{"paper_id":"05dd52c7-3cf4-4be5-94d6-dd4667630a7c","body_text":"Efficacy and Safety of Adalimumab in Pediatric Patients With Crohn’s Disease: A Systematic Review and Meta- analysis | 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 Research Article Efficacy and Safety of Adalimumab in Pediatric Patients With Crohn’s Disease: A Systematic Review and Meta- analysis Bin Chen, Zhuan Zou, Xiaoyan Zhang, Dongqiong Xiao, Xihong Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2781435/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: There is no curative treatment for childhood Crohn’s disease (CD). We conducted this meta-analysis to validate the efficacy and safety of adalimumab (ADA) in pediatric patients with CD. Methods: We searched and investigated all relevant studies in the PubMed, Web of Science, Embase, and Cochrane Library databases. Primary outcomes were induction (≤12 week) and maintenance (up to 48 week) of remission and response. Secondary outcomes were severe adverse events, opportunistic infections to adalimumab (ADA). The Cochrane bias assessment tool was used to assess the risk of bias in randomized controlled trials (RCTs). The methodological quality of single-arm studies was assessed using the methodological index for non-randomized studies (MINORS) tool. Results: A total of 10 clinical trials involving 885 patients were identified. Results indicate that 59% (95% confidence interval [CI]: 39%–80%) of the subjects treated with ADA achieved induction of remission and response 60% (95% CI: 35%–86%), 57% (95% CI: 44%–70%) achieved maintenance of remission, 63% (95% CI: 26%–69%) achieved maintenance of response. Conclusion: Current evidence indicates that ADA is effective in children and adolescents with CD and adverse events are varied but usually not sever. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023402199. Adalimumab Crohn’s disease Child Meta-analysis Efficacy and safety Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1 Introduction Crohn’s disease (CD) is a chronic, relapsing disease of the gastrointestinal tract resulting in significant morbidity and impact on quality of life. Nearly a quarter of people with CD develop it before the age of 20[ 1 , 2 ]. Children with CD account for 25% of the total CD [ 2 ]patients, and the most common age is school age and early adolescence [ 3 ]. Pediatric-onset CD is more extensive and severe at presentation with more aggressive disease course and worse prognosis when compared to adult-onset [ 4 ]. In addition to the clinical manifestations of recurrent abdominal pain, diarrhea and anal lesions common to adult CD, CD in children also has the characteristics of growth retardation, delayed puberty, decreased body mass index, affecting mental health, malnutrition and the need for surgery[ 5 ]. Treating CD is a huge challenge for clinicians because there is currently no curative treatment. Traditional therapy includes the use of corticosteroids, immunomodulators and exclusive enteral nutrition. Biologic therapy has completely changed the treatment strategy and disease course of CD. The biggest difference from traditional therapy is that the latter is to control clinical symptoms, while the former is to change the disease as its ultimate therapeutic goal. Anti-TNFα antibodies represent a valid therapeutic option for pediatric patients affected by CD. The first TNFα inhibitors approved for CD treatment was infliximab(IFX) in adults in 1998 and for children in 2006 [ 6 ]. Unfortunately, recent data report that about 30% of patients lose response within 3 years after starting IFX, and half withdrew within 5 years because they never responded to the drug [ 7 , 8 ]. Adalimumab(ADA), as a fully humanized TNF-α monoclonal antibody has been approved by the United States Food and Drug Administration for the treatment of moderate and severe CD in children, and recommended by the European consensus guidelines for the treatment of long-term active intestinal diseases in children [ 9 ]. Several systematic review and meta-analysis have demonstrated that ADA is safe and effective in the treatment of CD in adults[ 10 – 12 ]. However, it is unclear whether adalimumab has similar efficacy in children with CD. This systematic review aimed to examine the efficacy and safety of ADA for inducing and maintaining remission in pediatric patients with CD. 2 Methods The literature review was carried out according to the reporting items for systematic reviews and meta-analyses (PRISMA) guidelines[ 13 ]. 2.1 Search Strategy and Inclusion Criteria PubMed, Web of Science, Embase, and Cochrane Library were searched for clinical trials examining the effectiveness and safety of ADA in children with CD January 6, 2023. The cited references of retrieved articles and previous reviews were also manually checked to identify any additional eligible trials. The retrieved studies were imported into the EndNoteX9 software (Clarivate Analytics, London, UK). Two researchers (C.B. and Z.C.) independently searched and screened the candidate articles to check the eligibility for inclusion. The key words used as search terms were the following: “Crohn disease,” “Crohn's Disease,” “CD,” “Crohns disease,” “adalimumab,” “child,” “adolescent,” and so on. An example search strategy is presented in Supplemental Digital Content 1. We developed a “PICOS” (Patient, Intervention, Comparison, Outcome and Study design) approach as the eligibility criteria. (1) Population: children and adolescents (2–18 years of age) with CD; children with ulcerative colitis (UC) or unclassified IBD (UIBD) patients were excluded. (2) Intervention: ADA was administered subcutaneously. (3) Comparison: placebo or no therapy. (4) Outcome: eligible clinical trials had to present data on induction of remission(defined as clinical remission Pediatric CD Activity Index (PCDAI) score ≤ 10 after ≤ 12 weeks of treatment), induction of clinical response (defined as a PCDAI score > 10, and a decrease in PCDAI score ≥ 12.5 points from baseline), Maintenance of remission (defined as clinical remission after at least 48 weeks of treatment), Maintenance of response (defined as clinical response after ≤ 1 year of therapy), the primary outcome. The secondary outcome was the incidence of each adverse effect, such as infections, infusion-related reactions, and serious adverse events (SAEs) was individually examined. (5) Study design: randomized controlled trials (RCTs), retrospective or prospective cohort studies assessing the predefined outcomes were eligible; case-control studies and conference abstract data were excluded. Discrepancies regarding study inclusion were resolved through discussion with the correspondence author (L.X.H.). Only published data were used for those studies. For duplicated publications of the same clinical trial, we choose the latest updated data. 2.2 Date Extraction and Quality Assessment Two of the authors (Z.X.Y. and X.D.Q.) independently extracted relevant data from each included trials using a unified data form. The quality of the RCTs was assessed using the Cochrane Collaboration risk of bias assessment tool, the researchers evaluated the RCT studies item by item, and the evaluation results were expressed as low risk, high risk, or unclear[ 14 ]. The methodological quality of single-arm studies was assessed with using methodological index for non-randomized studies (MINORS) tool. The MINORS tool consists of eight items for noncomparative studies. An item was scored “0” when not reported, “1” when inadequately reported, and “2” when adequately reported, the maximum score was 16[ 15 ]. 2.3 Statistical Analysis For each outcome, proportions of outcomes were calculated for each treat arm. The pooled weighted proportions were calculated treated with ADA in STATA software (Stata-Corp LLC, College Station, TX, USA). Heterogeneity across studies was tested by I 2 statistic, and studies with an I 2 value of > 50% were considered to have significant heterogeneity. Random-effects model was applied to calculate pooled proportions and 95% confidence intervals (CIs). Sensitivity analyses were conducted by exclusion of any single arm and their combinations to investigate the influence on the pooled proportions. Publication bias was inspected by Egger test. A value of P < 0.05 was considered as statistically significant. Further subgroup analysis was conducted to analyze the heterogeneity between studies. P < 0.05 was considered statistically significant. 3 Results 3.1 Summary of study characteristics The flow diagram of the study selection process is shown in Figure 1. A total of 10 articles were considered eligible for inclusion in the systematic review, including 8 single-arm cohort studies and 2 RCTs[2, 16-24]. The basic characteristics of the included studies are summarized in Table 1. Most of the studies were conducted in Europe[2, 17, 18, 20, 22], North America[16, 23, 24], or both [19], with only one study from Asia [21]. The mean or median PCDAI above 30 in 4 treatment cohorts of 3 studies, signifying moderate to severe disease [17-19]. The mean or median PCDAI between 10 and 30 in 5 studies, which indicated mild disease on average[2, 16, 21, 23, 24]. Two studies did not report disease severity[20, 22]. The two RCTs comprised four treatment arms, all patients were randomly assigned at week 4 after induction treatment [19, 21]. One study investigated the efficacy of different maintenance treatment doses (high doses: 40mg or 20 mg for body weight ≥40 kg or＜40 kg and low doses: 20 mg or 10 mg for body weight ≥40 kg or＜40 kg) [19], whereas the other compared the efficacy of proactive(trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72) and reactive monitoring (physicians were informed of trough concentrations after loss of response) [21]. The therapeutic dose of ADA varied widely among included studies. Most subjects received standard adult ADA induction with 160 /80 mg, subcutaneous injection, every other week (eow). Maintenance dose of 40mg was used in 8 of the 12 treatment cohorts, one study used a higher maintenance dose(80mg or 40 mg for body weight ≥40 kg or＜40 kg eow), however, a lower maintenance dose was used in one of the therapeutic arms in the RCT study described above (20mg or 10 mg for body weight ≥40 kg or＜40 kg eow) . The subjects in the three studies were IFX-naïve [21-23]; Participants in two studies had prior IFX treatment, IFX was discontinued due to loss of efficacy or because of related adverse events [2, 20], in the remaining five studies, partial subjects experienced IFX failure prior to initiation of ADA therapy[16-19, 24]. 3.2 Quality Assessment The methodological quality of the two RCTs included is summarized in Figure 2 and Figure 3. One study was a phase 3, multicenter, randomized, open-label induction followed by double-blind maintenance trial, subjects were randomly assigned (1:1) to high-dose or low-dose ADA, however subjects stratified according to their week 4 responder status and prior exposure to infliximab [19]. Another study was a multicenter randomized controlled trial, with equal randomization (1:1 ratio), aimed at determining whether proactive TDM is superior to reactive TDM in children with CD under scheduled monitoring of clinical and biologic measures, however, the design of the study made it impossible to fully blind the method [21]. It is impossible to obtain an objective evaluation of the endpoint because there is no activity comparison in single-arm studies. Follow-up was less than 1 year in two studies[17, 24] and only 24 weeks in one [24]. 