapy group than in the combination therapy group (30.5% vs. 44.1%, p = 0.023). Moreover, ATI positivity was higher in the monotherapy group than in the combination therapy group (52.2% vs. 25.0%, p = 0.025). The detailed treatment outcomes of the two groups are presented in Table 2 . Table 2 Comparison of 1-year treatment outcomes between monotherapy and combination therapy groups Total ( n = 108) IFX monotherapy group ( n = 23) IFX + AZA combination therapy group ( n = 85) p -value WBC count, × 10 3 /uL 6.5 (5.5, 8.6) 6.3 (5.3, 7.9) 6.6 (5.5, 8.6) 0.679 Hematocrit, % 41.1 ± 3.8 42.7 ± 4.3 40.7 ± 3.5 0.037 Platelet count, × 10 3 /uL 256.0 (223.0, 292.5) 250.0 (212.8, 276.0) 257.5 (225.8, 308.3) 0.179 ESR, mm/h 5.0 (2.0, 10.3) 7.0 (3.8, 13.3) 4.0 (2.0, 10.0) 0.144 Albumin, g/dL 4.6 ± 0.3 4.5 ± 0.3 4.6 ± 0.3 0.715 CRP, mg/dL 0.06 (0.03, 0.09) 0.04 (0.03, 0.06) 0.06 (0.03, 0.09) 0.121 SES-CD 0.0 (0.0, 3.0) 1.0 (0.0, 5.5) 0.0 (0.0, 3.0) 0.083 Clinical remission at 1 year, n (%) 104 (96.3) 22 (95.8) 81 (96.4) > 0.99 Biochemical remission at 1 year, n (%) 94 (87.0) 16 (66.7) 78 (92.9) 0.003 Endoscopic healing at 1 year, n (%) 74 (68.5) 8 (33.3) 66 (78.6) < 0.001 Transmural healing at 1 year, n (%) 26 (24.5) 3 (13.6) 23 (27.4) 0.291 IFX trough concentration, µg/mL 4.3 (2.5, 6.5) 3.9 (1.4, 5.4) 4.6 (3.1, 7.4) 0.016 IFX trough concentration, n (%) 0.023 < 3 µg/mL 29 (27.1) 11 (47.8) 18 (21.4) 3–5 µg/mL 34 (31.8) 5 (21.7) 29 (34.5) ≥ 5 µg/mL 44 (41.1) 7 (30.5) 37 (44.1) ATI positivity, n (%) 33 (30.6) 12 (52.2) 21 (25.0) 0.025 Continuous variables are expressed as the median (interquartile range) or mean ± standard deviation. Abbreviations: IFX, infliximab; AZA, azathioprine; 6-TGN, 6-thioguanine nucleotide; TL, trough level; ATI, antibody-to-infliximab. Comparison of IFX durability between monotherapy and combination therapy groups Univariate and multivariate Cox proportional hazard regression analyses revealed that ATI positivity (HR 5.33, 95% CI: 1.61–17.60, p = 0.006) and combination therapy (HR: 0.13, 95% CI: 0.03–0.51, p = 0.004) were associated with IFX durability (Table 3 ). Table 3 Cox proportional hazard regression analysis of factors associated with infliximab durability in patients with Crohn's disease Univariate Cox analysis Multivariate analysis ( n = 108) HR 95% CI p HR 95% CI p Sex (female vs. male) 0.62 0.39–1.66 0.963 Age at diagnosis 0.95 0.85–1.06 0.366 Disease duration at IFX initiation, years 0.73 0.10–1.77 0.723 Any colonic involvement 1.66 0.25–14.48 0.528 Any upper gastrointestinal involvement 2.713 0.98–2.55 0.522 Disease behavior (B1 vs. B2, B3) 1.67 0.53–3.88 0.342 PCDAI at diagnosis 1.00 0.97–1.03 0.897 Erythrocyte sedimentation rate at diagnosis 1.00 0.99–1.01 0.393 Albumin at diagnosis 1.03 0.53–1.98 0.941 C-reactive protein at diagnosis 1.03 0.97–1.19 0.157 SES-CD at diagnosis 1.03 0.92–1.16 0.566 IFX trough concentration at 1 year 0.93 0.81–1.06 0.253 ATI positivity 2.64 1.26–5.53 0.010 5.33 1.61–17.60 0.006 IFX combination therapy vs. monotherapy 0.386 0.18–0.82 0.014 0.13 0.03–0.51 0.004 Abbreviations: IFX, infliximab; PCDAI, Pediatric Crohn’s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn's Disease; ATI, antibody-to-infliximab. Kaplan–Meier survival curves were used to evaluate IFX durability between the monotherapy and combination therapy groups. Notably, IFX durability was significantly higher in the combination therapy group than that in the monotherapy group ( p = 0.0026, log-rank test; Fig. 2 ). The 1-, 2-, and 5-year IFX durability rates were 67.1%, 39.4%, and 20.3%, respectively, in the monotherapy group, and 73.7%, 49.1%, and 26.2%, respectively, in the combination therapy group. Discussion The effectiveness of combination therapy with IFX and AZA versus IFX monotherapy in achieving EH and maintaining durability in pediatric patients with CD has not been previously evaluated. In this study, we demonstrated that combination therapy with IFX and AZA was superior to IFX monotherapy in terms of EH and IFX durability. Additionally, the combination therapy group exhibited higher IFX TLs and lower ATI formation rates than the monotherapy group, implicating pharmacokinetics as a mechanism for better clinical and endoscopic outcomes in the combination therapy group. Our findings demonstrated the superior effectiveness of initial combination therapy to IFX monotherapy in maintaining long-term remission in pediatric patients with CD. Many studies have evaluated the efficacy of combination therapy for moderate-to-severe CD, with a focus on clinical symptoms. A study on biologics in immunomodulatory-naïve patients with CD at week 26 showed that combination therapy was more effective than IFX monotherapy, including corticosteroid-free clinical remission 9 . Similarly, D’Haens et al. demonstrated that early combination therapy was superior to conventional therapy for CR induction and the reduction of corticosteroid use 18 . Although most previous studies have demonstrated the efficacy of combination therapy in the induction phase, some studies have demonstrated the efficacy of combination therapy over monotherapy in maintenance phase of remission in CD 19 , 20 . No noticeable difference in CR was observed in our study. However, consistent with the previous studies, combination therapy showed superiority over monotherapy in the maintenance of remission in pediatric patients with CD in this study. Since an update in STRIDE-Ⅱ in 2021, EH has been increasingly chosen as the primary treatment target for IBD 16 , and research on various treatment strategies for achieving higher EH rates is ongoing. To date, the efficacy of AZA in inducing EH has primarily been evaluated in adults. D’Haens et al. reported that 54% and 70% of adult patients with CD showed healing of the mucosal lesion in the ileum and colonic lesions, respectively, after a median treatment duration of 2 years with AZA 21 . In one prospective observational study targeting the pediatric CD population, 10 of 21 (47.6%) patients achieved EH after 52 weeks of AZA treatment without any biologic agents 22 . However, no studies have directly compared EH achievement in patients with CD receiving combination therapy versus those receiving monotherapy. In our study, the efficacy of combination therapy with IFX and AZA for EH after 1 year of treatment was higher than that of monotherapy (combination therapy group: 78.6% vs. monotherapy group: 33.3%, p < 0.001). Therefore, combination therapy with IFX and AZA can induce EH in patients with CD, including pediatric patients. Based on the literature, TH is associated with significantly higher rates of favorable long-term outcomes, including long-term CR, fewer therapeutic changes, reduced rates of CD hospitalization, and CD-related surgery 23 – 25 . However, TH-related treatment strategy factors remain unknown. In this study, unlike the EH results, the TH rate at 1 year of treatment with combination therapy was slightly higher than that with monotherapy (27.4% vs. 13.6%, p = 0.291), but the effect was not significant. Consequently, additional studies are required to determine the impact of TH on long-term outcomes and the factors associated with TH. The remission effect of combination therapy can be explained by decreased immunogenicity, implying lower ATI formation and higher median IFX TLs 9 , 26 . Additionally, this may lead to an even longer remission period due to a sustained pharmacokinetic effect. Although the mechanism through which thiopurines improve IFX pharmacokinetics remains unclear, it may be associated with a metabolic shift towards 6-thioguanine nucleotide (TGN) levels 27 , 28 . Although we could not determine 6-TGN levels in this study, we found that the proportion of patients with minimal maintenance of IFX threshold TLs for EH (5 µg/mL) increased with combination therapy and that the median IFX TLs were significantly higher in the combination therapy group (combination therapy group: 4.6 µg/mL vs. monotherapy group: 3.9 µg/mL, p = 0.016). Further, the ATI positivity rate in the combination therapy group (25.0%) was significantly lower than that in the monotherapy group (52.2%), suggesting that AZA decreased immunogenicity ( p = 0.025). Polakovicova et al. reported that the IFX TLs depend on the AZA dose 29 . However, considering the various side effects of AZA, studies have reported that achieving a 6-TGN level of ≥ 125 pmol/8 \(\times\) 10 8 RBC may be sufficient to optimize IFX therapeutic levels using combination therapy with AZA and reduce ATI development 27 , 28 . Notably, ATI positivity and combination therapy were significantly associated with IFX durability in our study. Our findings showed superior IFX durability of combination therapy to IFX monotherapy. Early combination therapy with AZA is more effective than monotherapy in pediatric patients 11 . Similarly, early combination therapy is more effective than anti-TNF monotherapy in adult patients and may increase the durability of anti-TNF treatment, which can be explained by IFX TLs and the formation of ATIs 9 . Although several studies have reported higher effectiveness of combination therapy with ADL and AZA than ADL monotherapy 30 , the results remain heterogeneous across studies 31 . The