Abstract
Background:
The objective of this study was to estimate the effectiveness of early biologics compared to conventional treatment in the management of Crohn’s disease among pediatric and adolescent patients.
Methods:
A comprehensive literature search was conducted in four electronic databases to identify relevant studies published from inception to 2023. The inclusion criteria comprised randomized controlled trials (RCTs) and cohort studies that reported on the efficacy and clinical outcomes of early biologic therapy compared to late/conventional therapy in children with Crohn’s disease. The quality of the studies was assessed using the Cochrane Risk of Bias tool and the Newcastle Ottawa scale.
Results:
A total of 13 studies (2 RCTs and 11 cohort studies), involving 861 patients, were included in the meta-analysis. The results demonstrated that early biologic therapy was associated with a significantly higher rate of clinical remission (risk ratio [RR] 1.30, 95% confidence interval [CI] 1.10–1.54), lower relapse rates (RR 0.33, 95% CI 0.21–0.53), and improved mucosal healing (RR 1.47, 95% CI 1.10–1.97) compared to late/conventional therapy. However, it should be noted that there was evidence of publication bias among studies reporting clinical remission.
Conclusion:
In conclusion, early biologic therapy is significantly more effective in achieving clinical remission (within two years of diagnosis), promoting mucosal healing, and reducing relapse rates in pediatric and adolescent patients with Crohn’s disease, compared to late/conventional therapy. These findings emphasize the importance of initiating biological therapy early in the treatment of Crohn’s disease in this patient population.
Keywords: Crohn’s disease, early biologics, meta-analysis, mucosal healing, relapse, remission
INTRODUCTION
The gastrointestinal system is often affected by a disabling, chronic, relapsing, and progressive condition known as Crohn’s disease (CD). CD is characterized by clinical symptoms, endoscopic findings, and pathology. Common signs and symptoms of CD include fever, stomach pain, diarrhea, and weight loss.[1] Endoscopic findings commonly include lesions, inflammation, and ulcers. CD can affect adults in their second and third decades of life, but children and adolescents can also be affected.[2] Chronic inflammation associated with CD leads to tissue damage, resulting in strictures, penetrating disease, and fistulas that may require surgical resections.[3]
Studies have shown that approximately 25% of CD cases occur during childhood, and pediatric CD is often more extensive and progressive compared to CD in adults.[4] It is important to note that pediatric CD is characterized by growth impairment, making the restoration of linear growth a challenging goal in its treatment.[5] The primary objectives of medical treatment are to establish clinical and endoscopic remission, including mucosal healing, to avoid complications and surgery.[6] For patients with early disease or a flare, the goals of medical care are rapid symptom alleviation and long-term disease control. Corticosteroids or tumor necrosis factor inhibitors (anti-tumour necrosis factor (TNF) or “biologics,” such as infliximab) may be used for quick symptom relief.[7] An immunomodulator (immunosuppressant) such as azathioprine (AZA) or methotrexate, along with an anti-TNF, is often used for the maintenance of remission. The selection of drugs and treatment approach depends on the phenotype, disease severity, and patient characteristics. The two possible strategies are the standard (or “step-up”) strategy and the early biologic (“top-down”) approach.
Traditionally, the “step-up” approach was used, starting with corticosteroids and adding an immunomodulatory if the patient does not respond. If the patient remains refractory to treatment, an anti-TNF-alpha may be added.[8] However, studies have shown that the step-up approach is associated with increased surgical interventions due to impaired mucosal healing, despite being cost-effective and producing clinical remission.[9]
When anti-TNF drugs are started early, it is referred to as the “top-down” strategy, either with or without immunomodulators. The “early combination” treatment approach involves administering immunomodulators alongside anti-TNF medications. The idea behind the top-down treatment is to promote early mucosal repair and reduce the likelihood of adverse effects such as surgery, relapse, and hospitalization.[10] Several studies in adults have shown the effectiveness of early biologic treatment along with immunosuppressants throughout the course of the disease.[11,12] However, there are limited data on the effectiveness and safety of early biologic treatment in children and adolescents. Hence, we conducted this review to understand the effect of early biologics compared to conventional treatment in pediatric and adolescent CD.
MATERIALS AND METHODS
Design
We conducted a systematic review and meta-analysis that included RCTs and observational cohort studies. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist to report our meta-analyses.[13] Since we performed a secondary data analysis using published articles, ethics approval was not required.
Research Question: What is the effect of early biologic therapy compared to late/conventional therapy on various clinical outcomes in children with CD?
Inclusion criteria
Type of Studies: We included all parallel-arm RCTs, post-hoc analyses of RCTs, and observational cohort studies. We searched databases including Medline, Google Scholar, EMBASE, ScienceDirect, and the Cochrane Central Register of Controlled Trials (CENTRAL) for free full-text papers published from inception until March 31, 2023. We only considered articles published in English.
