Practical guidelines on medical management of adults with moderate-to-severe inflammatory bowel disease

Mahmoud H Mosli; Badr Al-Bawardy; Turki AlAmeel; Nahla A Azzam; Shakir A Bakkari; Othman R Alharbi; Abdulelah Almutairdi; Yaser K Meeralam; Omar I Saadah; Majid A Almadi; Waleed Alhazzani; Haifa F Alotaibi; Khalidah A Alenzi; Bedor A Al-Omari; Hajer Y Almudaiheem; Ahmed H Al-Jedai

doi:10.4103/sjg.sjg_277_25

. 2025 Dec 19;32(4):254–297. doi: 10.4103/sjg.sjg_277_25

Practical guidelines on medical management of adults with moderate-to-severe inflammatory bowel disease

Mahmoud H Mosli ^1,^✉, Badr Al-Bawardy ^2,^3,⁴, Turki AlAmeel ⁵, Nahla A Azzam ⁶, Shakir A Bakkari ⁷, Othman R Alharbi ⁶, Abdulelah Almutairdi ⁸, Yaser K Meeralam ⁹, Omar I Saadah ¹⁰, Majid A Almadi ^11,¹², Waleed Alhazzani ^13,¹⁴, Haifa F Alotaibi ¹³, Khalidah A Alenzi ¹⁵, Bedor A Al-Omari ¹⁶, Hajer Y Almudaiheem ¹⁷, Ahmed H Al-Jedai ^17,¹⁸

¹Department of Internal Medicine, King Abdulaziz University, Inflammatory Bowel Disease Unit, King Abdulaziz University Hospital, Jeddah, Saudi Arabia

²Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

³Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA

⁴College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

⁵Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia

⁶Division of Gastroenterology, Department of Medicine, College of Medicine, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia

⁷Department of Gastroenterology, King Saud Medical City, Riyadh, Saudi Arabia

⁸Department of Medicine, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia

⁹Department of Gastroenterology, Digestive and Liver Health and Advanced Endoscopy Center, King Abdullah Medical City, Makkah, Saudi Arabia

¹⁰Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Inflammatory Bowel Disease Unit, King Abdulaziz University Hospital, Jeddah, Saudi Arabia

¹¹Division of Gastroenterology, King Khalid University Hospital, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia

¹²Division of Gastroenterology, The McGill University Health Center, Montreal General Hospital, McGill University, Montreal, Canada

¹³Health Research Centre, Ministry of Defence Health Services, Riyadh, Saudi Arabia

¹⁴Department of Critical Care and Internal Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

¹⁵Executive Management of Transformation, Planning, and Business Development, Tabuk Health Cluster, Tabuk, Saudi Arabia

¹⁶Department of Pharmaceutical Care Services, Prince Sultan Military Medical City, Riyadh, Saudi Arabia

¹⁷The Saudi Society of Clinical Pharmacy, Riyadh, Saudi Arabia

¹⁸Department of Pharmacy Practice, Colleges of Medicine and Pharmacy, Alfaisal University, Riyadh, Saudi Arabia

^✉

Address for Correspondence: Dr. Mahmoud H Mosli, Department of Internal Medicine, King Abdulaziz University, Inflammatory Bowel Disease Unit, King Abdulaziz University Hospital, Jeddah 21589, Saudi Arabia. E-mail: mmosli@kau.edu.sa

PMCID: PMC13441249 PMID: 41417004

Abstract

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder that predominantly includes Crohn’s disease (CD) and ulcerative colitis (UC). IBD has emerged as a significant healthcare challenge in Saudi Arabia, with a more than fivefold increase in annual incidence over the past 2 decades. These guidelines promote high-quality, evidence-based care for adult patients with moderate-to-severe CD and UC in Saudi Arabia. These guidelines were developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. A multidisciplinary panel of 16 experts created 41 PICO questions addressing CD and UC separately. Evidence was synthesized through major databases (PubMed, EMBASE, Cochrane Library), prioritizing high-quality studies published between 2015 and 2025. Evidence certainty was categorized as high, moderate, low, or very low. Recommendations were formulated based on evidence quality, risk–benefit analyses, and clinical expertise, requiring a minimum consensus threshold of 70% for approval. A total of 38 recommendations and two good practical statements address induction and maintenance of remission with advanced therapies, combination treatment sequences, treatment optimization strategies, and management of special clinical scenarios. These Saudi national guidelines provide an evidence-based approach for managing adult patients with moderate-to-severe IBD and establish a comprehensive framework for optimizing management and treatment with advanced therapies. However, further research on local/regional real-world evidence is necessary to refine and improve the efficacy of these guidelines.