open-label DIAMOND adult trial compared the efficacy of a combination of ADL and AZA and ADL alone 32 . In this study, the patients exhibited similar CR rates at 26 weeks and 12 months for both combination therapy and monotherapy. However, the 6-month endoscopic improvement rate was significantly higher in the ADL combination therapy group (84.2% vs. 63.8%, p = 0.049). Additionally, a post-hoc analysis of the pediatric IMAgINE-1 RCT demonstrated no difference in remission rates between patients who received a combination therapy with ADL and AZA and those who did not (38% vs. 30%, respectively) 33 . Notably, in terms of immunogenicity, opinions on ADL are disputed, and mechanisms underlying the effects of immunomodulators on the immunogenicity of anti-TNF antibodies remain elusive 34 . This may be explained by the fact that ADL is a humanized monoclonal antibody, IFX is a chimeric monoclonal antibody containing 75% human and 25% murine IgG1, and the mechanistic effects of immunomodulators on immunogenicity may vary depending on the biological agent 35 . In clinical practice, the duration for which the therapeutic effect of AZA lasts and whether discontinuing AZA treatment is safe, cost-effective, and feasible for patients with CD after achieving remission remain questionable for physicians. Consequently, an increasing number of attempts are being made to discontinue AZA therapy in patients with CD who have achieved remission, including the pediatric population. Notably, AZA discontinuation did not affect relapse in a study on pediatric patients with CD who maintained CR for at least 2 years and had achieved deep remission 36 . However, in terms of immunogenicity, EH, and IFX durability, combination therapy is recommended during the initial IFX treatment, including at least 1 year of treatment. This study has a few limitations. First, this study was a single-center retrospective study and had limitations in relatively unstructured follow-up schedules compared with prospective studies. However, all patients underwent regular examinations, such as ileocolonoscopy and biopsy, following the same principles. Further, clinical disease activity using the PCDAI, laboratory results, endoscopic findings, and MRE results from medical records was available for all patients. Second, as the metabolite-testing technique, including AZA metabolite testing, such as 6-thioguanine or 6-methilmercaptopurine, was introduced to our medical center midway through the study period, 6-TGN concentration could not be measured in all patients. Nevertheless, this would not affect the finding that AZA as a combination therapy was effective in achieving EH. Additional research is required to determine whether the EH rate varies with AZA metabolite concentration. Finally, the number of patients differed between the two groups. As most patients at our medical center receive combination therapy, enrolling patients with monotherapy was difficult. Most patients who received monotherapy in this study included those who first received AZA but discontinued the drug within the induction period due to side effects such as nausea, vomiting, and leukopenia, or did not receive AZA because genetic mutations were identified in thioprine methyltransferase or nudix hydrolase 15. In conclusion, IFX and AZA combination therapy was associated with higher EH rates and longer IFX durability than IFX monotherapy in pediatric patients with CD. Our results are significant because this is the first study to directly compare clinical outcomes, including EH and IFX durability, in pediatric patients with CD treated with combination therapy and monotherapy. Materials and methods Patients and data collection This retrospective observational study was conducted at the Department of Pediatrics of Samsung Medical Center between November 2012 and February 2022. Children and adolescents diagnosed with CD who were treated with IFX and/or AZA at < 19 years of age were included. Patients with missing baseline clinicodemographic data were excluded. CD was diagnosed based on the revised Porto criteria of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition 37 . This study was approved by the Institutional Review Board and adhered to the Declaration of Helsinki guidelines (Samsung Medical Center IRB File No. 2023-10-010). Informed consent and consent for publication were obtained from all participants and their guardians involved in the study. Baseline clinicodemographic and laboratory data at diagnosis, including sex, age, disease phenotype, growth indicators, and family history of IBD, were obtained from the electronic medical records (EMR). Clinical data and laboratory results at diagnosis and 1 year after IFX initiation, including IFX treatment duration, dose intensification, Pediatric Crohn's Disease Activity Index (PCDAI) score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum albumin, Simple Endoscopic Score for CD (SES-CD), TLs of IFX, and the presence of antibodies-to-IFX (ATIs), were collected retrospectively from EMR. ATIs were quantified using enzyme-linked immunosorbent assay kits (ELISA; Matriks Biotek Laboratories, Ankara, Turkey) at an optical density of 450 nm, and IFX TLs were assessed using IDK monitor®infliximab drug level ELISA for IFX prior to its administration. Ileocolonoscopy and magnetic resonance enterography (MRE) were performed at diagnosis and 1 year after biologic treatment. Endpoints, group allocation, and definitions The primary endpoint of this study were EH after 1 year of IFX treatment, and the secondary endpoint was IFX durability during the study period. Based on whether the patients received IFX monotherapy or combination therapy with IFX and AZA, they were divided into monotherapy or combo-therapy groups, respectively. Treatment outcomes, such as CR, biochemical remission (BR), EH, and transmural healing (TH), were evaluated using laboratory tests, ileocolonoscopy, and MRE after 1 year of treatment. CR and BR were defined as PCDAI < 10 and CRP < 0.3 mg/dL, respectively. EH was defined as an SES-CD ≤ 2, which corresponds to complete mucosal healing to normal 38 . TH was defined as a wall thickness < 3 mm in the absence of ulcers, edema, enhancement, and complications for all ileocolonic segments, as evaluated using MRE. IFX durability was defined as the continuous use of IFX, excluding situations requiring inevitable discontinuation of IFX, such as infusion reactions, surgery, or severe adverse events. Statistical analysis For statistical comparisons between the combination and monotherapy groups, Student's t -test and Wilcoxon rank-sum test were used for continuous variables, whereas the chi-square or Fischer's exact test was used for categorical variables. Univariate and multivariate Cox proportional hazards regression analyses were used to investigate factors associated with IFX durability. Factors with p < 0.1 in the univariate analyses were included in the multivariate analyses. The results were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Kaplan–Meier analysis and log-rank test were used to calculate IFX durability and the overall statistical differences, respectively. Statistical significance was set at p < 0.05. All statistical analyses were performed using Rex (Version 3.6.0, RexSoft Inc., Seoul, Korea). Data availability Data supporting the findings of this study are not publicly available due to privacy and ethical restrictions and can be obtained from the corresponding author upon request Abbreviations IBD inflammatory bowel disease UGI upper gastrointestinal PCDAI Pediatric Crohn's Disease Activity Index ESR erythrocyte sedimentation rate CRP C-reactive protein SES-CD Simple Endoscopic Score for Crohn's Disease. Declarations Author contributions Yoon Zi Kim: Data curation, Investigation; Validation; Writing – original draft; Writing – review & editing. Eun Sil Kim: Conceptualization; Data curation; Formal analysis; Investigation; Visualization; Validation; Writing – original draft; Writing – review & editing. Yiyoung Kwon: Data curation; Formal analysis. Seon Young Kim: Data curation; Formal analysis. Hansol Kim: Data curation; Formal analysis. Yon Ho Choi: Investigation; Supervision; Validation. Mi Jin Kim: Investigation; Supervision; Validation. Funding This work was supported by the Medical Research Funds from Kangbuk Samsung Hospital. Competing interests The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. References Torres, J., Mehandru, S., Colombel, J. F. & Peyrin-Biroulet, L. Crohn's disease. Lancet 389 , 1741-1755. http://doi.org/10.1016/S0140-6736(16)31711-1 (2017). Hong, S. J. et al. Characteristics and Incidence Trends for Pediatric Inflammatory Bowel Disease in Daegu-Kyungpook Province in Korea: a Multi-Center Study. J. Korean Med. Sci. 33 , e132. http://doi.org/10.3346/jkms.2018.33.e132 (2018). Rosen, M. J., Dhawan, A. & Saeed, S. A. Inflammatory Bowel Disease in Children and Adolescents. JAMA Pediatr. 169 , 1053-1060. http://doi.org/10.1001/jamapediatrics.2015.1982 (2015). Hyams, J. et al. 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Papamichael, K. et al. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases. Clin. Gastroenterol. Hepatol. 