Type of Participants: We included all RCTs involving pediatric patients and adolescents (<18 years) with a confirmed diagnosis of CD, using the MeSH term “Crohn’s Disease.”
Type of Intervention: We included studies that involved the early administration of widely prescribed biologics such as TNF-alpha antagonists (adalimumab and/or infliximab), certolizumab pegol, natalizumab, vedolizumab, ustekinumab, or any combinations of these medications, either alone or in conjunction with immunosuppressants (AZA, 6-mercaptopurine, methotrexate, and cyclosporine). This treatment was compared to a placebo control group or a group receiving standard care. There was no single specific cut-off for defining early biological therapy, thus for our review, we followed the definition as start of biologicals within 18–24 months of diagnosis of CD.[14]
Type of Outcome Measure: We included studies that reported clinical remission (CR), relapse rate, and mucosal healing in the pediatric population with CD.
Exclusion criteria
We excluded studies published with only an abstract or unpublished data, studies published in languages other than English, and studies involving adult patients.
Search strategy
We conducted a comprehensive electronic search in databases including Medline, Google Scholar, ScienceDirect, and the Cochrane Central Register of Controlled Trials (CENTRAL). We used a combination of medical subject headings (MeSH) and free-text phrases for the literature search. MeSH phrases such as “early treatment,” “earlier treatment,” “disease duration,” “late treatment,” “top-down,” and “step up” were used. We employed terms such as “randomized controlled trial,” “controlled trial,” “clinical trial,” “cohort studies,” “observational studies,” and “prospective studies” in all possible combinations. We also checked the references of primary trials and included relevant articles. Detailed search strategy is provided in Supplementary File 5.
Data collection and analysis
Selection of studies
Two independent investigators reviewed the title, abstract, and keywords of all identified studies for potential inclusion. Articles that met the initial criteria underwent a second round of screening based on pre-established criteria. Any disagreements between the investigators were resolved through discussion or consultation with a third investigator, who ensured the overall quality of the review process.
Data extraction and management
The primary investigators (LZ and ZJ) extracted information including the study title, year of publication, authors, study design, participants, study setting, number of participants in each arm, outcome measures, intervention details, drugs used, and outcomes assessed. A third investigator (JH) cross-checked the data for accuracy and any discrepancies were resolved through consensus.
Risk of bias assessment in included studies
Two independent investigators appraised the risk of bias for included studies using the Cochrane risk of bias tool for RCTs and the Newcastle Ottawa Scale (NOS) for cohort studies and post-hoc analysis studies.[15,16] The ROB scale assessed the risk of bias using seven domains and graded them as low (if adequate information is provided), high (if the information is inadequate or not performed), or unclear (if the information is missing).[17] The NOS scale, which has three domains, was used to rate the bias risk as high risk (one point) or low risk (zero point) based on the level of bias.[16] Studies scoring three or more points were considered to have a high bias risk.
Statistical analysis
The primary investigator transferred the collected data into Stata version 14.2 (StataCorp, College Station, TX, USA).[18] We pooled the effects across studies for the mentioned outcomes using the inverse variance method and risk ratios (RR) with a 95% confidence interval (CI) for binary outcomes, both for primary and secondary objectives. We used the inverse variance approach and applied a random effects model due to the anticipated heterogeneity. The estimates were visually represented using a forest plot.
Assessment of heterogeneity
To quantify the inconsistency, we used the Chi-square test of heterogeneity and I2 statistics to evaluate any evidence of between-study variance resulting from heterogeneity. Mild heterogeneity was defined as I2 less than 25%, moderate heterogeneity as 25–75%, and substantial heterogeneity as more than 75%. Fixed-effects models were used for analysis when significant heterogeneity was not observed. We used a funnel plot to evaluate and graphically display publication bias and assessed the plot’s asymmetry using Egger’s test. A P value of 0.10 or below was considered statistically significant for publication bias.[19] Additionally, we performed subgroup analysis to assess the impact of subgroups on the specified interventions.
RESULTS
Characteristics of the studies included
Our search strategy revealed approximately 2,358 citations, including citations from major databases such as PubMed (n = 37), ScienceDirect (n = 427), Cochrane (n = 141), Google Scholar (n = 1753), and 23 from additional records identified through other sources. After removing 1,988 duplicates, we found 393 articles eligible based on title and abstract. After the eligibility assessment, we arrived at 46 articles for further evaluation, eventually resulting in 13 articles for the systematic review and meta-analysis.[20-32] Figure 1 illustrates the study selection process using the PRISMA flow diagram. Among the 13 included studies, the majority were cohort studies (11 studies), while only 2 were RCTs. The studies had sample sizes ranging from 23 to 199, with follow-up periods ranging from two months to two years. Infliximab was the most commonly used biological agent in the majority of the studies. Further details regarding the study characteristics can be found in Table 1.
