Health Technology Review

Early Biologic Treatment for Inflammatory Bowel Disease

Authors: Shu-Ching Hsieh, Xiaoqin Wang, Zemin Bai, Becky Skidmore, Shannon E. Kelly, Melissa Brouwers, George Wells

This rapid review was conducted by the Post-Market Drug Evaluation Team (PODET) through the Post Market Drug Evaluation CoLab Network.

This rapid review updates the evidence for early biologic treatment versus conventional step-up therapy for patients with luminal Crohn disease, fistulizing Crohn disease, or ulcerative colitis.

Findings are based on 4 systematic reviews, 2 randomized controlled trials, and 3 updated clinical guidelines.

Luminal Crohn Disease

Three systematic reviews showed that early biologic treatment, initiated within 36 months of diagnosis, significantly improved clinical remission, mucosal healing, and reduced relapse rates, surgery needs, and disease progression compared to conventional strategies. Two randomized controlled trials found that early infliximab treatment led to better remission rates, quality of life, and safety outcomes compared with conventional treatment for both adults and children with newly diagnosed moderate-to-severe Crohn disease. These results are consistent with previous evidence suggesting that early biologic drugs improve clinical benefits compared with conventional strategies.

Clinical guidelines generally recommend biologic drugs as third-line treatment. One guideline targets adults and children with severe, active Crohn disease, and another focuses on children and adolescents with luminal Crohn disease regardless of severity. Of these, 1 guideline recommends first-line biologics for high-risk pediatric patients.

Fistulizing Crohn Disease

One guideline recommends third-line infliximab for patients with active fistulizing Crohn disease who did not respond, did not tolerate or had a contraindication to conventional therapy. First-line anti–tumour necrosis factor therapy was only recommended for children and adolescents with fistulizing perianal Crohn disease. No evidence was identified for this population.

Ulcerative Colitis

In 1 systematic review, early biologics were found to be associated with a higher risk of colectomy. However, these findings should be interpreted with caution as they are based on evidence from 3 observational studies. One guideline recommends infliximab as a third-line option for acute severe cases contraindicated to or clinically inappropriate with ciclosporin.

Introduction and Rationale

Background

Inflammatory bowel disease (IBD) results in inflammation of the gastrointestinal tract lining, impairing the body's ability to digest food, absorb nutrients, and eliminate waste effectively. Crohn disease (CD) and ulcerative colitis (UC) are the 2 distinct types of IBD, both causing inflammation and functional disruption. In Canada, the prevalence of IBD in 2023 is estimated at 825 per 100,000 individuals, with 410 per 100,000 for Crohn disease and 414 per 100,000 for UC and IBD-unclassified.¹ This translates to approximately 322,600 people in Canada living with IBD in 2023, with half of these cases comprising either UC or CD. By 2035, the prevalence is expected to increase to 1.1% of the population, or 1 in 91 people living in Canada.²

CD is a type of IBD that may affect any portion of the gastrointestinal tract from the mouth to the anus. Patients with CD have a higher risk of developing strictures, fistulas, and abscesses due to transmural inflammation, which is painful, reduces quality of life and causes other chronic or severe symptoms. It is estimated that 33% of CD patients may develop a fistula within 10 years of initial diagnosis, increasing to up to 50% within 20 years.³ Approximately one-quarter of the global Crohn disease population may develop perianal lesions, with 18% presenting as penetrating lesions such as fistulas or abscesses.³ The prevalence of perianal fistulas in Crohn disease varies according to disease location, being least common in isolated ileal disease (12%) or ileocolonic disease (15%) and most common in colonic disease (41%), particularly with rectal involvement (92%).⁴ Consequently, patients with Crohn disease typically experience periods of remission and relapse over time.^5,6 For the subtype of fistulizing Crohn disease, surgical interventions, such as bowel resection, are often necessary.^5,7 In contrast, UC is confined to the colon and rectum, with inflammation confined to the mucosal layer, though it presents a higher risk of colorectal cancer after 8 to 10 years of disease progression.⁸

According to the Crohn and Colitis Canada,² the economic burden of IBD is substantial. In 2023, approximately $5.38 billion was spent on IBD care, with $2.05 billion in indirect and out-of-pocket costs and $3.33 billion in direct health care costs. Health care utilization for IBD has shifted from inpatient to outpatient management, leading to fewer hospital admissions and surgeries but an increase in outpatient visits. Effective pharmacotherapy remains crucial, including treatment options such as aminosalicylates, corticosteroids, immunomodulators, Janus kinase (JAK) inhibitors, antibiotics, and biologics.

Biologics, despite their high cost, have undergone continuous evaluation for efficacy and safety within the constraints of limited health resources. In Canada, approved biologics for IBD include 3 tumour necrosis factor (TNF) antagonists (infliximab, adalimumab, and golimumab), 2 IL-12/IL-23 inhibitors (risankizumab, ustekinumab), and 1 anti-integrin drug (vedolizumab). In 2017, biologics accounted for approximately 50% of IBD-related health care costs, a proportion that has likely increased since then.² Reports from several provinces in Canada indicate a rapid rise in the use of biologics for both Crohn disease and UC.⁹

In the conventional treatment approach for IBD, medication follows a therapeutic hierarchy: starting with tier I 5-aminosalicylic acid, followed sequentially by tier II corticosteroids (prednisone or budesonide), tier III immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate), and finally tier IV biologic drugs (infliximab, adalimumab, or certolizumab pegol).¹⁰ Alternatively, the top-down or accelerated step-up approach administers more potent drugs early in patient care, often immediately after diagnosis. As evidence supporting the benefits of biologics continues to grow, the top-down approach with early biologic intervention has become increasingly central in IBD management. Two distinct treatment protocols have emerged: 1) early use of biologics alone, and 2) a combined top-down approach with early use of both immunomodulators and biologics.¹¹ Given that the top-down approach with biologics is relatively new and involves debates concerning its safety, efficacy, and cost, updated evidence is critical for informing stakeholders.