17 , 1655-1668 e3. http://doi.org/10.1016/j.cgh.2019.03.037 (2019). D'Haens, G. et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 371 , 660-667. http://doi.org/10.1016/S0140-6736(08)60304-9 (2008). Hazlewood, G. S. et al. Comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in Crohn's disease: a network meta-analysis. Gastroenterology 148 , 344-354 e5; quiz e14-15. http://doi.org/10.1053/j.gastro.2014.10.011 (2015). Van Assche, G. et al. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology 134 , 1861-1868. http://doi.org/10.1053/j.gastro.2008.03.004 (2008). D'Haens, G., Geboes, K., Ponette, E., Penninckx, F. & Rutgeerts, P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn's disease. Gastroenterology 112 , 1475-1481. http://doi.org/10.1016/s0016-5085(97)70027-1 (1997). Giugliano, F. P. et al. Does Azathioprine induce endoscopic and histologic healing in pediatric inflammatory bowel disease? A prospective, observational study. Dig. Liver Dis. 50 , 240-246. http://doi.org/10.1016/j.dld.2017.10.017 (2018). Lafeuille, P. et al. Transmural healing and MRI healing are associated with lower risk of bowel damage progression than endoscopic mucosal healing in Crohn's disease. Aliment. Pharmacol. Ther. 53 , 577-586. http://doi.org/10.1111/apt.16232 (2021). Fernandes, S. R. et al. Transmural Healing Is Associated with Improved Long-term Outcomes of Patients with Crohn's Disease. Inflamm. Bowel Dis. 23 , 1403-1409. http://doi.org/10.1097/MIB.0000000000001143 (2017). Deepak, P. et al. Radiological Response Is Associated With Better Long-Term Outcomes and Is a Potential Treatment Target in Patients With Small Bowel Crohn's Disease. Am. J. Gastroenterol. 111 , 997-1006. http://doi.org/10.1038/ajg.2016.177 (2016). Lichtenstein, G. R., Hanauer, S. B., Sandborn, W. J. & Practice Parameters Committee of American College of, G. Management of Crohn's disease in adults. Am. J. Gastroenterol. 104 , 465-483; quiz 464, 484. http://doi.org/10.1038/ajg.2008.168 (2009). Mogensen, D. V. et al. A Role for Thiopurine Metabolites in the Synergism Between Thiopurines and Infliximab in Inflammatory Bowel Disease. J. Crohns Colitis 12 , 298-305. http://doi.org/10.1093/ecco-jcc/jjx149 (2018). Yarur, A. J. et al. Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy. Clin. Gastroenterol. Hepatol. 13 , 1118-1124 e1113. http://doi.org/10.1016/j.cgh.2014.12.026 (2015). Polakovicova, V. et al. Positive pharmacokinetic effect of azathioprine co-medication on infliximab trough levels is dose-dependent. Dig. Liver Dis. 51 , 1112-1116. http://doi.org/10.1016/j.dld.2019.05.001 (2019). Cosnes, J. et al. Adalimumab or infliximab as monotherapy, or in combination with an immunomodulator, in the treatment of Crohn's disease. Aliment. Pharmacol. Ther. 44 , 1102-1113. http://doi.org/10.1111/apt.13808 (2016). Wong, D. R. et al. The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients. J. Crohns Colitis 8 , 120-128. http://doi.org/10.1016/j.crohns.2013.07.004 (2014). Matsumoto, T. et al. Adalimumab Monotherapy and a Combination with Azathioprine for Crohn's Disease: A Prospective, Randomized Trial. J. Crohns Colitis 10 , 1259-1266. http://doi.org/10.1093/ecco-jcc/jjw152 (2016). Hyams, J. S. et al. The effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in paediatric patients with Crohn's disease: a post hoc analysis. Aliment. Pharmacol. Ther. 49 , 155-164. http://doi.org/10.1111/apt.15054 (2019). Karmiris, K. et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn's disease. Gastroenterology 137 , 1628-1640. http://doi.org/10.1053/j.gastro.2009.07.062 (2009). Honda, N., Yamada, Y., Muramatsu, T., Fukatsu, H. & Segawa, A. [Anti-tumor effect of human recombinant tumor necrosis factor on the human renal cell carcinoma serially transplanted into nude mice]. Nihon Hinyokika Gakkai Zasshi 79 , 1613-1621. http://doi.org/10.5980/jpnjurol1928.79.10_1613 (1988). Jeong, T. J. et al. Discontinuation of Azathioprine could be considered in pediatric patients with Crohn's disease who have sustained clinical and deep remission. Sci. Rep. 12 , 507. http://doi.org/10.1038/s41598-021-04304-6 (2022). Levine, A. et al. ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J. Pediatr. Gastroenterol. Nutr. 58 , 795-806. http://doi.org/10.1097/MPG.0000000000000239 (2014). Daperno, M. et al. Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest. Endosc. 60 , 505-512. http://doi.org/10.1016/s0016-5107(04)01878-4 (2004). Additional Declarations No competing interests reported. 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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-4512921","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":316049774,"identity":"4d223ba5-e5e3-422b-9b05-bc706d84bc48","order_by":0,"name":"Yoon Zi Kim","email":"","orcid":"","institution":"Samsung Medical Center, Sungkyunkwan University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yoon","middleName":"Zi","lastName":"Kim","suffix":""},{"id":316049775,"identity":"d13c57b9-dfdd-4d64-9a13-e68ee5cae937","order_by":1,"name":"Eun Sil Kim","email":"","orcid":"","institution":"Kangbuk Samsung Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eun","middleName":"Sil","lastName":"Kim","suffix":""},{"id":316049776,"identity":"3e79e685-24c3-424c-82f5-2a93e07db07e","order_by":2,"name":"Yiyoung Kwon","email":"","orcid":"","institution":"Inha University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yiyoung","middleName":"","lastName":"Kwon","suffix":""},{"id":316049777,"identity":"60926dce-7b06-4600-aa0e-9d3887902e7c","order_by":3,"name":"Seon Young Kim","email":"","orcid":"","institution":"Samsung Medical Center, Sungkyunkwan University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Seon","middleName":"Young","lastName":"Kim","suffix":""},{"id":316049778,"identity":"88243150-cb0c-4743-b0db-9104b7e62ff0","order_by":4,"name":"Hansol Kim","email":"","orcid":"","institution":"Samsung Medical Center, Sungkyunkwan University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hansol","middleName":"","lastName":"Kim","suffix":""},{"id":316049779,"identity":"e1888f1f-f939-42fc-a070-62e34c4e5436","order_by":5,"name":"Yon Ho Choe","email":"","orcid":"","institution":"Samsung Medical Center, Sungkyunkwan University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yon","middleName":"Ho","lastName":"Choe","suffix":""},{"id":316049780,"identity":"f264fa99-f6c8-4c82-815e-6a52fe33c3da","order_by":6,"name":"Mi Jin Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIie3PP2rDMBTH8Z8RyMs7gENCegKDikFd0vgqCoZMLmQqGYrxlIxZO5QeQ7Pog04Gr+6YGwTSIUOhTdylQ+J6LFTfRSDeR38An+8vJmAc1IRSJ+Gw7E0W8xFaUvW+aseTE0Gw6jEcr7HlhRIUlHL28vZcXMWbSm/fMR3H5XmiGYYflSQB6fjO8rVt8ptkhCzRroOQIpIIyyNxgW1IDyO4me0mEVFLnorU1lUvoihqH1aK42SuB7vfiSElpOH8lTPbzO+HUB1/qatsTx+fqQpXyT5/KG5tzXZwWE7HlwhA5nsVP/YEqUvjp8IzhwWHLuHz+Xz/rS/eLl3a0jqgrwAAAABJRU5ErkJggg==","orcid":"","institution":"Samsung Medical Center, Sungkyunkwan University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Mi","middleName":"Jin","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2024-06-01 09:26:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4512921/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4512921/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-06445-4","type":"published","date":"2025-07-02T15:57:11+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":59051615,"identity":"a18d760b-80a4-46cd-9f66-65f26259152b","added_by":"auto","created_at":"2024-06-25 20:08:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65240,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of infliximab trough levels at 1 year between monotherapy and combination therapy groups\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4512921/v1/a5b3669449261e2c5da2ccdb.png"},{"id":59051616,"identity":"b712b5c6-30ed-4bd8-aa92-d13b5f62142f","added_by":"auto","created_at":"2024-06-25 20:08:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":68421,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of infliximab durability between monotherapy and combination therapy groups (Kaplan–Meier survival curves,\u003cem\u003e p\u003c/em\u003e = 0.0026)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4512921/v1/e263dbfb2f89663254e51781.png"},{"id":86178936,"identity":"bf4a98e2-4b72-4ca2-b682-0a3ef9f276ba","added_by":"auto","created_at":"2025-07-07 16:11:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1185027,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4512921/v1/17b025b0-bdc5-41eb-95a9-727d7d3becc1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of Endoscopic Healing and Durability between Combination Therapy with Infliximab and Azathioprine versus Infliximab Monotherapy in Pediatric Crohn's disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCrohn's disease (CD), a type of inflammatory bowel disease (IBD), is characterized by inflammation in the gastrointestinal tract\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. With an increasing prevalence of CD, numerous studies are being conducted on its treatment\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Notably, the emergence of biologics is widely regarded as a pivotal development in the effective treatment of CD.