Figure 1.
PRISMA flowchart describing the study selection process
Table 1.
Characteristics of included studies, n=13
| Study design and author | Single or multicentric | Study population | Sample size | Type of intervention | Primary and secondary outcomes | Description | Risk of bias |
|---|---|---|---|---|---|---|---|
| Markowitz 2000 (RCT)[20] | Double-blind, placebo-controlled trial | All subjects who were 18 years of age, and had CD diagnosed within 8 weeks of randomization | n=55 (intervention=27, control=28) | Subjects in the experimental (6-MP) group received both prednisone and 6-MP. Controls received prednisone plus placebo tablets identical to 6-MP | Primary outcomes: clinical remission and relapse rates Secondary outcomes: height, weight, change in HB score, adverse effects, and requirement for surgery | The Harvey–Bradshaw (HB) score to measure disease activity, and Pediatric Crohn’s Disease Activity Index (PCDAI) at the time of first randomization. A total HB score of 3 was used to characterize the inactive disease, 2 consecutive monthly total HB scores of 3 and 4 were used to define remission and relapse, respectively | Low risk |
| Punati 2008 (cohort)[21] | Multicentric | Individuals less than 16 years of age, newly diagnosed with CD | n=199 (early group, n=150, Conventional group, n=49) | IM use was categorized as “early” if IM was initiated within 3 months of diagnosis, and “late” if IM was started between 3 and 12 months from diagnosis | Primary outcomes: the rates of remission, corticosteroid use, infliximab use, hospitalizations, and CD-related surgery | PCDAI >30 or a physician global assessment (PGA) of moderate or severe were both considered to indicate moderate to severe disease. If the PCDAI was lower than 10 or the PGA was “inactive,” the subjects were deemed to be in remission | Good quality |
| Hyams 2009 (cohort) | Multicentric cohort | Children newly diagnosed with CD and who were enrolled in the Registry | n=54 (intervention=28, control=26) | Sixty patients (30%) initiated infliximab therapy within 3 months, 64 (32%) between 3 and 12 months, 47 (23%) between 12 and 24 months, and 31 (15%) >24 months of diagnosis | Primary outcome: clinical remission Secondary outcome: sustained clinical response | Infliximab usage was classified as either episodic, maintenance, or maintenance changed to episodic use. Episodic therapy was described as having no specific schedule after receiving one to three induction doses with intervals greater than 4–6 months between infusions | Good quality |
| Lee 2010 (cohort) | Single left | Patients <18 years and newly diagnosed as CD | n=26 (intervention=13, control groups=13) | The intervention group received infliximab and azathioprine for induction and maintenance therapy for the first year, and then azathioprine after 1 year. The control group received mesalamine after induction therapy with oral prednisolone | Primary outcomes: relapse rates Secondary outcomes: adverse events | PCDAI score of<10 points was used to describe remission of disease, whereas a score of more than 10 points was used to define relapse. The prevalence of relapse, more than once, following the achievement of a remission with treatment, was used to determine the relapse rate | Fair quality |
| Lee 2015 (cohort) | Single center | Children and adolescents <18 years with diagnosis made in accordance to the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition—Revised Porto criteria | n=51 (early biologics=31, control=20) | Patients in group A received infliximab, azathioprine, and mesalazine for induction and maintenance therapy for the first year. Patients in group B proved to be refractory, infliximab was administered with no changes in treatment with azathioprine and mesalazine | Primary: remission and relapse-free rates Secondary outcomes: Z scores to assess growth and adverse events | The relapse-free rate and remission period rate for 3 years were used to compare the effectiveness of infliximab treatment between the two groups. A PCDAI of less than 10 points was used to define clinical remission, and a PCDAI of more than 10 points following clinical remission was used to characterize relapse | Good quality |
| Kim 2011 (cohort) | Single center | Among pediatric patients who were diagnosed with CD, and followed for at least 12 months | n=29 (18 in the early biologics group and 11 in control group) | In ‘step-up’ group, prednisolone for induction, mesalamine or azathioprine for maintenance therapy | Primary: remission rates and PCDAI scores Secondary outcomes: incidence of adverse events and perianal fistula | A PCDAI score<10 was used to characterize illness remission, whereas a score of more than 10 was used to identify relapse. A score of more than 30 points was deemed to indicate moderate to severe illness | Good quality |