Policy Issue

To support decision-making about the current role of biologics in treating IBD, this rapid review provides an update to the 2019 CADTH Technology Review,¹² which summarized findings from 3 related rapid reviews^13-15 on the appropriate use of biologics in IBD management.

Policy Questions

Is there a role for earlier biologic therapy in IBD treatment:

1. For patients with moderate-to-severe luminal Crohn disease who have not received adequate trials of both corticosteroids and immunomodulators?

2. For patients with fistulizing Crohn disease who have not received a course of antibiotics and adequate trial of immunomodulators?

3. For patients with moderate-to-severe UC who have not received prior immunomodulating therapy?

Purpose

This Rapid Review aims to update and summarize evidence since 2018 on the earlier use of biologics for IBD to address the previously stated policy questions.

Research Questions

1. What is the clinical efficacy and safety of early biologic treatment compared with conventional step-up treatment for luminal Crohn disease?

2. What is the clinical efficacy and safety of early biologic treatment compared with conventional step-up treatment for fistulizing Crohn disease?

3. What is the clinical efficacy and safety of early biologic treatment compared with conventional step-up treatment for UC?

4. What are the evidence-based guidelines on the position of biologics in the sequencing of pharmacological treatments for Crohn disease and UC?

Methods

We conducted a rapid review on the efficacy and safety of early biologic treatment for IBD and sought updates to existing evidence-based guidelines.

Literature Search Methods

An experienced medical information specialist developed and refined the search strategies through an iterative process in consultation with the review team. The specialist then executed the searches in Ovid MEDLINE ALL (Ovid platform) and the Cochrane Library (Wiley) on July 19, 2024. The strategies utilized a combination of controlled vocabulary (e.g., “Colitis, Ulcerative,” “Crohn Disease,” “Biological Therapy”) and keywords (e.g., “colitis gravis,” “biosimilar,” “top-down”), adjusting the vocabulary and syntax as necessary across the databases. We limited results to citations published after November 1, 2018, and, where applicable, removed animal-only studies and opinion pieces. We downloaded and deduplicated the records using EndNote version 9.3.3 (Clarivate Analytics) and uploaded to Covidence (Veritas Health Innovation Ltd.).

We conducted a targeted search for relevant health technology assessments (HTAs) on the websites of HTA agencies in Canada, US, UK, Australia, and New Zealand via the CDA Grey Matters Checklist using keywords relevant to our research questions. One reviewer screened relevant reports and publications on HTA websites and downloaded the full text of any relevant reports for additional review to check for eligibility.

We did not search for evidence-based guidelines. Rather, we consulted the websites of clinical guideline developers with guidelines on the position of biologic drugs cited in the previous CDA report¹² to check for updated guidelines or recommendations. One reviewer checked relevant websites and downloaded the full text or link to any relevant guideline updates to check for eligibility.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first-level screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Where necessary, the criteria were aligned with research questions Q1 to Q4.

Table 1: Selection Criteria

NA = not applicable.

^aDuring screening, we included any relevant literature focusing on Crohn disease. During data extraction, we assessed eligibility and baseline information to differentiate between luminal and fistulizing subgroups of Crohn disease and identify any available subgroup analysis results. This same methodology was applied to identify evidence for the moderate-to-severe group within each subgroup.

^bInclude tier I to III medications for conventional therapy sequentially:¹⁰ 5-aminosalicylic acid, corticosteroids (prednisone or budesonide), and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate).

^cEligible randomized controlled trials in the included health technology assessment or systematic review were excluded.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria specified in Table 1, were duplicate reports as separate publications, or were published before November 2018. Additionally, we excluded non-English records, meeting abstracts, protocols, and studies in-progress.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)¹⁶ for systematic reviews, the Cochrane Risk of Bias tool (RoB v2)¹⁷ for randomized controlled trials (RCT), and 2 domains of the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument (rigour of development and editorial independence)¹⁸ for guidelines. Summary ratings were not assessed for the included studies; rather, the strengths and limitations of each included article were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 675 citations were identified in the literature search. After screening the titles and abstracts, 556 citations were excluded, and 119 potentially relevant reports from the electronic search were retrieved for full-text review. Additionally, 4 potentially relevant guideline updates were retrieved from the grey literature search for full-text review. In total, 9 publications met the inclusion criteria and were included in this review. These comprised of 4 systematic reviews, 2 RCTs, and 3 updated evidence-based guidelines. Appendix 1 presents the PRISMA flow chart of the study selection.

Appendix 6 provides several references for records which may be of potential interest but were not included in the review.

We searched 40 websites of 38 HTA agencies for relevant reports including 19 websites in Canada, 6 in Australia, 7 in the UK, 7 websites for 5 organizations in the US, and 1 in New Zealand. Six reports were reviewed and no eligible HTAs were located.

Study Characteristics

Further details regarding the characteristics of included systematic reviews, RCTs, and evidence-based guidelines are provided in Table 2 and Table 3 in Appendix 2, respectively.

Four SRs, 2 RCTs, and 3 updated evidence-based guidelines were identified that met the inclusion criteria.

Systematic Reviews

Four SRs^11,19-21 were included. All 4 SRs included RCTs and observational studies.