Keywords: Crohn’s disease, Guidelines, Inflammatory bowel disease, Saudi Arabia, Ulcerative colitis

INTRODUCTION

Inflammatory bowel disease (IBD) represents a chronic, relapsing inflammatory disorder, predominantly comprising two distinct clinical entities: ulcerative colitis (UC) and Crohn’s disease (CD).[1] They result in persistent, continuous inflammation of the gastrointestinal system, with interpersonal and intrapersonal variability in clinical presentations throughout the disease course.[1] IBD has evolved into a major global health concern, demanding integrated clinical strategies and systematic healthcare responses to manage its rising incidence and the complexities of patient care.[2]

Global epidemiological data indicate a substantial and consistent upward trend in the incidence and prevalence of CD, with annual incidence rates escalating by approximately 4% to 15% throughout the preceding 3 decades.[3] Despite extensive research, the exact etiopathogenesis of the disease remains unknown.[4] Current therapeutic strategies focus on achieving and maintaining inflammatory control through a combination of pharmacological and surgical interventions to mitigate the progressive bowel damage and alleviate symptom burden.[5]

UC is characterized by more localized and superficial inflammatory pathology, unlike CD, which affects any segment of the gastrointestinal tract transmurally.[6] Within Asian populations, prevalence varies considerably, with rates documented between 5.3 and 63.6 cases per 100,000 individuals.[7,8]

Subsequent research conducted in Saudi Arabia corroborates the progressive increase in IBD incidence throughout the country over time. Notably, the clinical presentation and associated morbidity among Saudi patients demonstrate comparable patterns to those observed in Western populations.[9] The data reveal a more than fivefold increase in the mean annual incidence rate, rising from 0.32 per 100,000 population during the initial decade to 1.66 per 100,000 during the subsequent 10-year period.[10] According to a previously published meta-analysis, both CD and UC are prevalent in the Arab world[11] as the quantitative analysis demonstrated that the incidence of UC occurrence is 2.33 per 100,000 person-years. CD exhibits a slightly lower pooled incidence rate of 1.46 per 100,000 person-years.[11,12]

These findings highlight the escalating burden of IBD in Saudi Arabia, which necessitates the development and implementation of comprehensive, nationally standardized clinical practice guidelines that endorse evidence-based strategies for early detection, effective management, and long-term care.[10,11]

The goal of this guideline is to promote evidence-based care for adult patients with moderate-to-severe CD and UC in Saudi Arabia, optimizing clinical outcomes while ensuring appropriate resource utilization across diverse healthcare settings. These recommendations offer clinicians clear guidance on pharmacological interventions, treatment optimization strategies, and management approaches for specific clinical scenarios, ultimately enhancing the value and consistency of IBD care nationwide.

Scope and purpose

Healthcare providers nationwide can rely on these research-driven guidelines to inform their clinical decision-making when caring for individuals with IBD. They focus on standardizing care approaches for all healthcare professionals, improving patient outcomes through effective symptom control and disease management, and providing treatment strategies specific to the local population. The guidelines address comprehensive treatment strategies to minimize IBD’s impact on patients’ QoL.

Goal

To provide recommendations for the standardized management of moderate to severe IBD among adult patients in the country, supporting healthcare professionals with practical guidance on the management of IBD, treatment optimization strategies, long-term care to improve symptom control, slow disease progression and enhance overall QoL.