12/115(10.4%)subjects loss to follow-up in one study[16], and 3/53(5.6%) in another study [20]. The sample size less than 100 in six studies[2, 17, 18, 20, 22, 23]. It is acceptable to evaluate items that the purpose of the research is clearly stated, the consistency of the results, the collection of expected data, the appropriateness of endpoint indicators to reflect the purpose of the study and the objectivity of endpoint evaluation. The quality for clinical trials enrolled was moderate to high(see Table3). Funnel plots were used to assess the potential publication bias in the reporting of maintenance of remission（Supplemental Digital Content 4）. The pooled results showed no evidence of significant publication bias. In addition, Egger’s test was used to evaluate the publication bias in the reporting of maintenance of remission. It was found that p =.633, corroborating that there was no significant publication bias (Supplemental Digital Content 5). 3.3 Outcomes of Interest The detailed outcomes of each included study are presented in Table 2. Calculation of the pooled weighted proportions indicates that 59% (95% CI: 25%–61%) of the subjects achieved induction of remission, 60% (95% CI: 6%–35%) achieved induction of response, 57% (95% CI: 55%–79%) achieved maintenance of remission and 63% (95% CI: 30%–87%) achieved maintenance of response (see Figure4-7). The most frequently reported adverse events were infection (reported by 8 studies), infusion related reactions (reported by 5 studies) and serious adverse event (reported by 6 studies). Only one study reported two deaths. Other common adverse effects included neurological symptoms, neutropenia, vasculitis, allergic and psoriasiform skin lesions. 3.4 Sensitivity and Subgroup Analysis The calculation of pooled weighted proportions indicated high heterogeneity among studies. Thus, further sensitivity and subgroup analysis was conducted to investigate the important confounding factors (sensitivity analysis see Supplemental Digital Content 2). The results of the subgroup analysis by baseline PCDAI score, study design, prior IFX exposed and maintenance dose are presented in Supplemental Digital Content 3. 3.4.1 Induction of remission On sensitivity analysis of induction of remission, exclusion of any single arm did not significantly alter heterogeneity among studies. Subgroup analysis suggests that subjects with PCDAI < 30 at baseline achieved significantly more induction of remission than those ≥30 (0.76 [0. 57–0.95] vs. 0.34 [0.20–0.49], P < 0.05). In the subgroup analysis of whether or not they had previously undergone IFX treatment, there is no significant difference between the subgroup with patients IFX-naïve and the subgroup with partial subjects prior treated with IFX (0.38 [0. 24–0.52] vs. 0.45 [0.17–0.74], P < 0.05), however, ADA was significantly effective in the subgroup with patients never prior treated with IFX (0.94 [0.90–0.98]), suggesting possible risk of bias. 3.4.2 Maintenance of remission Sensitivity analysis by exclusion of any single study did not significantly change the heterogeneity among studies. Subgroup analysis found that children with PCDAI < 30 at baseline achieved significantly more maintenance of remission than those ≥30 (0.69 [0. 59–0.80] vs. 0.39 [0.24–0.54], P < 0.05). There is no significant difference between non-RCTs and RCTs (0.61 [0.53–0.70] vs. 0.52 [0.24–0.80], P < 0.05). There was no significant difference in the proportion of doses of 40mg cohorts and ≥40mg arm (0.58 [0.42–0.74] vs. 0.65 [0.46–0.85], P < 0.05); however, the < 40mg arm achieved less maintenance remission 0.34 [0.25–0.44]. There is no significant difference between the subgroup with all patients who had not responded to IFX and the subgroup with partial subjects prior treated with IFX (0.66 [0. 42–0.91] vs. 0.46 [0.29–0.63], P < 0.05), however ADA was significantly effective in the subgroup with IFX-naïve patients (0.75 [0.65–0.86]) 3.4.3 Maintenance response On sensitivity analysis, exclusion of any single study did not materially alter heterogeneity among studies. Subgroup analysis found that there was no significant difference between the two cohorts with PCDAI > 30 and < 30 at baseline (0.61 [0. 31–0.91] vs. 0.68 [0. 0.57–0.78], P < 0.05). Subjects from non-RCTs achieved more response rates than those of RCTS (0.72 [0.56–0.88] vs. 0.35 [0.22–0.48], P < 0.05). In the ADA dose subgroup analysis, the response rate increased with the increase of dose (0.42 [0.32–0.52] vs. 0.57 [0.35–0.78] vs. 0.91 [0.80–1.03], P < 0.05) of < 40mg, 40mg and ≥40mg, respectively. There is no significant difference between partial or all subjects prior treated with IFX (0.63 [0.37–0.88] vs. 0.52 [0.24–0.79], P < 0.05), however ADA was significantly effective in the IFX- naïve subgroup (0.84 [0.72–0.97]) 4 Discussion Biological therapies have been used extensively in pediatric CD, since anti-TNFα agents demonstrated to positively modify the natural history of IBD and achieve mucosal healing. The efficacy of ADA in achieving clinical remission in children with CD has been demonstrated in various studies[ 16 , 18 , 19 ]. But different studies have used different criteria to assess disease severity with different therapeutic doses, follow-up, sample size, that limit their generalization in clinical practice and the possibility of comparisons among them. Therefore, we decided to evaluate the efficacy and safety of ADA in this systematic review and meta-analysis. In summary, we identified a total of 10 clinical trials enrolling 885 subjects that met the inclusion criteria. The major finding of our study was that the pooled remission and response rates of induction and maintenance of ADA were above 50%, suggest that ADA is effective in the treatment of children with CD. Adverse events are varied but usually not sever. In clinical practice, one of the therapeutic goals for a new agent is the rapid induction of response or remission. Adult data show that ADA has a long-term clinical benefit over years [ 25 ], however, a significant number of children and adults lose response to ADA over time, requiring either dose increase or reduction in dosing interval[ 16 , 26 ]. At present there are no published studies that adequately demonstrate the optimal dosing of ADA for pediatric patients with CD, either for the induction or maintenance of remission. Doses used in pediatric practice are therefore extrapolated from relevant adult studies, [ 7 , 27 ] from pediatric rheumatology studies.[ 28 ] Therefore, it is difficult at present to draw conclusions about the optimal dose for the treatment of CD in children. In the current study, most subjects received standard adult ADA induction dose with 160/80 mg, the 40 mg dose group is commonly used in maintenance therapy. Subgroup analysis showed that there was no significant difference in overall response rates between the 80mg and 40mg maintenance groups, however, the remission rate in the 20mg group was significantly lower than that in the 40mg group. The subgroup analysis suggested that dose of 40mg may be most effective in maintaining clinical remission and clinical response. ADA is also effective in maintaining long-term response and remission in children with CD. In the current study, the follow-up periods varied between 48 and 208 weeks, with one study lasting only 24 weeks [ 23 ]. Maintenance remission rates were 60%, 57%, and 62% at week 26, 52, and 104, respectively. In line with our data, the literature reports that Ada seems to work more effectively when introduced in an early stage of the disease[ 2 , 29 ]. CD patients previously exposed to TNF-α were more likely to have a refractory phenotype [ 30 , 31 ]. our subgroup analysis demonstrated that previous exposure to IFX have less effect on the efficacy of ADA compared with patients with IFX-naïve. This is consistent with the results of Song et al.[ 11 ] However, Yin et al.[ 12 ] assessed the efficacy and safety of ADA in inducing and maintaining remission of participants with CD, which included four RCTs and concluded that efficacy rates were similar between the TNF-α- naïve and TNF-α exposed subgroups. We think the possibility might be that patients with previous IFX treatment probably had more severe disease for a longer period of time, which led them to receive anti-TNF therapy. Then they might have lost response or become intolerant to IFX. Another speculative possibility might be that the inflammatory mechanism no longer TNF-dependent in some IFX-exposed patients. [ 32 ] However, these data need to be interpreted with caution because of several limitations: differences in design between the included studies, various periods of treatment and using different doses of ADA given at various intervals throughout the studies and irrespective of the concomitant therapy. So, these findings should be validated in large prospective clinical trial. In terms of side effects, the rate of severe adverse reactions was significantly lower, only two deaths reported in one study[ 18 ], the two deaths both from central venous catheter (CVC) sepsis leading to septic shock. Although there is a recognized morbidity and mortality rate in adult clinical studies, the combined mortality rate in clinical trials of ADA has not been reported to be higher than that expected of patients with CD overall [ 33 ] However, these data need to be interpreted with caution, patients in clinical trials might not represent patients seen in clinical practice, and follow-up might not be sufficiently long for some serious events such as malignancy to occur. This study was the first meta-analysis to evaluate the efficacy and safety of ADA in children with CD. However, the study had limitations. First, differences in study design, baseline disease severity and treatment dose may have contributed to heterogeneity in the meta-analysis outcomes. Second, The RCT is considered the most scientifically rigorous study design for evaluating effectiveness of interventions[ 34 ]. Taking into account the higher severity of the disease in pediatric patients and the fact that CD is involved in growth and development in children as a special group, parents are often reluctant to be included in such trials. Neither of the two RCTS included in this review were RCTS in which ADA was compared with an active comparator. Third, for many trials, length and adequacy of follow-up were unclear or were of concern. The majority of the included studies were limited by small sample size: only 3 examined more than 100 patients. Finally, a cost analysis was not addressed by this systematic review and meta-analysis because there was insufficient data. 5 Conclusion Our meta-analysis showed that ADA provides significant benefits in children with CD. however, the available literature was limited by risk of bias and small sample size. Further prospective studies are needed to confirm the efficacy and safety of this drug in pediatric CD. Declarations Acknowledgments We would like to thank the researchers and study participants for their contributions. We would also be very grateful to your journal for its useful comments on our manuscript. Author Contributions Bin Chen, Dongqiong Xiao and Xihong Li designed the study. Bin Chen and Zhuan Zou conducted the literature search, screened articles, performed data extraction, quality assessment, writing and drafting the manuscript. Xiaoyan Zhang and Dongqiong Xiao interpreted the data. Xiaoyan Zhang independently screened the titles and abstract. Dongqiong Xiao independently assessed the quality of all included studies. All authors critically reviewed and approved the manuscript. Funding This work was supported by grants from the National Science Foundation of China (82071353) Availability of data and materials All data generated or analyzed during this study are included in this published article. Ethics approval and consent to participate Not applicable. 