Systematic Reviews of Patients With Luminal Crohn Disease

While the scope of the 4 SRs considered populations broader than luminal CD, they provided relevant evidence for the research questions in this review. All 4 SRs included studies in patients with Crohn disease without distinguishing between luminal and fistulizing Crohn disease. We included these SRs as more than 80% of the populations were considered to have luminal Crohn disease while less than 20% had penetrating lesions (fistulas or abscesses) requiring medical treatment based on baseline disease descriptions.^7,22

All of the included SRs considered RCTs though a large proportion of the primary studies included were observational studies. Specifically, 2 of the 18 studies in the review by Law et al. (2024),²⁰ 2 of the 13 studies in the review by Zhang et al. (2023),²¹ 3 of the 11 studies in the review by Hamdeh et al. (2020),¹⁹ and 6 of the 19 studies in the review by Tsui, et al. (2018)¹¹ were either RCTs or posthoc analyses of RCTs. The 4 included SRs included primary studies published up to 2021.

Additional details on the included studies, including an assessment of overlap among the included primary studies across the 4 SRs is provided in Appendix 5.

Country of Origin

Two SRs were conducted by researchers from the US,^19,20 1 from Canada¹¹ and 1 from China.²¹

Patient Population

All 4 SRs focused on patients with Crohn disease. One SR²⁰ also considered UC as an indication. One of the reviews focused on adult populations,¹⁹ another on children and adolescents,²¹ and 2 addressed both children and adults.^11,20 One review²⁰ briefly described the included study populations as “moderate-to-severe Crohn disease,” 2 reviews summarized the characteristics of included studies where some were classified as having moderate-to-severe disease,^19,21 and 1 review¹¹ did not report any relevant details on disease severity.

Interventions and Comparators

Three systematic reviews compared early versus late administration of biologic drugs, with 2 explicitly defining early biologic drugs²⁰ and early anti–TNF-alpha¹⁹ as those administered within 3 years of disease onset. The third review²¹ did not provide a clear definition for the timing of prescribed biologics or what they considered to be early use. A time frame of “18-24 months” was inferred from the included studies. The comparators were generally referred to as late biologics,^20,21 late anti–TNF-alpha,¹⁹ or late/conventional treatment, which could include a placebo control group or standard care. A fourth SR¹¹ conducted a descriptive review and critical appraisal of the current literature on top-down therapy. The top-down therapy included 3 distinct treatment protocols: early use of biologics, such as infliximab, adalimumab, and certolizumab pegol; early use of immunomodulators, such as azathioprine, 6-mercaptopurine, and methotrexate; and early combined use of both immunomodulators and biologics. In contrast, traditional step-up approaches commence with locally acting oral steroids, followed by systemic steroids, and subsequently immunomodulators and biologic drugs for steroid-dependent or resistant patients. The review did not specify the timing of early use, but it was inferred from the treatment timing of included studies, ranging from week 0 to within 3 years of diagnosis for adult patients and from week 0 to within 3 months for pediatric patients.

Efficacy Outcomes

Three SRs^19-21 reported clinical outcomes of interest and conducted meta-analyses where feasible including:

• remission^19,21

• relapse²¹

• surgery^19,20

• mucosal healing^19,21

• disease progression¹⁹

• clinical response.¹⁹

One SR by Tsui (2018)¹¹ did not conduct any quantitative analysis and summarized the result for outcomes including remission and need for surgery narratively.

Safety Outcomes

None of the SRs reported any of the safety outcomes of interest.

Systematic Reviews of Patients With Fistulizing Crohn Disease

None of the included systematic reviews considered patients with fistulizing CD.

Systematic Reviews of Patients With UC

A single SR by Law et al. (2024),²⁰ considered UC in addition to Crohn disease. Three observational studies, 2 in adults and 1 in children, were included for UC with disease duration less than 3 years.

Country of Origin

The SR²⁰ was conducted by researchers in the US.

Patient Population

This SR²⁰ included studies of both CD and UC in both children and adults.

Interventions and Comparators

The included SR²⁰ compared early versus late administration of biologics, defining early biologic drugs as those administered within 3 years of disease onset.

Efficacy Outcomes

The included SR²⁰ reported a single clinical outcome — need for surgery.

Safety Outcomes

This included SR did not report any safety outcomes of interest.

Primary Studies

Two RCTs^23,24 were included. Neither RCT was included the SRs included in this review. We considered both to primarily support the evidence for luminal Crohn disease, given the disease characteristics and severity of the patients included in these studies. This included a low prevalence of patients with penetrating lesions (fistulas or abscesses) requiring medical treatment (less than 20%),^7,22 trial eligibility and/or a small portion of patients who were categorized with penetrating (classified as B3) disease behaviour at baseline. Specifically, Noor et al. (2024)²³ included only 1% (3/382) of patients with penetrating disease behaviour, while Jongsma et al. (2022)²⁴ excluded patients with active perianal fistulas and none classified as having penetrating disease behaviour.

RCTs of Patients With Luminal Crohn Disease

Country of Origin

One multicentre RCT²³ was conducted in 40 hospitals in the UK. A second multicentre RCT²⁴ was conducted in 12 hospitals located in the Netherlands, Croatia, and Finland.