| Walters 2014 (cohort) | Multicentric | Children and adolescents <17 newly diagnosed with inflammatory CD | n=136 (68 in control, 68 in intervention group) | Early anti-TNFa or IM monotherapy termed as treatment within 3 months of the initial diagnosis. Late therapy as therapy started between 3 and 12 months | Primary outcomes: CS-free clinical remission at 1 year Secondary: height, weight, and BMI Z scores at 1 year | A PCDAI of 10 or less indicates clinical remission, whereas a PCDAI of 30 or higher indicates moderate to highly active disease | Good quality |
| Nuti 2016 (cohort) | Single center | Children aged 6–18 years with diagnosis of CD | n=37 (18 in early biologics, 19 in conventional group) | Infliximab or adalimumab with a regular induction treatment IV at 0, 2, and 6 weeks for infliximab (160 mg), followed by every week of adalimumab, 80 mg sc), followed by maintenance therapy | Primary: remission rates, mucosal healing rates, and relapse rates Secondary outcomes: incidence of adverse events | PCDAI was used to measure disease activity at time 0 (T0) and the endoscopic follow-up (T2). A 15-point drop in PCDAI score was required for clinical response to therapy. Clinical remission was defined as the absence of CD and PCDAI 10-related symptoms | Good quality |
| Kang 2016 (cohort) | Single center | Pediatric patients diagnosed with moderate-to-severe luminal CD of nonpenetrating, nonstricturing behavior | n=71 (47 in early biologics, 24 in conventional group) | Early combination treatment with IFX and AZA within 1 month from diagnosis without corticosteroids (CS) induction. Treatment in the step-up group was started with oral CS | Primary outcomes: clinical remission, mucosal healing rates, and relapse rates | Moderate-to-severe CD at diagnosis was defined as a score of 30 points or greater according to the PCDAI. Disease classification and behavior was based on the Paris classification | Good quality |
| Lee 2015 (cohort) | Muticentric | Children/Young adults <22 years of age enrolled at the time of initiation of EN or anti-TNF therapy | n=90 (early biologics=52, conventional=38) | Not available | Primary outcomes: clinical remission and relapse rates | Clinical remission was defined as PCDAI 10 at week 8; clinical response was defined as a reduction in PCDAI of 10>15 points or a final PCDAI 10 | Good quality |
| Assa 2019 (RCT) | Multicenteric, nonblinded RCT | Biologic naïve children (6–17 years) with luminal CD | n=57 (early biologics=30, conventional=27) | All patients in both groups were initially scheduled to receive ADL every 2 weeks | Primary: corticosteroid-free clinical remission | A high PCDAI of 10 or an abnormal biomarker alone was considered to be loss of response (LOR) because LOR was defined as PCDAI >10 and/or CRP >0.5 mg/dL and/or calprotectin >150 mg/g | Unclear risk |
| Lee 2012 (cohort) | Single center | The study included patients <17 years who were diagnosed with CD, and had been followed for at least 36 months | n=26 (13 in top down, 13 in step-up approach) | In the ‘step-up’ group, oral corticosteroids were used for induction therapy. Mesalamine or azathioprine was provided for the conventional treatment as maintenance therapy | Primary: remission and relapse rates Secondary outcomes: adverse events and antibody titers to infliximab | A PCDAI score <10 indicates disease remission, and a score higher than 10 indicates disease return. The prevalence of relapse, more than once, following the achievement of a remission with treatment, was defined as the relapse rate. A score of more than 30 points was deemed to indicate moderate to severe illness | Fair quality |
| Olbjorn 2014 (cohort) | Multicentric study | All patients aged <18 years, with newly diagnosed inflammatory bowel disease (IBD) | n=36 (18 in early, 18 in conventional group) | As maintenance therapy azathioprine was started simultaneously. Infliximab was given in dosages of 5 mg/kg, starting with a standard induction regimen | Primary: mucosal healing rates Secondary outcomes: growth and adverse events | The PCDAI was used to grade the severity of the symptoms. A clinical remission was defined as a PCDAI score of less than 10 | Fair quality |
Meta-analysis
Clinical outcomes
For our systematic review and meta-analysis, we included a total of 13 articles (n = 861; early biologics = 512, conventional therapy = 349).[20-32] We pooled the RR estimates separately for clinical remission, relapse rates, and mucosal healing. For estimating clinical remission, we included 11 studies (2 RCTs + 9 cohort studies),[20-30] 5 studies (1 RCT + 4 cohort studies) for estimating relapse rates,[20,23,28,30,31] and 3 studies (all cohort studies) for pooling mucosal healing.[26,27,32] We observed that early biologic treatment, known as the “top-down approach,” was associated with a statistically significant improvement in clinical remission rates, with a pooled RR of 1.30 (95% CI: 1.10–1.54, I2 = 56.6%) [Figure 2]. Regarding relapse rates, we found that early biologic treatment was associated with a 65% reduction in relapse rates among pediatric CD cases compared to conventional therapy, with a pooled RR of 0.33 (95% CI: 0.21–0.53, I2 = 0.0%) [Figure 3].