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Deepak P, Stobaugh D, Ehrenpreis EJJog JGLD. ld: Infectious complications of TNF-α inhibitor monotherapy versus combination therapy with immunomodulators in inflammatory bowel disease: analysis of the Food and Drug Administration Adverse Event Reporting System. 2013, 22(3):269–276. Benmassaoud A, Al-Taweel T, Sasson M, Moza D, Strohl M, Kopylov U, Paradis-Surprenant L, Almaimani M, Bitton A, Afif W et al. Comparative Effectiveness of Infliximab Versus Adalimumab in Patients with Biologic-Naïve Crohn's Disease. 2018, 63(5):1302–1310. Plevris N, Jenkinson P, Arnott I, Jones G. Lees CJEjog, hepatology: Higher anti-tumor necrosis factor levels are associated with perianal fistula healing and fistula closure in Crohn's disease. 2020, 32(1):32–37. Behm B, Bickston SJTCdosr. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn's disease. 2008(1):CD006893. Colombel J, Sandborn W, Panaccione R, Robinson A, Lau W, Li J. Cardoso AJIbd: Adalimumab safety in global clinical trials of patients with Crohn's disease. 2009, 15(9):1308–1319. Evans, DJJocn. Hierarchy of evidence: a framework for ranking evidence evaluating healthcare interventions. 2003, 12(1):77–84. Tables Table 1. Characteristics of Included Clinical Trials Study Design Main inclusion criteria Age(years) N/Group Specific Study Outcomes Definition of remission Induction week Maintenance week AEs Rosh2009 Retrospective cohort Failed IFX treatment 11.1±3.1 115 PCDAI≤10 12 26 52 Infection Viola2009 Prospective cohort Active moderate-to-severe CD, failed IFX treatment 16.1(9-20) 23 PCDAI≤10 4 12 24 48 Multiple Russel2011 Retrospective cohort Refractory to conventional therapy (thiopurines/steroids/IFX) 14.8±3.1 70 PCDAI≤10 4 26 52 SAE Deaths Hyams2012 RCT Moderate to severe CD, Failed IFX treatment 13.5±2.47 G1:95 G2:93 PCDAI≤10 4 26 52 Multiple Cozijnsen2015 Retrospective cohort Failed IFX treatment 14(13-16) 53 PCDAI≤12.5 4 17 34 52 104 Multiple Assa2019 RCT Biologic-naïve with luminal CD 12.9±2.6 G1:38 G2:40 PCDAI＜10 4 16 24 56 72 Multiple Alvisi2019 Retrospective cohort Failed IFX treatment 14.8(9.9-17.1) 44 PCDAI≤10 2 26 52 78 Multiple Romeo2019 Retrospective Steroid dependency, chronically active disease, steroid resistance 15.1(13.6-16.0) 36 PCDAI≤10 26 52 104 Rinawi2020 Prospective cohort Luminal inflammatory CD 13.9(12.1-15.2) 65 PCDAI≤10 12 24 Rinawi2021 Retrospective cohort Active steroid-dependent CD, failed IFX treatment 14.1(12.5-15.7) 213 PCDAI＜10 12 Multiple RCT: Randomized Controlled Trial; CD: Crohn’s Disease; IFX: Infliximab; N: Number; G1:Gronp1; G2:Group2; PCDAI: Pediatric Crohn’s Disease Activity Index; AE: Adverse event; SAE: Serious Adverse Event. TABLE 2. The Detailed Outcomes at the End of Treatment Study Group Base line PCDAI Induction of clinical remission No. (%) Induction of clinical response No. (%) Maintenance of remission No. (%) Maintenance of response No. (%) maintenance dose Infusion-related reactions No. (%) Infection No. (%) SAE No. (%) Discontinuation Deaths No. (%) Rosh2009 25±15 21（31.8） 43（65.1） 16（48.4） 23（69.7） 40mg 2(1.7) 12(10.4) Viola2009 36.5±5.7 14（60.8） 23（86.9） 15（65.2） 21（91.3） 80mg（≥40kg） 40mg（＜40kg） 4(17.4) 2(8.7) 0 Russel2011 37.5 17（24.2） 35（50.0） 12（41.3） 12（41.3） 40mg 6(8.6) 4(5.7) 0 2(2.9) Hyams2012 G1 G2 ＞30 ＞30 NR NR NR NR 22（23.2） 32（34.4） 27（28.4） 39（41.9） 40mg（≥40kg） 20mg（≥40kg） 10（10.5） 9（9.7） 47（49.5） 56（60.2） 11（11.6） 19（20.4） 12(12.6) 15(16.1) Cozijnsen2015 NR 18（38.2） 8（17.0） 16（53.3） 4（13.3） 40-80mg（≥40kg） 20-40mg（＜40kg） 5（9.4） 14（26.4） 1（1.9） 3(5.6) Assa2019 G1 G2 A:18.3 B:17.5 34（89.4） 35（87.5） NR NR 32（84.2） 27（67.5） NR NR 40mg 40mg 1（2.6） 2（5） 4（10.5） 4（10） 2(5.2) 0 Alvisi2019 24.94 NR NR 25（78.1） 4（12.5） 40mg 1（2.2） 2（4.5） 2(4.5) Romeo2019 NR NR NR 23（71.9） 27（84.3） NR 0 Rinawi2020 17.5 60（92.3） NR 57（87.7） NR 40mg（≥40kg） 20mg（＜40kg） Rinawi2021 17.5 174（81.7） NR 138（64.8） NR 40mg 10（4.7） 4（1.9） 10（4.7） 10(4.6) No: Number; G1:NR: No report; PCDAI: Pediatric Crohn’s Disease Activity Index; AE: Adverse event; SAE: Serious Adverse Event. TABLE 3. Assessment of Study Quality (single-arm studies) Study The purpose of the research is clearly stated Consistency of enrolled patients Collection of expected data Endpoints that appropriately reflect the purpose of the study The objectivity of endpoint evaluation Adequate follow-up time Loss to follow-up rate is less than 5% Whether the sample size was estimated total Rosh2009 2 2 2 2 0 2 0 2 12 Viola2009 2 2 2 2 0 1 2 1 12 Russel2011 2 2 2 2 0 2 2 1 13 Cozijnsen2015 2 2 2 2 0 2 1 1 12 Alvisi2019 2 2 2 2 0 2 2 1 13 Romeo2019 2 2 2 2 0 2 2 1 13 Rinawi2020 2 2 2 2 0 0 2 1 11 Rinawi2021 2 2 2 2 0 2 2 2 14 Additional Declarations No competing interests reported. Supplementary Files SupplementaryAppendix.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-2781435\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":191247922,\"identity\":\"8180dc2a-8317-47b7-9804-9fb7837017e6\",\"order_by\":0,\"name\":\"Bin Chen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"West China Second University Hospital\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Bin\",\"middleName\":\"\",\"lastName\":\"Chen\",\"suffix\":\"\"},{\"id\":191247923,\"identity\":\"41518284-4246-4efd-9888-1f7239338afe\",\"order_by\":1,\"name\":\"Zhuan 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search.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2781435/v1/acd059a91f16215219a7592a.jpg\"},{\"id\":35769000,\"identity\":\"0e9b1474-6c06-429d-affa-bc123d7a6fe5\",\"added_by\":\"auto\",\"created_at\":\"2023-04-14 13:36:49\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":193711,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eRisk of bias graph (RCTs).\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2781435/v1/f56d486eb2f3f1e2e5525716.jpg\"},{\"id\":35769002,\"identity\":\"2e5c49e4-02aa-4c17-9a7a-4804d815f47c\",\"added_by\":\"auto\",\"created_at\":\"2023-04-14 13:36:49\",\"extension\":\"jpg\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":166848,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eRisk of bias summary (RCTs).\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure3.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2781435/v1/357eacedfc702fff81555b32.jpg\"},{\"id\":35769001,\"identity\":\"d4b2d576-799f-4c6b-9b46-bb163e754cab\",\"added_by\":\"auto\",\"created_at\":\"2023-04-14 13:36:49\",\"extension\":\"jpg\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":141723,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eForest plot of induction of remission. 95% CI, 95% confidence interval; ES: Effect Size. The diamond at the bottom indicates the pooled ES.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure4.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2781435/v1/030748286739b7f7186155dc.jpg\"},{\"id\":35769005,\"identity\":\"f744789b-22c8-4eea-abd8-97cbb77af5ef\",\"added_by\":\"auto\",\"created_at\":\"2023-04-14 13:36:49\",\"extension\":\"jpg\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":110095,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eForest plot of induction of response. 95% CI, 95% confidence interval; ES: Effect Size. The diamond at the bottom indicates the pooled ES.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure5.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2781435/v1/560025e179e550f77748e7ba.jpg\"},{\"id\":35770316,\"identity\":\"0f99e9da-3b32-49f0-82ef-87ba85024582\",\"added_by\":\"auto\",\"created_at\":\"2023-04-14 13:44:49\",\"extension\":\"jpg\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":181747,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eForest plot of maintenance of remission. 95% CI, 95% confidence interval; ES: Effect Size; The diamond at the bottom indicates the pooled ES.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure6.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2781435/v1/c3d65e560440ed5d5d777964.jpg\"},{\"id\":35770317,\"identity\":\"7abfcb28-f1fb-4710-9573-247b79b46cd7\",\"added_by\":\"auto\",\"created_at\":\"2023-04-14 13:44:49\",\"extension\":\"jpg\",\"order_by\":7,\"title\":\"Figure 7\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":146575,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eForest plot of maintenance of response. 95% CI, 95% confidence interval; ES: Effect Size; The diamond at the bottom indicates the pooled ES.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure7.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2781435/v1/0271c8c6a5b72f4c6e8263df.jpg\"},{\"id\":38047441,\"identity\":\"81edd9c7-392c-49af-85f7-7c353f64069d\",\"added_by\":\"auto\",\"created_at\":\"2023-06-05 18:29:31\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":964702,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2781435/v1/274c1c66-71c1-42b7-9c71-adbadf318c76.pdf\"},{\"id\":35769007,\"identity\":\"73137500-9d61-4c91-a963-efb051c4cfef\",\"added_by\":\"auto\",\"created_at\":\"2023-04-14 13:36:49\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":11884340,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"SupplementaryAppendix.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2781435/v1/05a0f9ea82945c40b0c8c27d.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Efficacy and Safety of Adalimumab in Pediatric Patients With Crohn’s Disease: A Systematic Review and Meta- analysis\",\"fulltext\":[{\"header\":\"1 Introduction\",\"content\":\"\\u003cp\\u003eCrohn\\u0026rsquo;s disease (CD) is a chronic, relapsing disease of the gastrointestinal tract resulting in significant morbidity and impact on quality of life. Nearly a quarter of people with CD develop it before the age of 20[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. Children with CD account for 25% of the total CD [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]patients, and the most common age is school age and early adolescence [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. Pediatric-onset CD is more extensive and severe at presentation with more aggressive disease course and worse prognosis when compared to adult-onset [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. In addition to the clinical manifestations of recurrent abdominal pain, diarrhea and anal lesions common to adult CD, CD in children also has the characteristics of growth retardation, delayed puberty, decreased body mass index, affecting mental health, malnutrition and the need for surgery[\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eTreating CD is a huge challenge for clinicians because there is currently no curative treatment. Traditional therapy includes the use of corticosteroids, immunomodulators and exclusive enteral nutrition. Biologic therapy has completely changed the treatment strategy and disease course of CD. The biggest difference from traditional therapy is that the latter is to control clinical symptoms, while the former is to change the disease as its ultimate therapeutic goal.\\u003c/p\\u003e \\u003cp\\u003eAnti-TNFα antibodies represent a valid therapeutic option for pediatric patients affected by CD. The first TNFα inhibitors approved for CD treatment was infliximab(IFX) in adults in 1998 and for children in 2006 [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. Unfortunately, recent data report that about 30% of patients lose response within 3 years after starting IFX, and half withdrew within 5 years because they never responded to the drug [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]. Adalimumab(ADA), as a fully humanized TNF-α monoclonal antibody has been approved by the United States Food and Drug Administration for the treatment of moderate and severe CD in children, and recommended by the European consensus guidelines for the treatment of long-term active intestinal diseases in children [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. Several systematic review and meta-analysis have demonstrated that ADA is safe and effective in the treatment of CD in adults[\\u003cspan additionalcitationids=\\\"CR11\\\" citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. However, it is unclear whether adalimumab has similar efficacy in children with CD.