Patient Population

The PROFILE trial (PRedicting Outcomes For Crohn disease using a moLecular biomarker)²³ included 386 adults with newly diagnosed active Crohn disease between December 29, 2017, and January 5, 2022. To be eligible, patients were required to have a Harvey-Bradshaw Index score of at least 7, elevated C-reactive protein, fecal calprotectin, or both, and endoscopic evidence of active inflammation. Participants were randomized into 2 groups: the top-down group (n = 193) and the accelerated step-up group (n = 193), with stratification by a blood-based prognostic biomarker subgroups [IBDhi (poor prognosis) versus IBDlo (better prognosis)], disease location (colon only versus other), and mucosal inflammation severity (mild, moderate, or severe). The mean age of participants was 33.6 years (SD 13.2), with 179 females (46%) and 207 males (54%). The median time from diagnosis to trial enrollment and initiation of treatment with the index course of steroids was 12 days (range 0 to 191). At baseline, the prevalence of penetrating (B3) disease behaviour was 1% in both the top-down group (1/192) and the accelerated step-up group (2/190). Patient characteristics and baseline disease activity were similar across both groups. After the 48-week study duration, primary outcome data were available for 379 participants (189 in the top-down group and 190 in the accelerated step-up group).

A second trial²⁴ included 100 newly diagnosed pediatric patients with moderate-to-severe CD between April 7, 2015, and November 19, 2018. These patients, aged 3 to 17 years, presented with untreated Crohn disease according to the revised Porto criteria, had a weighted Pediatric Crohn Disease Activity Index (wPCDAI) of more than 40, and weighed more than 10 kg at baseline. Patients with active perianal fistulas were excluded. Eligible patients were stratified by centre and equally randomized into 2 groups: the first-line infliximab (FL-IFX) group (n = 50) and the conventional treatment group (n = 50). The mean age of participants was 14.6 years (SD 3.5), with 48 females (48%) and 52 males (52%). The median time between diagnostic endoscopy and the start of treatment was 8 days (IQR 4 to 14). At baseline, 10% of patients in both the FL-IFX group and the conventional treatment group had perianal disease, such as inactive fistulas, skin tags, or anal fissures, but none were classified with penetrating (B3) disease behaviour. The other baseline characteristics were similar between treatment groups. After the 52-week study duration, primary outcome data were available for 94 participants (46 in the FL-IFX group and 48 in the conventional treatment group). Safety analyses included 97 patients who received actual treatment per protocol (50 in the FL-IFX group and 47 in the conventional treatment group).

Interventions and Comparators

Both trials^23,24 employed infliximab (IFX) as the investigated biologic, utilizing different comparative designs.

The PROFILE trial²³ aimed to compare 2 treatment strategies: top-down versus accelerated step-up. Both groups initiated steroid induction during the screening period (−2 weeks) and followed different medication algorithms at weeks 4, 16, 32, and 48 after randomization:

In the top-down group, IV IFX and an immunomodulator were started, and the steroid taper was continued. The treatment protocol was as follows:

• If in remission, continue IFX and the immunomodulator.

• If flare 1 occurred, administer an additional course of steroid medication.

• If flare 2 occurred, consider nonresponse and withdraw from the trial.

IFX was administered at a dose of 5 mg/kg with standard induction at 0, 2, and 6 weeks, followed by maintenance infusions every 8 weeks. Patients who did not respond after induction had early treatment withdrawal and returned to standard care with their local clinical team.

In the accelerated step-up group, the steroid taper was continued with the following protocol:

• If in remission, continue the current step of treatment.

• If flare 1 occurred, start steroids and an immunomodulator.

• If flare 2 occurred, start IFX alongside the immunomodulator.

For participants starting on an immunomodulator, the choice was at the local investigator's discretion among azathioprine, low-dose mercaptopurine with allopurinol, or methotrexate.

In the trial by Jongsma et al. (2022),²⁴ FL-IFX was compared to a conventional treatment strategy. Patients in the FL-IFX group received 5 IV infusions of IFX (Inflectra, CT-P13) at a dose of 5 mg/kg for induction at weeks 0, 2, and 6, followed by 2 maintenance infusions every 8 weeks. This regimen was combined with oral azathioprine as maintenance treatment, administered once daily at a dose of 2 to 3 mg/kg, starting on the day the induction treatment began. In the conventional strategy group patients received standard induction treatment with either exclusive enteral nutrition (polymeric feeding for 6 to 8 weeks, after which normal diet was gradually reintroduced within 2 to 3 weeks) or oral prednisolone (for 4 weeks 1 mg/kg daily with a maximum of 40 mg, followed by tapering down to 5 mg per week until stop). Induction treatment with enteral nutrition or prednisolone was based on patient preference. Ultimately, 27 patients (56%) received enteral nutrition, while 20 patients (42%) received prednisolone.

Efficacy Outcomes

The PROFILE trial²³ reported sustained steroid-free and surgery-free remission at week 48 as the primary outcome. It also assessed 7 secondary outcomes, including endoscopic remission, health-related quality of life (HRQoL, IBD-Q) numerical score, number of flares, number of steroid courses, number of hospital admissions, and number of surgeries. Additionally, 37 tertiary outcomes were detailed in an accompanying appendix (these outcomes were not exacted for this review).

The Jongsma et al. (2022)²⁴ trial reported clinical remission without the need for treatment escalation at week 52 as the primary outcome. Secondary outcomes were assessed at 2 time points: 10 weeks for the efficacy of induction therapy and 52 weeks after the treatment course. At 10 weeks, the study evaluated clinical remission, endoscopic remission, and fecal calprotectin levels. At 52 weeks, it assessed additional corticosteroid use, the need for treatment escalation, linear growth, clinical remission, endoscopic remission, and fecal calprotectin levels. HRQoL was measured with the validated IMPACT III questionnaire at week 14.

Safety Outcomes

Both included RCTs^23,24 reported safety outcomes, including any adverse events and serious adverse events.