Figure 2.
Forest plot showing the effectiveness of early biologics on clinical remission among pediatric and adolescents with Crohn’s disease compared to conventional therapy
Figure 3.
Forest plot showing the effectiveness of early biologics on relapse among pediatric and adolescents with Crohn’s disease compared to conventional therapy
For estimating the pooled effects of mucosal healing, which is considered an important additional effect of early biologic therapy, we used a fixed-effects model due to the absence of heterogeneity (I2 = 0.0%). The results showed that early biologics were associated with increased mucosal healing compared to conventional therapy for treating pediatric CD, with a pooled RR of 1.47 (95% CI: 1.10–1.97, I2 = 0.0%) [Figure 4].
Figure 4.
Forest plot showing the effectiveness of early biologics on mucosal healing among pediatric and adolescents with Crohn’s disease compared to conventional therapy
Subgroup analysis
Subgroup analysis based on the type of studies revealed that cohort studies involving early biologics significantly increased clinical remission (pooled RR = 1.27; 95% CI: 1.11–1.46, I2 = 15.7%) among pediatric CD patients; however, among RCTs, the effect was insignificant [Supplementary Figure 1 (148.3KB, tif) ]. In the case of subgroup analysis based on sample size, we noted that clinical remission remained significantly high among studies with smaller sample sizes (≤100), with a pooled RR of 1.34 (95% CI: 1.08–1.66, I2 = 27.7%) [Supplementary Figure 2 (145KB, tif) ]. Considering the duration of follow-up, we observed that early biologics significantly increased clinical remission rates when assessed at ≤1 year of follow-up [Supplementary Figure 3 (145.5KB, tif) ]. Regarding our secondary objective of relapse rates, we conducted subgroup analysis solely based on the duration of follow-up. We found that early biologics significantly reduced relapse rates at ≤1 year of follow-up (pooled RR = 0.35; 95% CI: 0.20–0.62, I2 = 0.0%) and with more than one year of follow-up (pooled RR = 0.30; 95% CI: 0.14–0.66, I2 = 0.0%) [Supplementary Figure 4 (111.1KB, tif) ].
Publication bias
We examined publication bias using Egger’s test and found statistically significant small study effects with a coefficient value of 2.03 and a P value of 0.04, indicating the presence of publication bias. Figure 5 depicts a funnel plot, graphically representing the test for publication bias. The funnel plot displayed a symmetric pattern, further suggesting the presence of publication bias.
Figure 5.
Funnel plot showing publication bias
DISCUSSION
Although conventional therapies such as corticosteroids and immunomodulators can induce remission, many patients struggle to maintain it and often require repeated medication. The evidence from our study, which included 13 studies (2 RCTs + 9 cohort), showed that early biological “top-down” therapy resulted in significantly higher rates of clinical remission (pooled RR = 1.30, 95% CI: 1.10–1.54, I2 = 56.6%, n = 805, P < 0.05), lower relapse rates (pooled RR = 0.33, 95% CI: 0.21–0.53, I2 = 0.0%, n = 206, P < 0.05), and improved mucosal healing (pooled RR = 1.47, 95% CI: 1.10–1.97, I2 = 0.0%, n = 138, P < 0.05) compared to conventional therapy.
The heterogeneity across the studies for the evaluated outcomes was low to moderate, and the pooled effect estimates remained consistent across various subgroups. Our results were consistent with previous research on pediatric CD.[33,34] However, the decision to initiate biologic therapy in children with CD should also consider the potential long-term risks and benefits of these medications, as well as the individual patient’s disease severity and response to conventional therapy.[35]
The concept of the top-down approach in treating CD originated in Europe, where D’Haens et al.[36] demonstrated that the top-down group, which received combined immunosuppression induction with AZA and infliximab infusion at weeks 0, 2, and 6, showed better clinical remission (60%) compared to the step-up group (36%, absolute difference of 24%, 95% CI: 7.3–40.8, P = 0.0062) at 26 weeks. Other trials such as the CHARM (Crohn’s trial of the fully Human antibody Adalimumab for remission Maintenance) trial have also demonstrated the safety and efficacy of early use of adalimumab 40 mg over conventional therapy for treating moderate to severe CD in adults. The justification for the top-down therapy of early CD is supported by data from various sources.[37,38] Subgroup analysis of placebo-controlled studies of certolizumab pegol and adalimumab has shown that patients with early CD derive greater benefit from TNF antagonist therapy than those with more advanced disease.[39] Studies have indicated that the top-down approach primarily promotes deep and durable mucosal healing, thereby reducing complications and the need for surgical procedures.[40]
A review conducted by Broide et al.[41] has also suggested that starting early biologics is more cost-effective when compared to surgery and conventional therapy among adults. Similar studies among children are necessary. Several studies have also established that children tolerate early biologics well and thus have a favorable safety profile compared to conventional therapy. A recent systematic review by Dziechciarz et al.[42] showed that only 12% of the pediatric cases treated with early biologics reported adverse events. A few studies conducted in varied study settings have also shown that early biologics initiation is associated with a reduction in corticosteroid use, hospitalization rate, and ultimately the rate of surgery.[21]
Our study was one of the few studies that comprehensively assessed the benefits of using early biologics for pediatric CD. Two independent authors screened and assessed all studies using validated quality assessment tools. However, there are limitations to our review. Majority of the papers included were non-randomized, which raised methodological concerns. Findings from five studies could not be generalized due to small sample sizes and being limited to a single hospital setting. We included only studies published in English language, which could introduce a linguistic bias. Variations in patient characteristics and primary diagnosis across trials may have influenced clinical outcomes. Additionally, studies differed in terms of induction doses and outcome definitions, and the follow-up periods varied. Almost all studies focused on TNF drugs, so the findings may not apply to other treatments. Furthermore, varying rates of concurrent immunomodulator use and placebo responses were observed, which may have affected the trial consistency.