\\u003c/p\\u003e \\u003cp\\u003e This systematic review aimed to examine the efficacy and safety of ADA for inducing and maintaining remission in pediatric patients with CD.\\u003c/p\\u003e\"},{\"header\":\"2 Methods\",\"content\":\"\\u003cp\\u003eThe literature review was carried out according to the reporting items for systematic reviews and meta-analyses (PRISMA) guidelines[\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.1 Search Strategy and Inclusion Criteria\\u003c/h2\\u003e \\u003cp\\u003ePubMed, Web of Science, Embase, and Cochrane Library were searched for clinical trials examining the effectiveness and safety of ADA in children with CD January 6, 2023. The cited references of retrieved articles and previous reviews were also manually checked to identify any additional eligible trials. The retrieved studies were imported into the EndNoteX9 software (Clarivate Analytics, London, UK). Two researchers (C.B. and Z.C.) independently searched and screened the candidate articles to check the eligibility for inclusion. The key words used as search terms were the following: \\u0026ldquo;Crohn disease,\\u0026rdquo; \\u0026ldquo;Crohn's Disease,\\u0026rdquo; \\u0026ldquo;CD,\\u0026rdquo; \\u0026ldquo;Crohns disease,\\u0026rdquo; \\u0026ldquo;adalimumab,\\u0026rdquo; \\u0026ldquo;child,\\u0026rdquo; \\u0026ldquo;adolescent,\\u0026rdquo; and so on. An example search strategy is presented in Supplemental Digital Content 1.\\u003c/p\\u003e \\u003cp\\u003eWe developed a \\u0026ldquo;PICOS\\u0026rdquo; (Patient, Intervention, Comparison, Outcome and Study design) approach as the eligibility criteria. (1) Population: children and adolescents (2\\u0026ndash;18 years of age) with CD; children with ulcerative colitis (UC) or unclassified IBD (UIBD) patients were excluded. (2) Intervention: ADA was administered subcutaneously. (3) Comparison: placebo or no therapy. (4) Outcome: eligible clinical trials had to present data on induction of remission(defined as clinical remission Pediatric CD Activity Index (PCDAI) score\\u0026thinsp;\\u0026le;\\u0026thinsp;10 after \\u0026le;\\u0026thinsp;12 weeks of treatment), induction of clinical response (defined as a PCDAI score\\u0026thinsp;\\u0026gt;\\u0026thinsp;10, and a decrease in PCDAI score\\u0026thinsp;\\u0026ge;\\u0026thinsp;12.5 points from baseline), Maintenance of remission (defined as clinical remission after at least 48 weeks of treatment), Maintenance of response (defined as clinical response after \\u0026le;\\u0026thinsp;1 year of therapy), the primary outcome. The secondary outcome was the incidence of each adverse effect, such as infections, infusion-related reactions, and serious adverse events (SAEs) was individually examined. (5) Study design: randomized controlled trials (RCTs), retrospective or prospective cohort studies assessing the predefined outcomes were eligible; case-control studies and conference abstract data were excluded. Discrepancies regarding study inclusion were resolved through discussion with the correspondence author (L.X.H.). Only published data were used for those studies. For duplicated publications of the same clinical trial, we choose the latest updated data.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.2 Date Extraction and Quality Assessment\\u003c/h2\\u003e \\u003cp\\u003eTwo of the authors (Z.X.Y. and X.D.Q.) independently extracted relevant data from each included trials using a unified data form. The quality of the RCTs was assessed using the Cochrane Collaboration risk of bias assessment tool, the researchers evaluated the RCT studies item by item, and the evaluation results were expressed as low risk, high risk, or unclear[\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. The methodological quality of single-arm studies was assessed with using methodological index for non-randomized studies (MINORS) tool. The MINORS tool consists of eight items for noncomparative studies. An item was scored \\u0026ldquo;0\\u0026rdquo; when not reported, \\u0026ldquo;1\\u0026rdquo; when inadequately reported, and \\u0026ldquo;2\\u0026rdquo; when adequately reported, the maximum score was 16[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e].\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.3 Statistical Analysis\\u003c/h2\\u003e \\u003cp\\u003eFor each outcome, proportions of outcomes were calculated for each treat arm. The pooled weighted proportions were calculated treated with ADA in STATA software (Stata-Corp LLC, College Station, TX, USA). Heterogeneity across studies was tested by I\\u003csup\\u003e2\\u003c/sup\\u003e statistic, and studies with an I\\u003csup\\u003e2\\u003c/sup\\u003e value of \\u0026gt;\\u0026thinsp;50% were considered to have significant heterogeneity. Random-effects model was applied to calculate pooled proportions and 95% confidence intervals (CIs). Sensitivity analyses were conducted by exclusion of any single arm and their combinations to investigate the influence on the pooled proportions. Publication bias was inspected by Egger test. A value of P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 was considered as statistically significant. Further subgroup analysis was conducted to analyze the heterogeneity between studies. P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 was considered statistically significant.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"3 Results\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003e3.1 Summary of study characteristics\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe flow diagram of the study selection process is shown in Figure 1. A total of 10 articles were considered eligible for inclusion in the systematic review, including 8 single-arm cohort studies and 2 RCTs[2, 16-24]. The basic characteristics of the included studies are summarized in Table 1. Most of the studies were conducted in Europe[2, 17, 18, 20, 22], North America[16, 23, 24], or both\\u0026nbsp;[19], with only one study from Asia\\u0026nbsp;[21].\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThe mean or median PCDAI above 30 in 4 treatment cohorts of 3 studies, signifying moderate to severe disease\\u0026nbsp;[17-19]. The mean or median PCDAI between 10 and 30 in 5 studies, which indicated mild disease on average[2, 16, 21, 23, 24]. Two studies did not report disease severity[20, 22].\\u003c/p\\u003e\\n\\u003cp\\u003eThe two RCTs comprised four treatment arms, all patients were randomly assigned at week 4 after induction treatment\\u0026nbsp;[19, 21]. One study investigated the efficacy of different maintenance treatment doses (high doses: 40mg or 20 mg for body weight\\u0026nbsp;\\u0026ge;40 kg or＜40 kg and low doses: 20 mg or 10 mg for body weight\\u0026nbsp;\\u0026ge;40 kg or＜40 kg)\\u0026nbsp;[19], whereas the other compared the efficacy of proactive(trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72) and reactive monitoring\\u0026nbsp;(physicians were informed of trough concentrations after loss of response)\\u0026nbsp;[21].\\u003c/p\\u003e\\n\\u003cp\\u003eThe therapeutic dose of ADA varied widely among included studies. Most subjects received standard adult ADA induction with 160 /80 mg, subcutaneous injection, every other week (eow). Maintenance dose of 40mg was used in 8 of the 12 treatment cohorts, one study used a higher maintenance dose(80mg or 40 mg for body weight\\u0026nbsp;\\u0026ge;40 kg or＜40 kg eow), however, a lower maintenance dose was used in one of the therapeutic arms in the RCT study described above (20mg or 10 mg for body weight\\u0026nbsp;\\u0026ge;40 kg or＜40 kg eow) .\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026nbsp; The subjects in the three studies were IFX-na\\u0026iuml;ve\\u0026nbsp;[21-23]; Participants in two studies had prior IFX treatment, IFX was discontinued due to loss of efficacy or because of related adverse events\\u0026nbsp;[2, 20], in the remaining five studies, partial subjects experienced IFX failure prior to initiation of ADA therapy[16-19, 24].\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3.2 Quality Assessment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe methodological quality of the two RCTs included is summarized in Figure 2 and Figure 3. One study was a phase 3, multicenter, randomized, open-label induction followed by double-blind maintenance trial, subjects were randomly assigned (1:1) to high-dose or low-dose ADA, however subjects stratified according to their week 4 responder status and prior exposure to infliximab\\u0026nbsp;[19]. Another study was a multicenter randomized controlled trial, with equal randomization (1:1 ratio), aimed at determining whether proactive TDM is superior to reactive TDM in children with CD under scheduled monitoring of clinical and biologic measures, however, the design of the study made it impossible to fully blind the method\\u0026nbsp;[21].\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026nbsp;It is impossible to obtain an objective evaluation of the endpoint because there is no activity comparison in single-arm studies. Follow-up was less than 1 year in two studies[17, 24]\\u0026nbsp;and only 24 weeks in one\\u0026nbsp;[24]. 12/115(10.4%)subjects loss to follow-up in one study[16], and 3/53(5.6%) in another study\\u0026nbsp;[20]. The sample size less than 100 in six studies[2, 17, 18, 20, 22, 23]. It is acceptable to evaluate items that the purpose of the research is clearly stated, the consistency of the results, the collection of expected data, the appropriateness of endpoint indicators to reflect the purpose of the study and the objectivity of endpoint evaluation. The quality for clinical trials enrolled was moderate to high(see Table3).\\u003c/p\\u003e\\n\\u003cp\\u003eFunnel plots were used to assess the potential publication bias in the reporting of maintenance of remission（Supplemental Digital Content 4）. The pooled results showed no evidence of significant publication bias. In addition, Egger\\u0026rsquo;s test was used to evaluate the publication bias in the reporting of maintenance of remission. It was found that p =.633, corroborating that there was no significant publication bias (Supplemental Digital Content 5).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3.3\\u003c/strong\\u003e \\u003cstrong\\u003eOutcomes of Interest\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe detailed outcomes of each included study are presented in Table 2. Calculation of the pooled weighted proportions indicates that 59% (95% CI: 25%\\u0026ndash;61%) of the subjects achieved induction of remission, 60% (95% CI: 6%\\u0026ndash;35%) achieved induction of response, 57% (95% CI: 55%\\u0026ndash;79%) achieved maintenance of remission and 63% (95% CI: 30%\\u0026ndash;87%) achieved maintenance of response (see Figure4-7).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThe most frequently reported adverse events were infection (reported by 8 studies), infusion related reactions (reported by 5 studies) and serious adverse event (reported by 6 studies). Only one study reported two deaths. Other common adverse effects included neurological symptoms, neutropenia, vasculitis, allergic and psoriasiform skin lesions.