RCT of Patients With Fistulizing Crohn Disease

No RCTs were identified.

RCT of Patients With UC

No RCTs were identified.

Evidence-Based Guidelines for Patients With Crohn Disease or UC

Three updated guidelines were identified, including 2 for CD^25,26 and 1 for UC.²⁷ Two versions of 1 updated guideline for UC published in Spanish are listed in Appendix 6.

Critical Appraisal

Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.

Critical Appraisal of Included Systematic Reviews

Although the 4 SRs^11,19-21 had broader scopes in terms of study design, participants, interventions and comparators, they clearly defined the patient, intervention, comparison and outcome (PICO) questions according to their specific research interests. Except for Tsui et al. (2018),¹¹ which conducted a qualitative systematic review, the remaining 3 SRs^19-21 performed independent screening and data extraction in duplicate and employed appropriate statistical methods. Zhang et al. (2023)²¹ and Hamdeh et al. (2020)¹⁹ used robust techniques for assessing the RoB in both RCTs and observational studies; whereas Law et al. (2024)²⁰ and Tsui et al. (2018)¹¹ assessed the RoB solely in RCTs. Common limitations across all SRs included the lack of information on preplanned protocols, no search for grey literature, and failure to list and justify excluded studies. Additionally, only Zhang et al. (2023)²¹ and Hamdeh et al. (2020)¹⁹ disclosed sources of conflict of interest, including any funding. Based on the critical appraisal, all included SRs were considered to have more than 1 critical flaw. According to guidance from AMSTAR2, more than 1 critical flaw in a SR indicates that the review should not be relied on to provide an accurate and comprehensive summary of the available studies.

Critical Appraisal of Included Primary Studies

Both RCTs^23,24 were judged to have good internal validity concerning randomization, outcome data analysis, and reporting. However, due to the complex nature of IBD care, blinding of researchers and participants (carers) was not feasible, and the assignment of interventions was transparent to all involved parties. This lack of blinding might have introduced bias due to deviations from intended interventions and the measurement of outcomes. Consequently, some concerns were raised regarding the evidence provided.

Critical Appraisal of Included Evidence-Based Guidelines

The 3 updated guidelines^25-27 were developed with high quality, demonstrating rigorous guideline development and editorial independence. They defined clear PICO criteria and employed systematic search strategies and formal methods for grading evidence and formulating recommendations, such as GRADE and the Oxford Centre approach. However, it is challenging to identify explicit links between recommendations and their supporting evidence. Specifically, 2 NICE guidelines^26,27 presented the evidence reviews separately from their recommendation documents, while the European Crohn and Colitis Organization-European Society for Paediatric Gastroenterology Hepatology and Nutrition (ECCO-ESPGHAN) guideline²⁵ included supporting evidence under each recommendation but did not provide evidence tables. Extensive external review was reported in ECCO-ESPGHAN guideline while it was not found in the 2 updated NICE guidelines and their evidence review documents. The NICE methodology manual outlines a procedure for updating guidelines, but no future updating information was reported in the ECCO-ESPGHAN guideline.²⁵ All 3 guidelines were developed by internal teams of the funding organizations, with established disclosure policies and declaration forms.

Findings

Appendix 4 presents findings for all included records (Table 7, Table 8, and Table 9).

Systematic Reviews

Effect estimates and findings for the included SRs are presented in Appendix 4 (Table 7).

Findings from Systematic Reviews of Patients With Luminal Crohn Disease

Based on the evidence from 4 SRs, the early use of biologics in CD (within 3 years after disease diagnosis), presents notable benefits to patients. Hamdeh (2020)¹⁹ indicated benefits of early biologics specifically on adult patients. Compared to late anti–tumour necrosis factor alpha (TNF-alpha), where biologics are used following the sequential failure of steroids and immunomodulators, early anti–TNF-alpha administration is associated with a statistically significant improvement in clinical remission rates, particularly in early remission (within 12 weeks). Early biologics also enhance mucosal healing and reduce relapse rates, disease progression, and the need for surgery.

In pediatric patients, Zhang et al. (2023)²¹ demonstrated that early biologic treatment is more effective than late or conventional therapy in achieving clinical remission, promoting mucosal healing, and reducing relapse rates in children and adolescents with CD.

Regarding evidence that combines both adult and pediatric populations, Tsui, et al. (2018)¹¹ summarized the findings of included studies and found that 4 studies reported overall positive outcomes with top-down therapy, while 1 study showed less favourable results compared to conventional treatment. Law et al. (2024)²⁰ concluded that early biologic therapy was associated with a lower likelihood of requiring surgery compared to late treatment.

Findings From Systematic Reviews of Patients With UC

Based on limited evidence presented for UC, early biologic therapy is associated with increased odds of colectomy, although this finding may be confounded by baseline disease severity.

Primary Studies

Findings From RCT With Luminal Crohn Disease

One RCT focused on pediatric patients,²⁴ while the other targeted adults.²³ The findings for these 2 populations were presented separately.

For Pediatric Patients

Results from a single RCT²⁴ show that 10 weeks after start of therapy, the proportion of children in clinical and endoscopic remission is significantly higher in the group treated with first-line infliximab than in the group that received exclusive enteral nutrition or prednisolone (conventional treatment). For maintenance, first-line IFX combined with azathioprine is also superior in achieving clinical remission at 1 year without the need for corticosteroids or further biologics. Contrarily, a significant proportion of children in the conventional treatment group received an additional course of corticosteroids. Despite the possibility to escalate to treatment with IFX, the group that received conventional treatment shows poorer growth at 1 year.

For safety, first-line IFX resulted in fewer adverse events and serious adverse events when compared to conventional treatment.