\u003c/p\u003e \u003cp\u003eA novel biologic therapy with anti-tumor necrosis factor alpha (anti-TNF α) agents, such as infliximab (IFX) or adalimumab (ADL), has revolutionized CD treatment. IFX, the first biologic agent, is highly effective in the induction and maintenance of remission in patients with moderate-to-severe CD, even pediatric patients\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, a considerable number of patients with CD undergoing anti-TNF α treatment experience a loss of response (LOR) to anti-TNF induction therapy called primary LOR or a LOR to treatment over time after initially experiencing clinical improvement called secondary LOR\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Secondary LOR is mainly attributed to pharmacokinetic problems and subtherapeutic drug concentrations due to the formation of anti-drug antibodies (ADAs) that neutralize biologics\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe landmark SONIC trial for CD demonstrated superior effectiveness of IFX and azathioprine (AZA), which is known as a combination therapy, to IFX monotherapy for corticosteroid-free clinical remission (CR) in na\u0026iuml;ve patients with moderate-to-severe disease\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Further, compared with monotherapy, combination therapy is also more effective for CR and reduces the LOR rate in pediatric patients with CD\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. In addition, the combination therapy prevents ADA formation and maintains higher median IFX trough levels (TLs), improving the remission rate in CD\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn an update on the selection of therapeutic targets in IBD (STRIDE-Ⅱ), treatment of the target of endoscopic healing (EH) has been associated with improvements in long-term outcomes, as mucosal inflammation is associated with long-term disease-related complications, even in CR\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. However, data on EH efficacy in combination therapy is limited compared with the monotherapy. Therefore, this study aimed to evaluate EH efficacy and the durability of IFX in combination therapy compared with monotherapy in pediatric patients with CD.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eBaseline characteristics\u003c/h2\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eA total of 108 patients were included in this study. Of these, 21.3% (23/108) and 78.7% (85/108) patients were assigned to the monotherapy and combination therapy groups, respectively. The mean age of the patients at diagnosis was 14.2 years, and 80.6% (87/108) were male. Four patients (3.7%) had a first-degree family history of IBD. No significant differences were observed in the baseline characteristics of the patients between the monotherapy and combination therapy groups. Disease phenotype, disease activity, and other baseline characteristics are presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;108)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIFX monotherapy group (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIFX\u0026thinsp;+\u0026thinsp;AZA combination therapy group (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;85)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale sex, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e87 (80.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19 (82.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e68 (80.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.2147\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge at diagnosis, \u003cem\u003eyears\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.948\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1st degree family history of IBD, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisease location, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIleal (L1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eColonic (L2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIleocolonic (L3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e92 (85.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20 (87.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72 (84.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUGI involvement, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.971\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15 (13.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (21.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProximal to the ligament of Treitz (L4a)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31 (28.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7 (30.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24 (28.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDistal to the ligament of Treitz and proximal to the distal 1/3 ileum (L4b)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (21.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19 (22.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBoth (L4ab)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38 (35.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6 (26.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32 (37.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLuminal disease behavior\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.804\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNonstricturing nonpenetrating (B1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e99 (91.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21 (91.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78 (91.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStricturing (B2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6 (5.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePenetrating (B3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePerianal disease, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e67 (62.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14 (60.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e53 (62.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.614\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrowth retardation, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28 (25.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6 (26.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22 (25.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.970\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePCDAI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32.5 (23.8, 40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32.5 (30.0, 40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32.5 (22.5, 40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.645\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWBC count, \u0026times;\u003cem\u003e10\u003c/em\u003e\u003csup\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e/uL\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.9 (7.1, 10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.6 (7.6, 9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.1 (7.0, 10.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.685\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHematocrit, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.756\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelet count, \u0026times;\u003cem\u003e10\u003c/em\u003e\u003csup\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e/uL\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e377.0 (308.5, 480.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e364.0 (320.0, 453.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e379.0 (322.0, 478.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.696\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eESR, \u003cem\u003emm/h\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37.5 (19.5, 62.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38.0 (25.5, 58.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37.0 (18.0, 64.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.813\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlbumin, \u003cem\u003eg/dL\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.259\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCRP, \u003cem\u003emg/dL\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.3 (0.3, 2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.1 (0.3, 2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.3 (0.3, 3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.626\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSES-CD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.0 (10.0, 22.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.0 (10.0, 22.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.0 (10.0, 22.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.801\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eContinuous variables are expressed as the median (interquartile range) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eAbbreviations: IBD, inflammatory bowel disease; UGI, upper gastrointestinal; PCDAI, Pediatric Crohn\u0026apos;s Disease Activity Index; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; SES-CD, Simple Endoscopic Score for Crohn\u0026apos;s Disease.