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3.4 Sensitivity and Subgroup Analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe calculation of pooled weighted proportions indicated high heterogeneity among studies. Thus, further sensitivity and subgroup analysis was conducted to investigate the important confounding factors (sensitivity analysis see Supplemental Digital Content 2). The results of the subgroup analysis by baseline PCDAI score, study design, prior IFX exposed and maintenance dose are presented in Supplemental Digital Content 3.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3.4.1 Induction of remission\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eOn sensitivity analysis of induction of remission, exclusion of any single arm did not significantly alter heterogeneity among studies. Subgroup analysis suggests that subjects with PCDAI \\u0026lt; 30 at baseline achieved significantly more induction of remission than those\\u0026nbsp;\\u0026ge;30 (0.76 [0. 57\\u0026ndash;0.95] vs. 0.34 [0.20\\u0026ndash;0.49], P \\u0026lt; 0.05). In the subgroup analysis of whether or not they had previously undergone IFX treatment, there is no significant difference between the subgroup with patients IFX-na\\u0026iuml;ve and the subgroup with partial subjects prior treated with IFX (0.38 [0. 24\\u0026ndash;0.52] vs. 0.45 [0.17\\u0026ndash;0.74], P \\u0026lt; 0.05), however, ADA was significantly effective in the subgroup with patients never prior treated with IFX (0.94 [0.90\\u0026ndash;0.98]), suggesting possible risk of bias.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3.4.2\\u003c/strong\\u003e \\u003cstrong\\u003eMaintenance of remission\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp; \\u0026nbsp;\\u003c/strong\\u003eSensitivity analysis by exclusion of any single study did not significantly change the heterogeneity among studies. Subgroup analysis found that children with PCDAI \\u0026lt; 30 at baseline achieved significantly more maintenance of remission than those\\u0026nbsp;\\u0026ge;30 (0.69 [0. 59\\u0026ndash;0.80] vs. 0.39 [0.24\\u0026ndash;0.54], P \\u0026lt; 0.05). There is no significant difference between non-RCTs and RCTs (0.61 [0.53\\u0026ndash;0.70] vs. 0.52 [0.24\\u0026ndash;0.80], P \\u0026lt; 0.05). There was no significant difference in the proportion of doses of 40mg cohorts and\\u0026nbsp;\\u0026ge;40mg arm (0.58 [0.42\\u0026ndash;0.74] vs. 0.65 [0.46\\u0026ndash;0.85], P \\u0026lt; 0.05); however, the \\u0026lt; 40mg arm achieved less maintenance remission 0.34 [0.25\\u0026ndash;0.44]. There is no significant difference between the subgroup with all patients who had not responded to IFX and the subgroup with partial subjects prior treated with IFX (0.66 [0. 42\\u0026ndash;0.91] vs. 0.46 [0.29\\u0026ndash;0.63], P \\u0026lt; 0.05), however ADA was significantly effective in the subgroup with IFX-na\\u0026iuml;ve patients (0.75 [0.65\\u0026ndash;0.86])\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3.4.3\\u003c/strong\\u003e \\u003cstrong\\u003eMaintenance response\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eOn sensitivity analysis, exclusion of any single study did not materially alter heterogeneity among studies. Subgroup analysis found that there was no significant difference between the two cohorts with PCDAI \\u0026gt; 30 and \\u0026lt; 30 at baseline (0.61 [0. 31\\u0026ndash;0.91] vs. 0.68 [0. 0.57\\u0026ndash;0.78], P \\u0026lt; 0.05). Subjects from non-RCTs achieved more response rates than those of RCTS (0.72 [0.56\\u0026ndash;0.88] vs. 0.35 [0.22\\u0026ndash;0.48], P \\u0026lt; 0.05). In the ADA dose subgroup analysis, the response rate increased with the increase of dose (0.42 [0.32\\u0026ndash;0.52] vs. 0.57 [0.35\\u0026ndash;0.78] vs. 0.91 [0.80\\u0026ndash;1.03], P \\u0026lt; 0.05) of \\u0026lt; 40mg, 40mg and \\u0026ge;40mg, respectively. There is no significant difference between partial or all subjects prior treated with IFX (0.63 [0.37\\u0026ndash;0.88] vs. 0.52 [0.24\\u0026ndash;0.79], P \\u0026lt; 0.05), however ADA was significantly effective in the IFX- na\\u0026iuml;ve subgroup (0.84 [0.72\\u0026ndash;0.97])\\u003c/p\\u003e\"},{\"header\":\"4 Discussion\",\"content\":\"\\u003cp\\u003eBiological therapies have been used extensively in pediatric CD, since anti-TNFα agents demonstrated to positively modify the natural history of IBD and achieve mucosal healing. The efficacy of ADA in achieving clinical remission in children with CD has been demonstrated in various studies[\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e]. But different studies have used different criteria to assess disease severity with different therapeutic doses, follow-up, sample size, that limit their generalization in clinical practice and the possibility of comparisons among them. Therefore, we decided to evaluate the efficacy and safety of ADA in this systematic review and meta-analysis. In summary, we identified a total of 10 clinical trials enrolling 885 subjects that met the inclusion criteria. The major finding of our study was that the pooled remission and response rates of induction and maintenance of ADA were above 50%, suggest that ADA is effective in the treatment of children with CD. Adverse events are varied but usually not sever.\\u003c/p\\u003e \\u003cp\\u003eIn clinical practice, one of the therapeutic goals for a new agent is the rapid induction of response or remission. Adult data show that ADA has a long-term clinical benefit over years [\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e], however, a significant number of children and adults lose response to ADA over time, requiring either dose increase or reduction in dosing interval[\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]. At present there are no published studies that adequately demonstrate the optimal dosing of ADA for pediatric patients with CD, either for the induction or maintenance of remission. Doses used in pediatric practice are therefore extrapolated from relevant adult studies, [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e] from pediatric rheumatology studies.[\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e] Therefore, it is difficult at present to draw conclusions about the optimal dose for the treatment of CD in children. In the current study, most subjects received standard adult ADA induction dose with 160/80 mg, the 40 mg dose group is commonly used in maintenance therapy. Subgroup analysis showed that there was no significant difference in overall response rates between the 80mg and 40mg maintenance groups, however, the remission rate in the 20mg group was significantly lower than that in the 40mg group. The subgroup analysis suggested that dose of 40mg may be most effective in maintaining clinical remission and clinical response.\\u003c/p\\u003e \\u003cp\\u003eADA is also effective in maintaining long-term response and remission in children with CD. In the current study, the follow-up periods varied between 48 and 208 weeks, with one study lasting only 24 weeks [\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. Maintenance remission rates were 60%, 57%, and 62% at week 26, 52, and 104, respectively. In line with our data, the literature reports that Ada seems to work more effectively when introduced in an early stage of the disease[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eCD patients previously exposed to TNF-α were more likely to have a refractory phenotype [\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e]. our subgroup analysis demonstrated that previous exposure to IFX have less effect on the efficacy of ADA compared with patients with IFX-na\\u0026iuml;ve. This is consistent with the results of Song et al.[\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e] However, Yin et al.[\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e] assessed the efficacy and safety of ADA in inducing and maintaining remission of participants with CD, which included four RCTs and concluded that efficacy rates were similar between the TNF-α- na\\u0026iuml;ve and TNF-α exposed subgroups. We think the possibility might be that patients with previous IFX treatment probably had more severe disease for a longer period of time, which led them to receive anti-TNF therapy. Then they might have lost response or become intolerant to IFX. Another speculative possibility might be that the inflammatory mechanism no longer TNF-dependent in some IFX-exposed patients. [\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e] However, these data need to be interpreted with caution because of several limitations: differences in design between the included studies, various periods of treatment and using different doses of ADA given at various intervals throughout the studies and irrespective of the concomitant therapy. So, these findings should be validated in large prospective clinical trial.\\u003c/p\\u003e \\u003cp\\u003eIn terms of side effects, the rate of severe adverse reactions was significantly lower, only two deaths reported in one study[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e], the two deaths both from central venous catheter (CVC) sepsis leading to septic shock. Although there is a recognized morbidity and mortality rate in adult clinical studies, the combined mortality rate in clinical trials of ADA has not been reported to be higher than that expected of patients with CD overall [\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e] However, these data need to be interpreted with caution, patients in clinical trials might not represent patients seen in clinical practice, and follow-up might not be sufficiently long for some serious events such as malignancy to occur.\\u003c/p\\u003e \\u003cp\\u003eThis study was the first meta-analysis to evaluate the efficacy and safety of ADA in children with CD. However, the study had limitations. First, differences in study design, baseline disease severity and treatment dose may have contributed to heterogeneity in the meta-analysis outcomes. Second, The RCT is considered the most scientifically rigorous study design for evaluating effectiveness of interventions[\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e]. Taking into account the higher severity of the disease in pediatric patients and the fact that CD is involved in growth and development in children as a special group, parents are often reluctant to be included in such trials. Neither of the two RCTS included in this review were RCTS in which ADA was compared with an active comparator. Third, for many trials, length and adequacy of follow-up were unclear or were of concern. The majority of the included studies were limited by small sample size: only 3 examined more than 100 patients. Finally, a cost analysis was not addressed by this systematic review and meta-analysis because there was insufficient data.\\u003c/p\\u003e\"},{\"header\":\"5 Conclusion\",\"content\":\"\\u003cp\\u003eOur meta-analysis showed that ADA provides significant benefits in children with CD. however, the available literature was limited by risk of bias and small sample size. Further prospective studies are needed to confirm the efficacy and safety of this drug in pediatric CD.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe would like to thank the researchers and study participants for their contributions. We would also be very grateful to your journal for its useful comments on our manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor Contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eBin Chen, Dongqiong Xiao and Xihong Li designed the study. Bin Chen and Zhuan Zou conducted the literature search, screened articles, performed data extraction, quality assessment, writing and drafting the manuscript. Xiaoyan Zhang and Dongqiong Xiao interpreted the data. Xiaoyan Zhang independently screened the titles and abstract. Dongqiong Xiao independently assessed the quality of all included studies. All authors critically reviewed and approved the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis work was supported by grants from the National Science Foundation of China (82071353)\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll data generated or analyzed during this study are included in this published article.