For Adults

Results from a single RCT²³ show that top-down treatment with combination infliximab and immunomodulator was significantly better than accelerated step-up (conventional) treatment in maintaining steroid-free and surgery-free remission throughout 48 weeks of follow-up. Top-down treatment also showed greater efficacy in achieving endoscopic remission.

The top-down treatment also improved HRQoL, reduced number of flares requiring treatment escalation, and reduced need for urgent abdominal surgery. Although not powered to show a difference in safety end points, there were fewer adverse events or serious adverse events in the top-down group than in the accelerated step-up group. There was no difference in risk of serious infection between treatment strategies and no reported malignancies or deaths during the trial.

Evidence-Based Guidelines

Findings From Evidence-Based Guidelines of Patients With Luminal Crohn Disease

Two updated guidelines^25,26 recommend the use of biologics for patients with CD. The NICE guideline²⁶ encompasses all CD populations, while the ECCO-ESPGHAN guideline²⁵ specifically addresses children and adolescents with luminal CD.

For Pediatric Patients

For children and adolescents with luminal CD, biologics use is recommended as the third-line pharmacotherapy for induction or maintenance. For induction, anti-TNF drugs are recommended in patients who fail to achieve or maintain remission with an immunomodulator. Specifically, the guidelines suggest using infliximab in combination with an immunomodulator, or adalimumab either as monotherapy or in combination therapy. Ustekinumab and vedolizumab are recommended only for patients who have not responded to anti-TNF drugs. However, for maintenance therapy, anti-TNF drugs are recommended solely for postoperative patients at high risk of recurrence.

The early use of anti-TNF drugs in pediatric patients with luminal CD is recommended only for children and adolescents who are newly diagnosed and with high risk.

For Adults

We consider the following recommendations from the NICE CD guideline²⁶ to focus on luminal CD, as it specifically addresses fistulizing CD separately.

For induction therapy, it recommends the use of biologics based on the patient's age, disease severity, and specific subgroups of CD:

• Adults with severe active CD: Infliximab or adalimumab monotherapy or combined with an immunosuppressant if not responded, not tolerated or contraindicated to conventional therapy.

• People (6 to 17 years) with severe active CD: Infliximab if not responded, not tolerated or contraindicated to conventional therapy (including corticosteroids, immunomodulators and primary nutrition therapy).

• Adults with moderate-to-severe active CD after previous treatment: Ustekinumab or vedolizumab, if inadequate response with, lost response to, intolerant or contraindicated to either conventional therapy or a TNF-alpha inhibitor.

For maintenance therapy, only infliximab or adalimumab is recommended, with reassessment every 12 months or restarting treatment upon relapse. Specifically, for patients who have completed macroscopic resection of ileocolonic CD, it is recommended not to offer biologics for maintenance of remission and to opt for azathioprine and metronidazole instead.

Findings From Evidence-Based Guidelines of Patients With Fistulizing Crohn Disease

For Pediatric Patients

The ECCO-ESPGHAN guideline²⁵ recommends first-line anti-TNF therapy for children and adolescents with fistulizing perianal CD, both for induction (in combination with antibiotic therapy, surgical intervention, or both) and for maintenance (in combination with antibiotic therapy).

For Adults

The NICE guideline²⁶ recommends infliximab as a third-line pharmacotherapy for patients with active fistulizing CD who do not respond to, not tolerate, or contraindicate to conventional therapies, including antibiotics, drainage, and immunosuppressants.

Findings From Evidence-Based Guidelines of Patients With UC

The NICE guideline²⁷ recommends infliximab as a third-line pharmacotherapy for patients with acute severe UC who are contraindicated or clinically inappropriate for ciclosporin, and otherwise only for experimental use in clinical trials of patients with acute severe UC.

Limitations

The SRs included in the review has several limitations. Three of the 4 SRs had broad scopes and included populations and study designs that extended beyond our research questions, resulting in limited retrievable evidence for the populations of interest. The timing of early biologic treatment was broadly 3 years postdiagnosis; however, the definitions provided were not clear. As such, we were unable to determine whether the patients included in these reviews might have been exposed sufficiently to conventional treatments. Whereas 3 systematic reviews compared early versus late administration of biologics, the only SR comparing top-down treatment strategies to step-up therapy did not provide any quantitative results. There was no safety data reported in the included SRs. Therefore, there was limited evidence in the included SRs to inform the research questions.

The 2 included RCTs may provide more relevant insight into the research questions on clinical efficacy and safety, as they involved newly diagnosed Crohn disease patients. However, both trials were conducted in Europe, which may limit their external validity due to variations in clinical practices and health care settings. This issue is particularly pertinent in 1 RCT focused on pediatric Crohn disease, where 56% of patients in the conventional treatment group received exclusive enteral nutrition, an intervention not commonly regarded as a standard component of conventional therapy. In addition, both RCTs used infliximab as the investigated biologic, so the findings may not be generalizable to other biologic drugs, particularly those with different molecular structures or mechanisms of action that target the immune system to inflammation.

Conclusions and Implications for Decision- or Policy-Making

In CD, early use of biologics within 3 years from diagnosis improves remission rates, mucosal healing, and reduces relapse rates and surgery needs. Specific findings relevant to fistulizing CD are unclear. At least 1 guideline recommended early use of biologic drugs in high-risk populations of children and adolescents with luminal or fistulizing disease. Findings in CD patients are generally consistent with those reported in the previous CADTH Technology Review.¹²

In UC, limited evidence from 3 observational studies included in 1 systematic review suggest a higher associated risk of colectomy. This finding should be interpreted with caution due to the paucity of available evidence. Guidelines do not recommend early use of biologics in these patients.