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eComparison of treatment outcomes between monotherapy and combination therapy groups\u003c/h2\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eNo significant differences in the proportion of patients with CR and TH at 1 year (CR: 95.8% vs. 96.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.99; TH: 13.6% vs. 27.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.291) were observed between the monotherapy and combination therapy groups. The laboratory results and SES-CDs were also comparable between the two groups (SES-CD: 1.0 vs. 0.0, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.083). However, the proportion of patients with BR and EH at 1 year was significantly lower in the monotherapy group than in the combination therapy group (BR: 66.7% vs. 92.9%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003; EH: 33.3% vs. 78.6%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n \u003cp\u003eMedian IFX TLs were significantly lower in the monotherapy group compared with the combination therapy group (3.9 \u0026micro;g/mL vs. 4.6 \u0026micro;g/mL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016; Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Further, the proportion of patients with minimal maintenance of IFX threshold TLs for EH (5 \u0026micro;g/mL)\u003csup\u003e17\u003c/sup\u003e was lower in the monotherapy group than in the combination therapy group (30.5% vs. 44.1%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023). Moreover, ATI positivity was higher in the monotherapy group than in the combination therapy group (52.2% vs. 25.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025). The detailed treatment outcomes of the two groups are presented in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparison of 1-year treatment outcomes between monotherapy and combination therapy groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;108)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIFX monotherapy group (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIFX\u0026thinsp;+\u0026thinsp;AZA combination therapy group (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;85)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWBC count, \u0026times;\u003cem\u003e10\u003c/em\u003e\u003csup\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e/uL\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.5 (5.5, 8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.3 (5.3, 7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.6 (5.5, 8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.679\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHematocrit, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e41.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelet count, \u0026times;\u003cem\u003e10\u003c/em\u003e\u003csup\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e/uL\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e256.0 (223.0, 292.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e250.0 (212.8, 276.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e257.5 (225.8, 308.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eESR, \u003cem\u003emm/h\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.0 (2.0, 10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.0 (3.8, 13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.0 (2.0, 10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.144\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlbumin, \u003cem\u003eg/dL\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.715\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCRP, \u003cem\u003emg/dL\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.06 (0.03, 0.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.04 (0.03, 0.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.06 (0.03, 0.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.121\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSES-CD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.0 (0.0, 3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.0 (0.0, 5.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.0 (0.0, 3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical remission at 1 year, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e104 (96.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22 (95.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e81 (96.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBiochemical remission at 1 year, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e94 (87.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78 (92.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndoscopic healing at 1 year, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e74 (68.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e66 (78.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTransmural healing at 1 year, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26 (24.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23 (27.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.291\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIFX trough concentration, \u003cem\u003e\u0026micro;g/mL\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.3 (2.5, 6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.9 (1.4, 5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.6 (3.1, 7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIFX trough concentration, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;3 \u0026micro;g/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29 (27.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11 (47.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u0026ndash;5 \u0026micro;g/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34 (31.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (21.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29 (34.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;5 \u0026micro;g/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44 (41.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7 (30.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37 (44.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eATI positivity, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33 (30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12 (52.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eContinuous variables are expressed as the median (interquartile range) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eAbbreviations: IFX, infliximab; AZA, azathioprine; 6-TGN, 6-thioguanine nucleotide; TL, trough level; ATI, antibody-to-infliximab.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eComparison of IFX durability between monotherapy and combination therapy groups\u003c/h2\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eUnivariate and multivariate Cox proportional hazard regression analyses revealed that ATI positivity (HR 5.33, 95% CI: 1.61\u0026ndash;17.60, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006) and combination therapy (HR: 0.13, 95% CI: 0.03\u0026ndash;0.51, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) were associated with IFX durability (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCox proportional hazard regression analysis of factors associated with infliximab durability in patients with Crohn\u0026apos;s disease\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"7\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eUnivariate Cox analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eMultivariate analysis (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;108)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex (female vs. male)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.39\u0026ndash;1.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.963\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.85\u0026ndash;1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.366\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisease duration at IFX initiation, \u003cem\u003eyears\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.10\u0026ndash;1.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.723\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny colonic involvement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.25\u0026ndash;14.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.528\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny upper gastrointestinal involvement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.713\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.98\u0026ndash;2.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.522\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisease behavior (B1 vs. B2, B3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.53\u0026ndash;3.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.342\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePCDAI at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.97\u0026ndash;1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.897\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eErythrocyte sedimentation rate at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.99\u0026ndash;1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.393\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlbumin at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.53\u0026ndash;1.