In summary, our meta-analysis suggests that early use of biologics is a viable option for children with CD as it increases remission (within two years of diagnosis) and mucosal healing rates and also reduces relapse rates. However, despite these data, pediatric CD patients with early-stage disease still have low biologic utilization. It is essential to educate clinicians, policymakers, and other stakeholders to improve access to and utilization of biologics among the pediatric population with moderate to severe CD. However, further large population-based clinical trials and prospective studies are necessary to evaluate the cost-effectiveness and long-term outcomes in the pediatric population.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Forest plot showing the effectiveness of early biologics on clinical remission among pediatric and adolescents with Crohn’s disease compared to conventional therapy across different study designs
Forest plot showing the effectiveness of early biologics on clinical remission among pediatric and adolescents with Crohn’s disease compared to conventional therapy across various sample sizes
Forest plot showing the effectiveness of early biologics on clinical remission among pediatric and adolescents with Crohn’s disease compared to conventional therapy across follow-up
Forest plot showing the effectiveness of early biologics on relapse rates among pediatric and adolescents with Crohn’s disease compared to conventional therapy across follow-up
SUPPLEMENTARY FILE 5
Search strategy
PubMed.
| S.No | Search terms | Results |
|---|---|---|
| #1 | Search: ((((Early treatment) AND (biologics)) AND (crohns disease)) AND (paediatric)) AND (adolescents)) AND (cohort study) “Early”[All Fields] AND (“therapeutics”[MeSH Terms] OR “therapeutics”[All Fields] OR “treatments”[All Fields] OR “therapy”[MeSH Subheading] OR “therapy”[All Fields] OR “treatment”[All Fields] OR “treatment s”[All Fields]) AND (“biological products”[MeSH Terms] OR (“biological”[All Fields] AND “products”[All Fields]) OR “biological products”[All Fields] OR “biologic”[All Fields] OR “biologicals”[All Fields] OR “biological factors”[MeSH Terms] OR (“biological”[All Fields] AND “factors”[All Fields]) OR “biological factors”[All Fields] OR “biologics”[All Fields] OR “biologically”[All Fields] OR “biology”[MeSH Terms] OR “biology”[All Fields] OR “biological”[All Fields]) AND (“crohn disease”[MeSH Terms] OR (“crohn”[All Fields] AND “disease”[All Fields]) OR “crohn disease”[All Fields] OR (“crohns”[All Fields] AND “disease”[All Fields]) OR “crohns disease”[All Fields]) AND (“paediatrics”[All Fields] OR “pediatrics”[MeSH Terms] OR “pediatrics”[All Fields] OR “paediatric”[All Fields] OR “pediatric”[All Fields]) AND (“adolescences”[All Fields] OR “adolescency”[All Fields] OR “adolescent”[MeSH Terms] OR “adolescent”[All Fields] OR “adolescence”[All Fields] OR “adolescents”[All Fields] OR “adolescent s”[All Fields]) AND (“cohort studies”[MeSH Terms] OR (“cohort”[All Fields] AND “studies”[All Fields]) OR “cohort studies”[All Fields] OR (“cohort”[All Fields] AND “study”[All Fields]) OR “cohort study”[All Fields]) Translations treatment: “therapeutics”[MeSH Terms] OR “therapeutics”[All Fields] OR “treatments”[All Fields] OR “therapy”[Subheading] OR “therapy”[All Fields] OR “treatment”[All Fields] OR “treatment’s”[All Fields] biologics: “biological products”[MeSH Terms] OR (“biological”[All Fields] AND “products”[All Fields]) OR “biological products”[All Fields] OR “biologic”[All Fields] OR “biologicals”[All Fields] OR “biological factors”[MeSH Terms] OR (“biological”[All Fields] AND “factors”[All Fields]) OR “biological factors”[All Fields] OR “biologics”[All Fields] OR “biologically”[All Fields] OR “biology”[MeSH Terms] OR “biology”[All Fields] OR “biological”[All Fields] crohns disease: “crohn disease”[MeSH Terms] OR (“crohn”[All Fields] AND “disease”[All Fields]) OR “crohn disease”[All Fields] OR (“crohns”[All Fields] AND “disease”[All Fields]) OR “crohns disease”[All Fields] paediatric: “paediatrics”[All Fields] OR “pediatrics”[MeSH Terms] OR “pediatrics”[All Fields] OR “paediatric”[All Fields] OR “pediatric”[All Fields] adolescents: “adolescences”[All Fields] OR “adolescency”[All Fields] OR “adolescent”[MeSH Terms] OR “adolescent”[All Fields] OR “adolescence”[All Fields] OR “adolescents”[All Fields] OR “adolescent’s”[All Fields] cohort study: “cohort studies”[MeSH Terms] OR (“cohort”[All Fields] AND “studies”[All Fields]) OR “cohort studies”[All Fields] OR (“cohort”[All Fields] AND “study”[All Fields]) OR “cohort study”[All Fields] | 47 |
| #2 | Search: ((((Early treatment) AND (biologics)) AND (crohns disease)) AND (paediatric)) AND (adolescents)) Filters: Randomized Controlled Trial (“Early”[All Fields] AND (“therapeutics”[MeSH Terms] OR “therapeutics”[All Fields] OR “treatments”[All Fields] OR “therapy”[MeSH Subheading] OR “therapy”[All Fields] OR “treatment”[All Fields] OR “treatment s”[All Fields]) AND (“biological products”[MeSH Terms] OR (“biological”[All Fields] AND “products”[All Fields]) OR “biological products”[All Fields] OR “biologic”[All Fields] OR “biologicals”[All Fields] OR “biological factors”[MeSH Terms] OR (“biological”[All Fields] AND “factors”[All Fields]) OR “biological factors”[All Fields] OR “biologics”[All Fields] OR “biologically”[All Fields] OR “biology”[MeSH Terms] OR “biology”[All Fields] OR “biological”[All Fields]) AND (“crohn disease”[MeSH Terms] OR (“crohn”[All Fields] AND “disease”[All Fields]) OR “crohn disease”[All Fields] OR (“crohns”[All Fields] AND “disease”[All Fields]) OR “crohns disease”[All Fields]) AND (“paediatrics”[All Fields] OR “pediatrics”[MeSH Terms] OR “pediatrics”[All Fields] OR “paediatric”[All Fields] OR “pediatric”[All Fields]) AND (“adolescences”[All Fields] OR “adolescency”[All Fields] OR “adolescent”[MeSH Terms] OR “adolescent”[All Fields] OR “adolescence”[All Fields] OR “adolescents”[All Fields] OR “adolescent s”[All Fields])) AND (randomizedcontrolledtrial[Filter]) Translations treatment: “therapeutics”[MeSH Terms] OR “therapeutics”[All Fields] OR “treatments”[All Fields] OR “therapy”[Subheading] OR “therapy”[All Fields] OR “treatment”[All Fields] OR “treatment’s”[All Fields] biologics: “biological products”[MeSH Terms] OR (“biological”[All Fields] AND “products”[All Fields]) OR “biological products”[All Fields] OR “biologic”[All Fields] OR “biologicals”[All Fields] OR “biological factors”[MeSH Terms] OR (“biological”[All Fields] AND “factors”[All Fields]) OR “biological factors”[All Fields] OR “biologics”[All Fields] OR “biologically”[All Fields] OR “biology”[MeSH Terms] OR “biology”[All Fields] OR “biological”[All Fields] crohns disease: “crohn disease”[MeSH Terms] OR (“crohn”[All Fields] AND “disease”[All Fields]) OR “crohn disease”[All Fields] OR (“crohns”[All Fields] AND “disease”[All Fields]) OR “crohns disease”[All Fields] paediatric: “paediatrics”[All Fields] OR “pediatrics”[MeSH Terms] OR “pediatrics”[All Fields] OR “paediatric”[All Fields] OR “pediatric”[All Fields] adolescents: “adolescences”[All Fields] OR “adolescency”[All Fields] OR “adolescent”[MeSH Terms] OR “adolescent”[All Fields] OR “adolescence”[All Fields] OR “adolescents”[All Fields] OR “adolescent’s”[All Fields] | 3 |