While additional studies, especially RCTs, focusing on specific patient subgroups would strengthen the evidence base, it is difficult to adequately capture patient subgroups in an RCT due to challenges of designing and implementing a trial to overcome potential bias from nonblinding/concealment of treatment, especially when dealing with sequences of therapies with different means of administration and side effect profiles.

The definition of early use of biologic drugs was unclear. It should include newly diagnosed patients or those naive to specific drugs. A clearer definition would ensure decisions are based on practical and precise criteria. Additionally, further such studies comparing biologics other than infliximab and corresponding treatment regimens would be beneficial.

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Authors and Contributors

Authors

Shu-Ching Hsieh contributed to the conception and design of the review, conducted literature screening and study selection, data abstraction and risk of bias assessment for primary studies, interpretation, and writing of the final report.

Xiaoqin Wang contributed to the conception and design of the review, conducted literature screening and study selection, data abstraction, risk of bias assessment, and interpretation for systematic reviews, prepared the result materials, and review the final report.

Zemin Bai contributed to the conception and design of the review, conducted literature screening and study selection, data abstraction, risk of bias assessment, and interpretation for clinical guidelines, prepared the result materials, and review the final report.

Shannon E. Kelly contributed to the conception and design of the review, provided oversight to the research process, provided feedback on the implementation process and methods, and reviewed and provided feedback on the final report.

Melissa Brouwers contributed to study questions, protocol development, co-oversight of protocol implementation, data interpretation, drafting, editing, and refining paper, and approval of final draft.

George Wells provided oversight and was involved in the conception, design, and implementation of the review, as well as the review of the final report.

Research Information Science

Becky Skidmore designed and executed search strategies in consultation with the review team (data acquisition), provided search documentation and wrote the literature search methods

Contributors

We thank Kaitryn Campbell, MLIS, MSc (Hamilton, ON) for peer review of the MEDLINE search strategy.

Conflicts of Interest

George A. Wells disclosed the following:

• VBI Vaccines Inc. (2020-Current): Coronavirus Vaccine. Data Safety Monitoring Board — Member.

• Thermedical (2021-Current): Ablation system and catheter needle. Design and analysis advice for preparation of FDA Submission

• VBI Vaccines Inc. (2020-Current): Coronavirus Vaccine. Design and Analysis Advice for preparation of FDA Submission

No other conflicts of interest were declared.

Appendix 1: Selection of Included Studies

Figure 1: PRISMA Flow Chart of Selected Reports

Appendix 2: Characteristics of Included Publications

Table 2: Characteristics of Included Systematic Reviews

CD = Crohn disease; NR = not reported; RCT = randomized controlled trial; TNF-alpha = tumour necrosis factor alpha; UC = ulcerative colitis.

Note: This table has not been copy-edited.

Table 3: Characteristics of Included Primary Clinical Studies- RCTs

AZA = azathioprine; CD = Crohn disease; CRP = C-reactive protein; EEN = exclusive enteral nutrition; HRQoL = health-related quality of life; IFX = infliximab; HBI = Harvey-Bradshaw Index; IQR = interquartile range; MTX = methotrexate; SD = standard deviation; SES-CD = Simple Endoscopic Score for Crohn disease; TNF = tumour necrosis factor; ULN = upper limit of normal; wPCDAI = weighted Paediatric CD Activity Index score.

^aIBDhi (IBD2) = poor prognosis subgroup and IBDlo (IBD1) = better prognosis subgroup), both are blood-based prognostic biomarker (classifier) developed and validated by a whole blood qPCR assay.

Note: This appendix has not been copy-edited.

Appendix 3: Critical Appraisal of Included Publications

Please note that this appendix has not been copy-edited.

Table 4: Strengths and Limitations of Systematic Reviews Using AMSTAR 2¹⁶

AMSTAR 2 = A MeaSurement Tool to Assess systematic Reviews 2; RCT = randomized controlled trial; CD = Crohn disease; PICO = population, intervention, comparator, outcomes.

Table 5: Strengths and Limitations of Clinical Studies Using RoB v2¹⁷

EEN = exclusive enteral nutrition; IBD = inflammatory bowel disease.

Table 6: Strengths and Limitations of Guidelines Using AGREE II¹⁸

AGREE II = Appraisal of Guidelines for Research and Evaluation II; CD = Crohn disease; ECCO = European Crohn and Colitis Organization; ESPGHAN = European Society for Pediatric Gastroenterology, Hepatology and Nutrition; GRADE = Grading of Recommendations Assessment, Development and Evaluation; NICE = National Institute for Health and Care Excellence; NMA = network meta-analysis; RCT = randomized controlled trial; ROB = risk of bias; TNF = tumour necrosis factor; UC = ulcerative colitis.

^aCrohn disease: management. Evidence review for postsurgical maintenance of remission. NICE guideline NG129, Evidence review, May 2019 https://www.nice.org.uk/guidance/ng129/evidence/postsurgical-maintenance-of-remission-pdf-6777581006

^bDeveloping NICE guidelines: the manual. NICE process and methods. Published: 31 October 2014. Last updated: 29 May 2024 www.nice.org.uk/process/pmg20

^cUlcerative colitis. Evidence reviews for induction of remission in mild-to-moderate ulcerative colitis. NICE guideline NG130, Evidence review, May 2019 https://www.nice.org.uk/guidance/ng130/evidence/may-2019-evidence-review-pdf-6777260893

Appendix 4: Main Study Findings

Please note that this appendix has not been copy-edited.