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.941\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC-reactive protein at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.97\u0026ndash;1.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.157\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSES-CD at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.92\u0026ndash;1.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.566\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIFX trough concentration at 1 year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.81\u0026ndash;1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eATI positivity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.26\u0026ndash;5.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.61\u0026ndash;17.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIFX combination therapy vs. monotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.386\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.18\u0026ndash;0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.03\u0026ndash;0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eAbbreviations: IFX, infliximab; PCDAI, Pediatric Crohn\u0026rsquo;s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn\u0026apos;s Disease; ATI, antibody-to-infliximab.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eKaplan\u0026ndash;Meier survival curves were used to evaluate IFX durability between the monotherapy and combination therapy groups. Notably, IFX durability was significantly higher in the combination therapy group than that in the monotherapy group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0026, log-rank test; Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The 1-, 2-, and 5-year IFX durability rates were 67.1%, 39.4%, and 20.3%, respectively, in the monotherapy group, and 73.7%, 49.1%, and 26.2%, respectively, in the combination therapy group.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe effectiveness of combination therapy with IFX and AZA versus IFX monotherapy in achieving EH and maintaining durability in pediatric patients with CD has not been previously evaluated. In this study, we demonstrated that combination therapy with IFX and AZA was superior to IFX monotherapy in terms of EH and IFX durability. Additionally, the combination therapy group exhibited higher IFX TLs and lower ATI formation rates than the monotherapy group, implicating pharmacokinetics as a mechanism for better clinical and endoscopic outcomes in the combination therapy group. Our findings demonstrated the superior effectiveness of initial combination therapy to IFX monotherapy in maintaining long-term remission in pediatric patients with CD.\u003c/p\u003e \u003cp\u003eMany studies have evaluated the efficacy of combination therapy for moderate-to-severe CD, with a focus on clinical symptoms. A study on biologics in immunomodulatory-na\u0026iuml;ve patients with CD at week 26 showed that combination therapy was more effective than IFX monotherapy, including corticosteroid-free clinical remission\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Similarly, D\u0026rsquo;Haens et al. demonstrated that early combination therapy was superior to conventional therapy for CR induction and the reduction of corticosteroid use\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Although most previous studies have demonstrated the efficacy of combination therapy in the induction phase, some studies have demonstrated the efficacy of combination therapy over monotherapy in maintenance phase of remission in CD\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. No noticeable difference in CR was observed in our study. However, consistent with the previous studies, combination therapy showed superiority over monotherapy in the maintenance of remission in pediatric patients with CD in this study.\u003c/p\u003e \u003cp\u003eSince an update in STRIDE-Ⅱ in 2021, EH has been increasingly chosen as the primary treatment target for IBD\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, and research on various treatment strategies for achieving higher EH rates is ongoing. To date, the efficacy of AZA in inducing EH has primarily been evaluated in adults. D\u0026rsquo;Haens et al. reported that 54% and 70% of adult patients with CD showed healing of the mucosal lesion in the ileum and colonic lesions, respectively, after a median treatment duration of 2 years with AZA\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. In one prospective observational study targeting the pediatric CD population, 10 of 21 (47.6%) patients achieved EH after 52 weeks of AZA treatment without any biologic agents\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. However, no studies have directly compared EH achievement in patients with CD receiving combination therapy versus those receiving monotherapy. In our study, the efficacy of combination therapy with IFX and AZA for EH after 1 year of treatment was higher than that of monotherapy (combination therapy group: 78.6% vs. monotherapy group: 33.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Therefore, combination therapy with IFX and AZA can induce EH in patients with CD, including pediatric patients.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003eBased on the literature, TH is associated with significantly higher rates of favorable long-term outcomes, including long-term CR, fewer therapeutic changes, reduced rates of CD hospitalization, and CD-related surgery\u003csup\u003e\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. However, TH-related treatment strategy factors remain unknown. In this study, unlike the EH results, the TH rate at 1 year of treatment with combination therapy was slightly higher than that with monotherapy (27.4% vs. 13.6%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.291), but the effect was not significant. Consequently, additional studies are required to determine the impact of TH on long-term outcomes and the factors associated with TH.\u003c/p\u003e \u003cp\u003eThe remission effect of combination therapy can be explained by decreased immunogenicity, implying lower ATI formation and higher median IFX TLs\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Additionally, this may lead to an even longer remission period due to a sustained pharmacokinetic effect. Although the mechanism through which thiopurines improve IFX pharmacokinetics remains unclear, it may be associated with a metabolic shift towards 6-thioguanine nucleotide (TGN) levels\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Although we could not determine 6-TGN levels in this study, we found that the proportion of patients with minimal maintenance of IFX threshold TLs for EH (5 \u0026micro;g/mL) increased with combination therapy and that the median IFX TLs were significantly higher in the combination therapy group (combination therapy group: 4.6 \u0026micro;g/mL vs. monotherapy group: 3.9 \u0026micro;g/mL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016). Further, the ATI positivity rate in the combination therapy group (25.0%) was significantly lower than that in the monotherapy group (52.2%), suggesting that AZA decreased immunogenicity (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025). Polakovicova et al. reported that the IFX TLs depend on the AZA dose\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. However, considering the various side effects of AZA, studies have reported that achieving a 6-TGN level of \u0026ge;\u0026thinsp;125 pmol/8\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\times\\)\u003c/span\u003e\u003c/span\u003e10\u003csup\u003e8\u003c/sup\u003e RBC may be sufficient to optimize IFX therapeutic levels using combination therapy with AZA and reduce ATI development\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Notably, ATI positivity and combination therapy were significantly associated with IFX durability in our study.\u003c/p\u003e \u003cp\u003eOur findings showed superior IFX durability of combination therapy to IFX monotherapy. Early combination therapy with AZA is more effective than monotherapy in pediatric patients\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Similarly, early combination therapy is more effective than anti-TNF monotherapy in adult patients and may increase the durability of anti-TNF treatment, which can be explained by IFX TLs and the formation of ATIs\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlthough several studies have reported higher effectiveness of combination therapy with ADL and AZA than ADL monotherapy\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e, the results remain heterogeneous across studies\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. The open-label DIAMOND adult trial compared the efficacy of a combination of ADL and AZA and ADL alone\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. In this study, the patients exhibited similar CR rates at 26 weeks and 12 months for both combination therapy and monotherapy. However, the 6-month endoscopic improvement rate was significantly higher in the ADL combination therapy group (84.2% vs. 63.