| Search: (((((Early treatment) AND (biologics)) OR (top-down) AND (crohns disease)) AND (paediatric)) AND (adolescents)) ((“Early”[All Fields] AND (“therapeutics”[MeSH Terms] OR “therapeutics”[All Fields] OR “treatments”[All Fields] OR “therapy”[MeSH Subheading] OR “therapy”[All Fields] OR “treatment”[All Fields] OR “treatment s”[All Fields]) AND (“biological products”[MeSH Terms] OR (“biological”[All Fields] AND “products”[All Fields]) OR “biological products”[All Fields] OR “biologic”[All Fields] OR “biologicals”[All Fields] OR “biological factors”[MeSH Terms] OR (“biological”[All Fields] AND “factors”[All Fields]) OR “biological factors”[All Fields] OR “biologics”[All Fields] OR “biologically”[All Fields] OR “biology”[MeSH Terms] OR “biology”[All Fields] OR “biological”[All Fields])) OR “top-down”[All Fields]) AND(“crohn disease”[MeSH Terms] OR | ||
| (“crohn”[All Fields] AND “disease”[All Fields]) OR “crohn disease”[All Fields] OR (“crohns”[All Fields] AND “disease”[All Fields]) OR “crohns disease”[All Fields]) AND (“paediatrics”[All Fields] OR “pediatrics”[MeSH Terms] OR “pediatrics”[All Fields] OR “paediatric”[All Fields] OR “pediatric”[All Fields]) AND (“adolescences”[All Fields] OR “adolescency”[All Fields] OR “adolescent”[MeSH Terms] OR “adolescent”[All Fields] OR “adolescence”[All Fields] OR “adolescents”[All Fields] OR “adolescent s”[All Fields]) Translations treatment: “therapeutics”[MeSH Terms] OR “therapeutics”[All Fields] OR “treatments”[All Fields] OR “therapy”[Subheading] OR “therapy”[All Fields] OR “treatment”[All Fields] OR “treatment’s”[All Fields] biologics: “biological products”[MeSH Terms] OR (“biological”[All Fields] AND “products”[All Fields]) OR “biological products”[All Fields] OR “biologic”[All Fields] OR “biologicals”[All Fields] OR “biological factors”[MeSH Terms] OR (“biological”[All Fields] AND “factors”[All Fields]) OR “biological factors”[All Fields] OR “biologics”[All Fields] OR “biologically”[All Fields] OR “biology”[MeSH Terms] OR “biology”[All Fields] OR “biological”[All Fields] crohns disease: “crohn disease”[MeSH Terms] OR (“crohn”[All Fields] AND “disease”[All Fields]) OR “crohn disease”[All Fields] OR (“crohns”[All Fields] AND “disease”[All Fields]) OR “crohns disease”[All Fields] paediatric: “paediatrics”[All Fields] OR “pediatrics”[MeSH Terms] OR “pediatrics”[All Fields] OR “paediatric”[All Fields] OR “pediatric”[All Fields] adolescents: “adolescences”[All Fields] OR “adolescency”[All Fields] OR “adolescent”[MeSH Terms] OR “adolescent”[All Fields] OR “adolescence”[All Fields] OR “adolescents”[All Fields] OR “adolescent’s”[All Fields] | 92 | |
| #3 | #1 AND #2 AND #3 | 37 |
science direct
| S.No | Search terms | Results |
|---|---|---|
| #1 | (((((Early treatment) AND (biologics)) OR (top-down) AND (Crohn’s disease)) AND (paediatric)) AND (adolescents)) AND (Randomised control trial) AND (Cohort study)) | 427 |
Google scholar: 1753
Early treatment
Biologics
Top-down
Step-up
Crohn's disease
Pediatrics
Adolescents
Remission
Relapse
Mucosal healing
Randomised control trial
Cohort studies
Cochrane
| Id | Search terms | Results |
|---|---|---|
| #1 | Early Biologics | 3200 |
| #2 | Crohn’s disease | 5501 |
| #3 | Top-down | 148 |
| #4 | Conventional therapy | 36694 |
| #5 | Mucosal healing | 1665 |
| #6 | Pediatrics Crohn’s disease | 432 |
| #7 | Randomised control trial | 706148 |
| #8 | Cohort studies | 64347 |
| #9 | #1 AND #9 | 141 |
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Forest plot showing the effectiveness of early biologics on clinical remission among pediatric and adolescents with Crohn’s disease compared to conventional therapy across different study designs
Forest plot showing the effectiveness of early biologics on clinical remission among pediatric and adolescents with Crohn’s disease compared to conventional therapy across various sample sizes
Forest plot showing the effectiveness of early biologics on clinical remission among pediatric and adolescents with Crohn’s disease compared to conventional therapy across follow-up
Forest plot showing the effectiveness of early biologics on relapse rates among pediatric and adolescents with Crohn’s disease compared to conventional therapy across follow-up