Table 7: Outcomes Reported in the Systematic Reviews- for Luminal Crohn Disease

CD = Crohn disease; IBD = inflammatory bowel disease; NA = not applicable; RR = relative risk; TNF alpha = tumour necrosis factor alpha; UC = ulcerative colitis.

^aNo quantitative findings reported.

Table 8: Outcomes Reported in the Primary Studies- Randomized Controlled Trials

AE = adverse events; CD = Crohn disease; IBD-Q = Inflammatory Bowel Disease Questionnaire; CI = confidence interval; IFX = infliximab; IQR = interquartile range; L = litres; n = number of participants; NR = not reported; HRQoL = health-related quality of life; SAE = severe adverse event; SES-CD = Simple Endoscopic Score for Crohn Disease; wPCDAI = weighted Paediatric CD Activity Index score.

Table 9: Summary of Recommendations in Included Guidelines

CD = Crohn disease; ECCO- ESPGHAN = European Crohn and Colitis Organization-European Society for Paediatric Gastroenterology Hepatology and Nutrition; EEN = exclusive enteral nutrition; IBD = inflammatory bowel disease; IV = IV; LoE = level of evidence; NA = not applicable; NICE = National Institute for Health and Care Excellence; TNF = tumour necrosis; UC = ulcerative colitis.

Appendix 5: Overlap Between Included Systematic Reviews

Please note that this appendix has not been copy-edited.

Table 10: Overlap in Relevant Primary Studies Between Included Systematic Reviews

Appendix 6: References of Potential Interest

Please note that this appendix has not been copy-edited.

Evidence-Based Guideline

Published in Spanish

Sicilia B, García-López S, González-Lama Y, et al. GETECCU 2020 guidelines for the treatment of ulcerative colitis. Developed using the GRADE approach. Gastroenterol Hepatol. 2020 Aug;43 Suppl 1:1-57. PubMed

Fuxman C, Sicilia B, Linares ME, et al. GADECCU 2022 Guideline for the treatment of Ulcerative Colitis. Adaptation and updating of the GETECCU 2020 Guideline. Gastroenterol Hepatol. 2023 Mar;46 Suppl 1:S1-S56. PubMed

Systematic Reviews

Alternate Comparator

Avedillo-Salas A, Corral-Cativiela S, Fanlo-Villacampa A, Vicente-Romero J. The Efficacy and Safety of Biologic Drugs in the Treatment of Moderate-Severe Crohn's Disease: A Systematic Review. Pharmaceuticals (Basel). 2023;16(11). PubMed

Shehab M, Alrashed F, Heron V, Restellini S, Bessissow T. Comparative Efficacy of Biologic Therapies for Inducing Response and Remission in Fistulizing Crohn's Disease: Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. Inflamm Bowel Dis. 2023;29(3):367-375. PubMed

Yin J, Li Y, Chen Y, Wang C, Song X. Adalimumab for induction of remission in patients with Crohn's disease: a systematic review and meta-analysis. Eur J Med Res. 2022;27(1):190. PubMed

Rui M, Fei Z, Wang Y, et al. Will the Inducing and Maintaining Remission of Non-biological Agents and Biological Agents Differ for Crohn's Disease? The Evidence From the Network Meta-Analysis. Front Med (Lausanne). 2021;8:679258. PubMed

Singh S, Murad MH, Fumery M, et al. Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn's disease: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(12):1002-1014. PubMed

Singh S, Murad MH, Fumery M, Dulai PS, Sandborn WJ. First- and Second-Line Pharmacotherapies for Patients With Moderate to Severely Active Ulcerative Colitis: An Updated Network Meta-Analysis. Clin Gastroenterol Hepatol. 2020;18(10):2179-2191 e2176. PubMed

Singh S, Facciorusso A, Dulai PS, Jairath V, Sandborn WJ. Comparative Risk of Serious Infections With Biologic and/or Immunosuppressive Therapy in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2020;18(1):69-81 e63. PubMed

Abbass M, Cepek J, Parker CE, et al. Adalimumab for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2019;2019(11). PubMed

Trigo-Vicente C, Gimeno-Ballester V, Garcia-Lopez S, Lopez-Del Val A. Systematic review and network meta-analysis of treatment for moderate-to-severe ulcerative colitis. Int J Clin Pharm. 2018;40(6):1411-1419. PubMed

Nelson SM, Nguyen TM, McDonald JW, MacDonald JK. Natalizumab for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2018;8(8):CD006097. PubMed

Lee MJ, Parker CE, Taylor SR, et al. Efficacy of Medical Therapies for Fistulizing Crohn's Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16(12):1879-1892. PubMed

Alternate Definition for “Early Use” of Biologics (Not in Scope)

Attauabi M, Steenholdt C, Poulsen A, et al. Network meta-analysis: Comparative onset of early effect of biologics and small molecules in moderately to severely active luminal Crohn's disease. Aliment Pharmacol Ther. 2024;60(2):124-143. PubMed

Gordon M, Sinopoulou V, Akobeng AK, Sarian A, Moran GW. Infliximab for maintenance of medically-induced remission in Crohn's disease. Cochrane Database Syst Rev. 2024;2(2):CD012609. PubMed

Gao J, Nie R, Chen Y, Yang W, Ren Q. Comparative of the effectiveness and safety of biological agents, small molecule drugs, and microbiome therapies in ulcerative colitis: Systematic review and network meta-analysis. Medicine (Baltimore). 2023;102(43):e35689. PubMed

Gordon M, Sinopoulou V, Akobeng AK, et al. Infliximab for medical induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2023;11(11):CD012623. PubMed