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049). Additionally, a post-hoc analysis of the pediatric IMAgINE-1 RCT demonstrated no difference in remission rates between patients who received a combination therapy with ADL and AZA and those who did not (38% vs. 30%, respectively)\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Notably, in terms of immunogenicity, opinions on ADL are disputed, and mechanisms underlying the effects of immunomodulators on the immunogenicity of anti-TNF antibodies remain elusive\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. This may be explained by the fact that ADL is a humanized monoclonal antibody, IFX is a chimeric monoclonal antibody containing 75% human and 25% murine IgG1, and the mechanistic effects of immunomodulators on immunogenicity may vary depending on the biological agent\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn clinical practice, the duration for which the therapeutic effect of AZA lasts and whether discontinuing AZA treatment is safe, cost-effective, and feasible for patients with CD after achieving remission remain questionable for physicians. Consequently, an increasing number of attempts are being made to discontinue AZA therapy in patients with CD who have achieved remission, including the pediatric population. Notably, AZA discontinuation did not affect relapse in a study on pediatric patients with CD who maintained CR for at least 2 years and had achieved deep remission\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. However, in terms of immunogenicity, EH, and IFX durability, combination therapy is recommended during the initial IFX treatment, including at least 1 year of treatment.\u003c/p\u003e \u003cp\u003eThis study has a few limitations. First, this study was a single-center retrospective study and had limitations in relatively unstructured follow-up schedules compared with prospective studies. However, all patients underwent regular examinations, such as ileocolonoscopy and biopsy, following the same principles. Further, clinical disease activity using the PCDAI, laboratory results, endoscopic findings, and MRE results from medical records was available for all patients. Second, as the metabolite-testing technique, including AZA metabolite testing, such as 6-thioguanine or 6-methilmercaptopurine, was introduced to our medical center midway through the study period, 6-TGN concentration could not be measured in all patients. Nevertheless, this would not affect the finding that AZA as a combination therapy was effective in achieving EH. Additional research is required to determine whether the EH rate varies with AZA metabolite concentration. Finally, the number of patients differed between the two groups. As most patients at our medical center receive combination therapy, enrolling patients with monotherapy was difficult. Most patients who received monotherapy in this study included those who first received AZA but discontinued the drug within the induction period due to side effects such as nausea, vomiting, and leukopenia, or did not receive AZA because genetic mutations were identified in thioprine methyltransferase or nudix hydrolase 15.\u003c/p\u003e \u003cp\u003eIn conclusion, IFX and AZA combination therapy was associated with higher EH rates and longer IFX durability than IFX monotherapy in pediatric patients with CD. Our results are significant because this is the first study to directly compare clinical outcomes, including EH and IFX durability, in pediatric patients with CD treated with combination therapy and monotherapy.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatients and data collection\u003c/h2\u003e \u003cp\u003eThis retrospective observational study was conducted at the Department of Pediatrics of Samsung Medical Center between November 2012 and February 2022. Children and adolescents diagnosed with CD who were treated with IFX and/or AZA at \u0026lt;\u0026thinsp;19 years of age were included. Patients with missing baseline clinicodemographic data were excluded. CD was diagnosed based on the revised Porto criteria of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. This study was approved by the Institutional Review Board and adhered to the Declaration of Helsinki guidelines (Samsung Medical Center IRB File No. 2023-10-010). Informed consent and consent for publication were obtained from all participants and their guardians involved in the study.\u003c/p\u003e \u003cp\u003eBaseline clinicodemographic and laboratory data at diagnosis, including sex, age, disease phenotype, growth indicators, and family history of IBD, were obtained from the electronic medical records (EMR). Clinical data and laboratory results at diagnosis and 1 year after IFX initiation, including IFX treatment duration, dose intensification, Pediatric Crohn's Disease Activity Index (PCDAI) score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum albumin, Simple Endoscopic Score for CD (SES-CD), TLs of IFX, and the presence of antibodies-to-IFX (ATIs), were collected retrospectively from EMR. ATIs were quantified using enzyme-linked immunosorbent assay kits (ELISA; Matriks Biotek Laboratories, Ankara, Turkey) at an optical density of 450 nm, and IFX TLs were assessed using IDK monitor\u0026reg;infliximab drug level ELISA for IFX prior to its administration. Ileocolonoscopy and magnetic resonance enterography (MRE) were performed at diagnosis and 1 year after biologic treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEndpoints, group allocation, and definitions\u003c/h2\u003e \u003cp\u003eThe primary endpoint of this study were EH after 1 year of IFX treatment, and the secondary endpoint was IFX durability during the study period. Based on whether the patients received IFX monotherapy or combination therapy with IFX and AZA, they were divided into monotherapy or combo-therapy groups, respectively.\u003c/p\u003e \u003cp\u003eTreatment outcomes, such as CR, biochemical remission (BR), EH, and transmural healing (TH), were evaluated using laboratory tests, ileocolonoscopy, and MRE after 1 year of treatment. CR and BR were defined as PCDAI\u0026thinsp;\u0026lt;\u0026thinsp;10 and CRP\u0026thinsp;\u0026lt;\u0026thinsp;0.3 mg/dL, respectively. EH was defined as an SES-CD\u0026thinsp;\u0026le;\u0026thinsp;2, which corresponds to complete mucosal healing to normal\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. TH was defined as a wall thickness\u0026thinsp;\u0026lt;\u0026thinsp;3 mm in the absence of ulcers, edema, enhancement, and complications for all ileocolonic segments, as evaluated using MRE. IFX durability was defined as the continuous use of IFX, excluding situations requiring inevitable discontinuation of IFX, such as infusion reactions, surgery, or severe adverse events.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eFor statistical comparisons between the combination and monotherapy groups, Student's \u003cem\u003et\u003c/em\u003e-test and Wilcoxon rank-sum test were used for continuous variables, whereas the chi-square or Fischer's exact test was used for categorical variables.\u003c/p\u003e \u003cp\u003eUnivariate and multivariate Cox proportional hazards regression analyses were used to investigate factors associated with IFX durability. Factors with \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.1 in the univariate analyses were included in the multivariate analyses. The results were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Kaplan\u0026ndash;Meier analysis and log-rank test were used to calculate IFX durability and the overall statistical differences, respectively. Statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All statistical analyses were performed using Rex (Version 3.6.0, RexSoft Inc., Seoul, Korea).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eData supporting the findings of this study are not publicly available due to privacy and ethical restrictions and can be obtained from the corresponding author upon request\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIBD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einflammatory bowel disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUGI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eupper gastrointestinal\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePCDAI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePediatric Crohn's Disease Activity Index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eESR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eerythrocyte sedimentation rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSES-CD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSimple Endoscopic Score for Crohn's Disease.