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare no competing interests.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor details\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003csup\\u003e1\\u003c/sup\\u003eDepartment of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China;\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003csup\\u003e2\\u003c/sup\\u003eKey Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eWu J, Lubman D, Kugathasan S, Denson L, Hyams J, Dubinsky M, Griffiths A, Baldassano R, Noe J, Rabizadeh S et al. Serum Protein Biomarkers of Fibrosis Aid in Risk Stratification of Future Stricturing Complications in Pediatric Crohn\\u0026apos;s Disease. 2019, 114(5):777\\u0026ndash;785.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eAlvisi P, Arrigo S, Cucchiara S, Lionetti P, Miele E, Romano C, Ravelli A, Knafelz D, Martelossi S, Guariso G et al. Efficacy of adalimumab as second-line therapy in a pediatric cohort of Crohn\\u0026apos;s disease patients who failed infliximab therapy: the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition experience. 2019, 13:13\\u0026ndash;21.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eD\\u0026auml;britz J, Gerner P, Enninger A, Cla\\u0026szlig;en M. Radke MJDAi: Inflammatory Bowel Disease in Childhood and Adolescence. 2017, 114(19):331\\u0026ndash;338.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eFumery M, Pariente B, Sarter H, Savoye G, Spyckerelle C, Djeddi D, Mouterde O, Bouguen G, Ley D, Peneau A et al. Long-term outcome of pediatric-onset Crohn\\u0026apos;s disease: A population-based cohort study. 2019, 51(4):496\\u0026ndash;502.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eAmaro F, Chiarelli FJB. Growth and Puberty in Children with Inflammatory Bowel Diseases. 2020, 8(11).\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eTarnok A, Kiss Z, Kadenczki O, Veres, GJEoobt. 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Adalimumab for induction of remission in patients with Crohn\\u0026apos;s disease: a systematic review and meta-analysis. 2022, 27(1):190.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eMoher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eHiggins JP, Altman DG, G\\u0026oslash;tzsche PC, J\\u0026uuml;ni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA. The Cochrane Collaboration\\u0026apos;s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eSlim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg. 2003;73(9):712\\u0026ndash;6.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eRosh J, Lerer T, Markowitz J, Goli S, Mamula P, Noe J, Pfefferkorn M, Kelleher K, Griffiths A, Kugathasan S et al. Retrospective Evaluation of the Safety and Effect of Adalimumab Therapy (RESEAT) in pediatric Crohn\\u0026apos;s disease. 2009, 104(12):3042\\u0026ndash;3049.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eViola F, Civitelli F, Di Nardo G, Barbato M, Borrelli O, Oliva S, Conte F. Cucchiara SJTAjog: Efficacy of adalimumab in moderate-to-severe pediatric Crohn\\u0026apos;s disease. 2009, 104(10):2566\\u0026ndash;2571.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eRussell R, Wilson M, Loganathan S, Bourke B, Kiparissi F, Mahdi G, Torrente F, Rodrigues A, Davies I, Thomas A et al. A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease. 2011, 33(8):946\\u0026ndash;953.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eHyams J, Griffiths A, Markowitz J, Baldassano R, Faubion W, Colletti R, Dubinsky M, Kierkus J, Rosh J, Wang Y et al. Safety and efficacy of adalimumab for moderate to severe Crohn\\u0026apos;s disease in children. 2012, 143(2):365\\u0026ndash;374.e362.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eCozijnsen M, Duif V, Kokke F, Kindermann A, van Rheenen P, de Meij T, Schaart M, Damen G, Norbruis O, Pelleboer R et al. Adalimumab therapy in children with Crohn disease previously treated with infliximab. 2015, 60(2):205\\u0026ndash;210.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eAssa A, Matar M, Turner D, Broide E, Weiss B, Ledder O, Guz-Mark A, Rinawi F, Cohen S, Topf-Olivestone C et al. Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn\\u0026apos;s Disease Compared With Reactive Monitoring. 2019, 157(4):985\\u0026ndash;996.e982.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eRomeo A, Ventimiglia M, Dipasquale V, Orlando A, Citrano M, Pellegrino S, Accomando S, Cottone M, Romano CJC, hepatology ri. : Effectiveness and safety of biologics in pediatric inflammatory boweldisease: Real-life data from the Sicilian Network. 2020, 44(2):223\\u0026ndash;229.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eRinawi F, Ricciuto A, Church P, Frost K, Crowley E, Walters T. Griffiths AJIbd: Association of Early Postinduction Adalimumab Exposure With Subsequent Clinical and Biomarker Remission in Children with Crohn\\u0026apos;s Disease. 2021, 27(7):1079\\u0026ndash;1087.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eRinawi F, Popalis C, Tersigni C, Frost K, Muise A, Church P, Walters T, Ricciuto A. Griffiths AJJopg, nutrition: Long-Term Outcomes With Adalimumab Therapy in Pediatric Crohn Disease: Associations With Adalimumab Exposure. 2022, 74(3):389\\u0026ndash;395.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003ePanaccione R, Colombel J, Sandborn W, Rutgeerts P, D\\u0026apos;Haens G, Robinson A, Chao J, Mulani P. Pollack PJAp, therapeutics: Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn\\u0026apos;s disease. 2010, 31(12):1296\\u0026ndash;1309.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eOussalah A, Danese S, Peyrin-Biroulet, LJCdt. Efficacy of TNF antagonists beyond one year in adult and pediatric inflammatory bowel diseases: a systematic review. 2010, 11(2):156\\u0026ndash;175.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eLichtiger S, Binion D, Wolf D, Present D, Bensimon A, Wu E, Yu A, Cardoso A, Chao J, Mulani P et al. The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn\\u0026apos;s disease who failed prior infliximab therapy. 2010, 32(10):1228\\u0026ndash;1239.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eLovell D, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, Nemcova D, Mouy R, Sandborg C, Bohnsack J et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. 2008, 359(8):810\\u0026ndash;820.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eDeepak P, Stobaugh D, Ehrenpreis EJJog JGLD. ld: Infectious complications of TNF-\\u0026alpha; inhibitor monotherapy versus combination therapy with immunomodulators in inflammatory bowel disease: analysis of the Food and Drug Administration Adverse Event Reporting System. 2013, 22(3):269\\u0026ndash;276.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eBenmassaoud A, Al-Taweel T, Sasson M, Moza D, Strohl M, Kopylov U, Paradis-Surprenant L, Almaimani M, Bitton A, Afif W et al. Comparative Effectiveness of Infliximab Versus Adalimumab in Patients with Biologic-Na\\u0026iuml;ve Crohn\\u0026apos;s Disease. 2018, 63(5):1302\\u0026ndash;1310.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003ePlevris N, Jenkinson P, Arnott I, Jones G. Lees CJEjog, hepatology: Higher anti-tumor necrosis factor levels are associated with perianal fistula healing and fistula closure in Crohn\\u0026apos;s disease. 2020, 32(1):32\\u0026ndash;37.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eBehm B, Bickston SJTCdosr. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn\\u0026apos;s disease. 2008(1):CD006893.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eColombel J, Sandborn W, Panaccione R, Robinson A, Lau W, Li J. Cardoso AJIbd: Adalimumab safety in global clinical trials of patients with Crohn\\u0026apos;s disease. 2009, 15(9):1308\\u0026ndash;1319.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eEvans, DJJocn. Hierarchy of evidence: a framework for ranking evidence evaluating healthcare interventions. 2003, 12(1):77\\u0026ndash;84.\\u003c/span\\u003e\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eTable 1.\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003eCharacteristics of Included Clinical Trials\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\" width=\\\"916\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd rowspan=\\\"2\\\" valign=\\\"top\\\" width=\\\"10.262008733624453%\\\"\\u003e\\n \\u003cp\\u003eStudy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" valign=\\\"top\\\" width=\\\"9.279475982532752%\\\"\\u003e\\n \\u003cp\\u003eDesign\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" valign=\\\"top\\\" width=\\\"21.61572052401747%\\\"\\u003e\\n \\u003cp\\u003eMain inclusion criteria\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" valign=\\\"top\\\" width=\\\"11.353711790393014%\\\"\\u003e\\n \\u003cp\\u003eAge(years)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" valign=\\\"top\\\" width=\\\"7.205240174672489%\\\"\\u003e\\n \\u003cp\\u003eN/Group\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"8\\\" valign=\\\"top\\\" width=\\\"40.28384279475983%\\\"\\u003e\\n \\u003cp\\u003eSpecific Study Outcomes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.097826086956523%\\\"\\u003e\\n \\u003cp\\u003eDefinition of remission\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"17.934782608695652%\\\"\\u003e\\n \\u003cp\\u003eInduction week\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"5\\\" valign=\\\"top\\\" width=\\\"41.03260869565217%\\\"\\u003e\\n \\u003cp\\u003eMaintenance week\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"17.934782608695652%\\\"\\u003e\\n \\u003cp\\u003eAEs\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.284463894967177%\\\"\\u003e\\n \\u003cp\\u003eRosh2009\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003eRetrospective\\u003c/p\\u003e\\n \\u003cp\\u003ecohort\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.663019693654267%\\\"\\u003e\\n \\u003cp\\u003eFailed IFX treatment\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.37855579868709%\\\"\\u003e\\n \\u003cp\\u003e11.1\\u0026plusmn;3.1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e115\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003ePCDAI\\u0026le;10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e26\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e52\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"4.157549234135668%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003eInfection\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.284463894967177%\\\"\\u003e\\n \\u003cp\\u003eViola2009\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003eProspective\\u003c/p\\u003e\\n \\u003cp\\u003ecohort\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.663019693654267%\\\"\\u003e\\n \\u003cp\\u003eActive moderate-to-severe CD, failed IFX treatment\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.37855579868709%\\\"\\u003e\\n \\u003cp\\u003e16.1(9-20)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e23\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003ePCDAI\\u0026le;10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e24\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e48\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"4.157549234135668%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003eMultiple\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.284463894967177%\\\"\\u003e\\n \\u003cp\\u003eRussel2011\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003eRetrospective\\u003c/p\\u003e\\n \\u003cp\\u003ecohort\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.663019693654267%\\\"\\u003e\\n \\u003cp\\u003eRefractory to conventional therapy (thiopurines/steroids/IFX)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.37855579868709%\\\"\\u003e\\n \\u003cp\\u003e14.8\\u0026plusmn;3.1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e70\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003ePCDAI\\u0026le;10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e26\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e52\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"4.157549234135668%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003eSAE\\u003c/p\\u003e\\n \\u003cp\\u003eDeaths\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.284463894967177%\\\"\\u003e\\n \\u003cp\\u003eHyams2012\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003eRCT\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.663019693654267%\\\"\\u003e\\n \\u003cp\\u003eModerate to severe CD, Failed IFX treatment\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.37855579868709%\\\"\\u003e\\n \\u003cp\\u003e13.5\\u0026plusmn;2.47\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003eG1:95\\u003c/p\\u003e\\n \\u003cp\\u003eG2:93\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003ePCDAI\\u0026le;10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e26\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e52\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"4.157549234135668%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003eMultiple\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.284463894967177%\\\"\\u003e\\n \\u003cp\\u003eCozijnsen2015\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003eRetrospective\\u003c/p\\u003e\\n \\u003cp\\u003ecohort\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.663019693654267%\\\"\\u003e\\n \\u003cp\\u003eFailed IFX treatment\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.37855579868709%\\\"\\u003e\\n \\u003cp\\u003e14(13-16)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e53\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003ePCDAI\\u0026le;12.5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e17\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e34\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e52\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"4.157549234135668%\\\"\\u003e\\n \\u003cp\\u003e104\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003eMultiple\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.284463894967177%\\\"\\u003e\\n \\u003cp\\u003eAssa2019\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003eRCT\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.663019693654267%\\\"\\u003e\\n \\u003cp\\u003eBiologic-na\\u0026iuml;ve with luminal CD\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.37855579868709%\\\"\\u003e\\n \\u003cp\\u003e12.9\\u0026plusmn;2.6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003eG1:38\\u003c/p\\u003e\\n \\u003cp\\u003eG2:40\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003ePCDAI＜10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e24\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e56\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e72\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"4.157549234135668%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003eMultiple\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.284463894967177%\\\"\\u003e\\n \\u003cp\\u003eAlvisi2019\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003eRetrospective\\u003c/p\\u003e\\n \\u003cp\\u003ecohort\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.663019693654267%\\\"\\u003e\\n \\u003cp\\u003eFailed IFX treatment\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.37855579868709%\\\"\\u003e\\n \\u003cp\\u003e14.8(9.9-17.1)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e44\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003ePCDAI\\u0026le;10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e26\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e52\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e78\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"4.157549234135668%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003eMultiple\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.284463894967177%\\\"\\u003e\\n \\u003cp\\u003eRomeo2019\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003eRetrospective\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.663019693654267%\\\"\\u003e\\n \\u003cp\\u003eSteroid dependency,\\u0026nbsp;chronically active disease,\\u0026nbsp;steroid resistance\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.37855579868709%\\\"\\u003e\\n \\u003cp\\u003e15.1(13.6-16.0)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e36\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003ePCDAI\\u0026le;10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e26\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e52\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"4.157549234135668%\\\"\\u003e\\n \\u003cp\\u003e104\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.284463894967177%\\\"\\u003e\\n \\u003cp\\u003eRinawi2020\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003eProspective\\u003c/p\\u003e\\n \\u003cp\\u003ecohort\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.663019693654267%\\\"\\u003e\\n \\u003cp\\u003eLuminal inflammatory CD\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.37855579868709%\\\"\\u003e\\n \\u003cp\\u003e13.9(12.1-15.2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e65\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003ePCDAI\\u0026le;10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e24\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"4.157549234135668%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.284463894967177%\\\"\\u003e\\n \\u003cp\\u003eRinawi2021\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003eRetrospective\\u003c/p\\u003e\\n \\u003cp\\u003ecohort\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.663019693654267%\\\"\\u003e\\n \\u003cp\\u003eActive steroid-dependent CD, failed IFX treatment\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.37855579868709%\\\"\\u003e\\n \\u003cp\\u003e14.1(12.5-15.7)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e213\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.299781181619256%\\\"\\u003e\\n \\u003cp\\u003ePCDAI＜10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"3.063457330415755%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"4.157549234135668%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.2210065645514225%\\\"\\u003e\\n \\u003cp\\u003eMultiple\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eRCT: Randomized Controlled Trial; CD: Crohn\\u0026rsquo;s Disease; IFX: Infliximab; N: Number; G1:Gronp1; G2:Group2; PCDAI: Pediatric Crohn\\u0026rsquo;s Disease Activity Index; AE: Adverse event; SAE: Serious Adverse Event.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTABLE 2. The Detailed Outcomes at the End of Treatment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\" width=\\\"907\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.287292817679559%\\\"\\u003e\\n \\u003cp\\u003eStudy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"5.193370165745856%\\\"\\u003e\\n \\u003cp\\u003eGroup\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eBase line PCDAI\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eInduction of clinical remission\\u003c/p\\u003e\\n \\u003cp\\u003eNo. (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eInduction of clinical response\\u003c/p\\u003e\\n \\u003cp\\u003eNo. (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eMaintenance of remission\\u003c/p\\u003e\\n \\u003cp\\u003eNo. (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eMaintenance of response\\u003c/p\\u003e\\n \\u003cp\\u003eNo. (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"12.486187845303867%\\\"\\u003e\\n \\u003cp\\u003emaintenance dose\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.397790055248619%\\\"\\u003e\\n \\u003cp\\u003eInfusion-related reactions\\u003c/p\\u003e\\n \\u003cp\\u003eNo. (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eInfection\\u003c/p\\u003e\\n \\u003cp\\u003eNo. (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eSAE\\u003c/p\\u003e\\n \\u003cp\\u003eNo. (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eDiscontinuation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eDeaths\\u003c/p\\u003e\\n \\u003cp\\u003eNo. (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.287292817679559%\\\"\\u003e\\n \\u003cp\\u003eRosh2009\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"5.193370165745856%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e25\\u0026plusmn;15\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e21（31.8）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e43（65.1）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e16（48.4）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e23（69.7）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"12.486187845303867%\\\"\\u003e\\n \\u003cp\\u003e40mg\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.397790055248619%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e2(1.7)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e12(10.4)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.287292817679559%\\\"\\u003e\\n \\u003cp\\u003eViola2009\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"5.193370165745856%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e36.5\\u0026plusmn;5.7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e14（60.8）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e23（86.9）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e15（65.2）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e21（91.3）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"12.486187845303867%\\\"\\u003e\\n \\u003cp\\u003e80mg（\\u0026ge;40kg）\\u003c/p\\u003e\\n \\u003cp\\u003e40mg（＜40kg）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.397790055248619%\\\"\\u003e\\n \\u003cp\\u003e4(17.4)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e2(8.7)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.287292817679559%\\\"\\u003e\\n \\u003cp\\u003eRussel2011\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"5.193370165745856%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e37.5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e17（24.2）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e35（50.0）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e12（41.3）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e12（41.3）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"12.486187845303867%\\\"\\u003e\\n \\u003cp\\u003e40mg\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.397790055248619%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e6(8.6)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e4(5.7)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e2(2.9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.287292817679559%\\\"\\u003e\\n \\u003cp\\u003eHyams2012\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"5.193370165745856%\\\"\\u003e\\n \\u003cp\\u003eG1\\u003c/p\\u003e\\n \\u003cp\\u003eG2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e＞30\\u003c/p\\u003e\\n \\u003cp\\u003e＞30\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e22（23.2）\\u003c/p\\u003e\\n \\u003cp\\u003e32（34.4）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e27（28.4）\\u003c/p\\u003e\\n \\u003cp\\u003e39（41.9）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"12.486187845303867%\\\"\\u003e\\n \\u003cp\\u003e40mg（\\u0026ge;40kg）\\u003c/p\\u003e\\n \\u003cp\\u003e20mg（\\u0026ge;40kg）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.397790055248619%\\\"\\u003e\\n \\u003cp\\u003e10（10.5）\\u003c/p\\u003e\\n \\u003cp\\u003e9（9.7）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e47（49.5）\\u003c/p\\u003e\\n \\u003cp\\u003e56（60.2）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e11（11.6）\\u003c/p\\u003e\\n \\u003cp\\u003e19（20.4）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e12(12.6)\\u003c/p\\u003e\\n \\u003cp\\u003e15(16.1)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.287292817679559%\\\"\\u003e\\n \\u003cp\\u003eCozijnsen2015\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"5.193370165745856%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e18（38.2）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e8（17.0）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e16（53.3）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e4（13.3）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"12.486187845303867%\\\"\\u003e\\n \\u003cp\\u003e40-80mg（\\u0026ge;40kg）\\u003c/p\\u003e\\n \\u003cp\\u003e20-40mg（＜40kg）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.397790055248619%\\\"\\u003e\\n \\u003cp\\u003e5（9.4）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e14（26.4）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e1（1.9）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e3(5.6)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.287292817679559%\\\"\\u003e\\n \\u003cp\\u003eAssa2019\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"5.193370165745856%\\\"\\u003e\\n \\u003cp\\u003eG1\\u003c/p\\u003e\\n \\u003cp\\u003eG2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eA:18.3\\u003c/p\\u003e\\n \\u003cp\\u003eB:17.5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e34（89.4）\\u003c/p\\u003e\\n \\u003cp\\u003e35（87.5）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e32（84.2）\\u003c/p\\u003e\\n \\u003cp\\u003e27（67.5）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"12.486187845303867%\\\"\\u003e\\n \\u003cp\\u003e40mg\\u003c/p\\u003e\\n \\u003cp\\u003e40mg\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.397790055248619%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e1（2.6）\\u003c/p\\u003e\\n \\u003cp\\u003e2（5）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e4（10.5）\\u003c/p\\u003e\\n \\u003cp\\u003e4（10）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e2(5.2)\\u003c/p\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.287292817679559%\\\"\\u003e\\n \\u003cp\\u003eAlvisi2019\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"5.193370165745856%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e24.94\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e25（78.1）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e4（12.5）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"12.486187845303867%\\\"\\u003e\\n \\u003cp\\u003e40mg\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.397790055248619%\\\"\\u003e\\n \\u003cp\\u003e1（2.2）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e2（4.5）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e2(4.5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.287292817679559%\\\"\\u003e\\n \\u003cp\\u003eRomeo2019\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"5.193370165745856%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e23（71.9）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e27（84.3）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"12.486187845303867%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.397790055248619%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.287292817679559%\\\"\\u003e\\n \\u003cp\\u003eRinawi2020\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"5.193370165745856%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e17.5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e60（92.3）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e57（87.7）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"12.486187845303867%\\\"\\u003e\\n \\u003cp\\u003e40mg（\\u0026ge;40kg）\\u003c/p\\u003e\\n \\u003cp\\u003e20mg（＜40kg）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.397790055248619%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.287292817679559%\\\"\\u003e\\n \\u003cp\\u003eRinawi2021\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"5.193370165745856%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e17.5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e174（81.7）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e138（64.8）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003eNR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"12.486187845303867%\\\"\\u003e\\n \\u003cp\\u003e40mg\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.397790055248619%\\\"\\u003e\\n \\u003cp\\u003e10（4.7）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e4（1.9）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e10（4.7）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e10(4.6)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.292817679558011%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eNo: Number; G1:NR: No report; PCDAI: Pediatric Crohn\\u0026rsquo;s Disease Activity Index; AE: Adverse event; SAE: Serious Adverse Event.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTABLE 3. Assessment of Study Quality (single-arm studies)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.885057471264368%\\\"\\u003e\\n \\u003cp\\u003eStudy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.689655172413794%\\\"\\u003e\\n \\u003cp\\u003eThe purpose of the research is clearly stated\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003eConsistency of enrolled patients\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003eCollection of expected data\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"16.32183908045977%\\\"\\u003e\\n \\u003cp\\u003eEndpoints that appropriately reflect the purpose of the study\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003eThe objectivity of endpoint evaluation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003eAdequate follow-up time\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003eLoss to follow-up rate is less than 5%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003eWhether the sample size was estimated\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"7.586206896551724%\\\"\\u003e\\n \\u003cp\\u003etotal\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.885057471264368%\\\"\\u003e\\n \\u003cp\\u003eRosh2009\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"10.689655172413794%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.32183908045977%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"7.586206896551724%\\\"\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.885057471264368%\\\"\\u003e\\n \\u003cp\\u003eViola2009\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"10.689655172413794%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.32183908045977%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"7.586206896551724%\\\"\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.885057471264368%\\\"\\u003e\\n \\u003cp\\u003eRussel2011\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"10.689655172413794%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.32183908045977%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"7.586206896551724%\\\"\\u003e\\n \\u003cp\\u003e13\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.885057471264368%\\\"\\u003e\\n \\u003cp\\u003eCozijnsen2015\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"10.689655172413794%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.32183908045977%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n 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width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.32183908045977%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.735632183908047%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.770114942528735%\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"7.586206896551724%\\\"\\u003e\\n \\u003cp\\u003e13\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"9.885057471264368%\\\"\\u003e\\n \\u003cp\\u003eRomeo2019\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"10.689655172413794%\\\"\\u003e\\n 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Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Adalimumab, Crohn’s disease, Child, Meta-analysis, Efficacy and safety\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-2781435/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-2781435/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground:\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThere is no curative treatment for childhood Crohn’s disease (CD). We conducted this meta-analysis to validate the efficacy and safety of adalimumab (ADA) in pediatric patients with CD.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods:\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe searched and investigated all relevant studies in the PubMed, Web of Science, Embase, and Cochrane Library databases. Primary outcomes were induction (≤12 week) and maintenance (up to 48 week) of remission and response. Secondary outcomes were severe adverse events, opportunistic infections to adalimumab (ADA). The Cochrane bias assessment tool was used to assess the risk of bias in randomized controlled trials (RCTs). The methodological quality of single-arm studies was assessed using the methodological index for non-randomized studies (MINORS) tool.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults:\\u003c/strong\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eA total of 10 clinical trials involving 885 patients were identified. Results indicate that 59% (95% confidence interval [CI]: 39%–80%) of the subjects treated with ADA achieved induction of remission and response 60% (95% CI: 35%–86%), 57% (95% CI: 44%–70%) achieved maintenance of remission, 63% (95% CI: 26%–69%) achieved maintenance of response.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusion:\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eCurrent evidence indicates that ADA is effective in children and adolescents with CD and adverse events are varied but usually not sever.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSystematic Review Registration:\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003ehttps://www.crd.york.ac.uk/prospero/, identifier\\u003c/p\\u003e\\n\\u003cp\\u003eCRD42023402199.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Efficacy and Safety of Adalimumab in Pediatric Patients With Crohn’s Disease: A Systematic Review and Meta- analysis\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2023-04-14 13:36:44\",\"doi\":\"10.21203/rs.3.rs-2781435/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"8b4dd590-939e-405f-b3ca-c0e41376b0ee\",\"owner\":[],\"postedDate\":\"April 14th, 2023\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2023-06-28T09:29:13+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2023-04-14 13:36:44\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-2781435\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-2781435\",\"identity\":\"rs-2781435\",\"version\":[\"v1\"]},\"buildId\":\"-HB7Z8yhvgn0wM9Nzuekk\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}