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYoon Zi Kim:\u0026nbsp;\u003c/strong\u003eData curation, Investigation; Validation; Writing – original draft; Writing – review\u0026nbsp;\u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEun Sil Kim:\u003c/strong\u003e Conceptualization; Data curation; Formal analysis; Investigation; Visualization; Validation; Writing – original draft; Writing – review\u0026nbsp;\u0026amp; editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYiyoung Kwon:\u003c/strong\u003e Data curation; Formal analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSeon Young Kim:\u0026nbsp;\u003c/strong\u003eData curation; Formal analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHansol Kim:\u0026nbsp;\u003c/strong\u003eData curation; Formal analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYon Ho Choi:\u003c/strong\u003e Investigation; Supervision; Validation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMi Jin Kim:\u003c/strong\u003e Investigation; Supervision; Validation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Medical Research\u0026nbsp;Funds from Kangbuk Samsung Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that this research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict\u0026nbsp;of interest.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eTorres, J., Mehandru, S., Colombel, J. 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Ther.\u003c/em\u003e \u003cstrong\u003e53\u003c/strong\u003e, 577-586. http://doi.org/10.1111/apt.16232 (2021).\u003c/li\u003e\n \u003cli\u003eFernandes, S. R.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Transmural Healing Is Associated with Improved Long-term Outcomes of Patients with Crohn\u0026apos;s Disease. \u003cem\u003eInflamm. Bowel Dis.\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 1403-1409. http://doi.org/10.1097/MIB.0000000000001143 (2017).\u003c/li\u003e\n \u003cli\u003eDeepak, P.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Radiological Response Is Associated With Better Long-Term Outcomes and Is a Potential Treatment Target in Patients With Small Bowel Crohn\u0026apos;s Disease. \u003cem\u003eAm. J. Gastroenterol.\u003c/em\u003e \u003cstrong\u003e111\u003c/strong\u003e, 997-1006. http://doi.org/10.1038/ajg.2016.177 (2016).\u003c/li\u003e\n \u003cli\u003eLichtenstein, G. R., Hanauer, S. B., Sandborn, W. 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Hepatol.\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 1118-1124 e1113. http://doi.org/10.1016/j.cgh.2014.12.026 (2015).\u003c/li\u003e\n \u003cli\u003ePolakovicova, V.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Positive pharmacokinetic effect of azathioprine co-medication on infliximab trough levels is dose-dependent. \u003cem\u003eDig. Liver Dis.\u003c/em\u003e \u003cstrong\u003e51\u003c/strong\u003e, 1112-1116. http://doi.org/10.1016/j.dld.2019.05.001 (2019).\u003c/li\u003e\n \u003cli\u003eCosnes, J.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Adalimumab or infliximab as monotherapy, or in combination with an immunomodulator, in the treatment of Crohn\u0026apos;s disease. \u003cem\u003eAliment. Pharmacol. Ther.\u003c/em\u003e \u003cstrong\u003e44\u003c/strong\u003e, 1102-1113. http://doi.org/10.1111/apt.13808 (2016).\u003c/li\u003e\n \u003cli\u003eWong, D. R.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn\u0026apos;s disease patients. \u003cem\u003eJ. Crohns Colitis\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, 120-128. http://doi.org/10.1016/j.crohns.2013.07.004 (2014).\u003c/li\u003e\n \u003cli\u003eMatsumoto, T.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Adalimumab Monotherapy and a Combination with Azathioprine for Crohn\u0026apos;s Disease: A Prospective, Randomized Trial. \u003cem\u003eJ. Crohns Colitis\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 1259-1266. http://doi.org/10.1093/ecco-jcc/jjw152 (2016).\u003c/li\u003e\n \u003cli\u003eHyams, J. S.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e The effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in paediatric patients with Crohn\u0026apos;s disease: a post hoc analysis. \u003cem\u003eAliment. Pharmacol. 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J.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Discontinuation of Azathioprine could be considered in pediatric patients with Crohn\u0026apos;s disease who have sustained clinical and deep remission. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 507. http://doi.org/10.1038/s41598-021-04304-6 (2022).\u003c/li\u003e\n \u003cli\u003eLevine, A.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. \u003cem\u003eJ. Pediatr. Gastroenterol. Nutr.\u003c/em\u003e \u003cstrong\u003e58\u003c/strong\u003e, 795-806. http://doi.org/10.1097/MPG.0000000000000239 (2014).\u003c/li\u003e\n \u003cli\u003eDaperno, M.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Development and validation of a new, simplified endoscopic activity score for Crohn\u0026apos;s disease: the SES-CD. \u003cem\u003eGastrointest. Endosc.\u003c/em\u003e \u003cstrong\u003e60\u003c/strong\u003e, 505-512. http://doi.org/10.1016/s0016-5107(04)01878-4 (2004).\u003c/li\u003e\n\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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"inflammatory bowel disease, endoscopic healing, infliximab, durability, pediatric","lastPublishedDoi":"10.21203/rs.3.rs-4512921/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4512921/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study aimed to evaluate endoscopic healing (EH) efficacy and the durability of infliximab (IFX) in combination therapy with IFX and AZA versus IFX monotherapy in pediatric patients with Crohn’s disease (CD). In this retrospective observational study, clinical remission (CR), biochemical remission (BR), EH, transmural healing (TH) after 1-year of treatment, IFX trough levels (TLs), antibodies-to-IFX (ATIs), and IFX durability of 108 patients receiving IFX therapy, who were grouped into AZA combo-therapy (combination therapy group) and IFX monotherapy (monotherapy group), were compared. Of 108 patients who received IFX therapy, 85 (78.7%) received AZA combo-therapy for ≥3 months, and 23 (21.3%) received IFX monotherapy. No significant differences were observed in CR and TH at 1-year between the groups. However, the BR (92.9% vs. 66.7%, \u003cem\u003ep \u003c/em\u003e= 0.003) and EH (78.6% vs. 33.3%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) were higher in the combination therapy group than in the monotherapy group. Further, the proportion of patients with TLs above the therapeutic drug levels was significantly higher in the combination therapy group than in the monotherapy group (\u003cem\u003ep \u003c/em\u003e= 0.023). ATI formation was also significantly lower in the combination therapy group than in the monotherapy group (25.0% vs. 52.2%, \u003cem\u003ep \u003c/em\u003e= 0.025). Multivariable Cox proportional hazard regression analysis showed that ATI positivity (hazard ratio [HR] 5.33, 95% CI [confidence interval] 1.61–17.60, \u003cem\u003ep \u003c/em\u003e= 0.006) and combination therapy with IFX and AZA (HR 0.13, 95% CI 0.03–0.51, \u003cem\u003ep \u003c/em\u003e= 0.004) were associated with IFX durability. Kaplan–Meier survival curves revealed significantly higher IFX durability in the combination therapy group (log-rank test, \u003cem\u003ep \u003c/em\u003e= 0.0026) than in the monotherapy group. Compared with IFX monotherapy,\u003cstrong\u003e \u003c/strong\u003ecombination therapy with IFX and AZA was associated with higher EH rates and longer IFX durability in pediatric patients with CD.\u003c/p\u003e","manuscriptTitle":"Comparison of Endoscopic Healing and Durability between Combination Therapy with Infliximab and Azathioprine versus Infliximab Monotherapy in Pediatric Crohn's disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-25 20:08:05","doi":"10.21203/rs.3.rs-4512921/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-08T12:07:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-02T13:20:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"108255103807067978283801258463107489318","date":"2024-06-22T12:55:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-18T17:44:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"167366975853294575412540672358462736929","date":"2024-06-18T10:35:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-10T09:25:02+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-10T09:20:48+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-10T08:26:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-05T07:27:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-06-01T09:25:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6c94bf8d-bdcf-4d3f-a4a5-f148833e1e99","owner":[],"postedDate":"June 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":33422721,"name":"Health sciences/Gastroenterology"},{"id":33422722,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-07-07T16:00:36+00:00","versionOfRecord":{"articleIdentity":"rs-4512921","link":"https://doi.org/10.1038/s41598-025-06445-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-07-02 15:57:11","publishedOnDateReadable":"July 2nd, 2025"},"versionCreatedAt":"2024-06-25 20:08:05","video":"","vorDoi":"10.1038/s41598-025-06445-4","vorDoiUrl":"https://doi.org/10.1038/s41598-025-06445-4","workflowStages":[]},"version":"v1","identity":"rs-4512921","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4512921","identity":"rs-4512921","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}