Objectives

The guidelines for IBD provide practical guidance for professionals and IBD patients in Saudi Arabia with the following aims:

These guidelines are designed to function as a thorough national standard for IBD clinical practice while addressing the particular medical and cultural needs that characterize Saudi patients.
Standardize the management approach through evidence-based recommendations applicable to all healthcare professionals involved in IBD care across Saudi healthcare facilities.
Optimize guidance for different treatment modalities and therapeutic approaches for managing various presentations and severities of IBD in the Saudi context.
Improve patient outcomes for Saudi IBD patients regarding disease remission rates, prevention of complications, and enhancement of overall QoL.

Guidelines, scope

What are the most effective advanced therapies for inducing and maintaining remission in adults with moderate-to-severe CD and UC?
How should treatment be optimized in patients with CD or UC who experience partial loss of response to advanced therapies?
When should combination therapies (e.g., biologics with immunomodulators) be used in CD and UC management?
What is the recommended approach for managing complex or refractory cases, including perianal CD, acute severe UC, postoperative CD, and recurrent pouchitis?
What is the part of biosimilars in treating CD and UC, including switching strategies in stable patients?

End-users

The clinical recommendations presented serve multiple stakeholder groups across Saudi Arabia’s healthcare landscape, including specialized gastroenterologists, colorectal surgeons, primary care physicians, internal medicine practitioners, clinical pharmacists, and those involved in healthcare policy development. These evidence-based guidelines provide essential knowledge on IBD management strategies for healthcare executives, hospital administrative teams, clinical researchers, and professionals responsible for developing treatment protocols within Saudi Arabia’s medical infrastructure. The scope of beneficiaries extends beyond healthcare professionals to encompass patients living with IBD diagnoses, advocacy organizations representing patient interests, and family members or caregivers who provide support to individuals managing inflammatory bowel diseases throughout the Kingdom.

Process of guideline development and guidance on their implementation

The Ministry of Health of Saudi Arabia, in collaboration with the Saudi Gastroenterology Association and the Saudi Society of Clinical Pharmacy, aims to provide clinicians with guidelines for optimizing the management and treatment of IBD among adults of all genders across the Kingdom. As with other guidelines, this will follow the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.

Each recommendation is followed by panel statements addressing factors such as values, resource use, feasibility, equity, and acceptability within the Saudi healthcare context.

Medical professionals must frequently adapt their clinical strategies to accommodate the distinctive needs and specific circumstances of each patient, carefully evaluating the potential therapeutic benefits against possible risks associated with different management options, while prioritizing the patient’s comprehensive health outcomes and overall quality of life.

These guidelines should be viewed as a supportive tool to enhance clinical decision-making rather than replacing it, acknowledging the complexities and variations in IBD presentation and management within the Saudi population.

METHODOLOGY

These guidelines were developed using the GRADE approach.[13]

Panel composition

These Saudi IBD guidelines were conducted in collaboration with the Ministry of Health, the Saudi Gastroenterology Association, and the Saudi Society of Clinical Pharmacy. The panel comprised two methodologists and 14 clinical experts with extensive clinical and academic experience in IBD. The panel members were selected based on their demonstrated expertise as gastroenterologists, clinical pharmacists, and methodologists, ensuring comprehensive coverage of IBD management aspects. Among the panel members, ten were gastroenterologists, four were pharmacists, and two were methodologists. Patients were not involved in the development of these guidelines, including the selection and prioritization of outcomes.

Group interaction and process

The development of these comprehensive IBD guidelines for Saudi Arabia involved a systematic collaborative framework utilizing the GRADE methodology, which promoted transparent communication channels, fostered consensus-building among stakeholders, and ensured the meaningful integration of varied expert opinions and clinical insights gathered from medical professionals across different regions of the Kingdom. This approach minimized potential biases and ensured the collection of high-quality evidence, taking into account the specific context of Saudi healthcare. Panel members, representing various specialties involved in IBD care in Saudi Arabia, actively participated in discussions to define review protocols, evaluate the reliability of the evidence, and develop well-supported recommendations. The multidisciplinary panel engaged in structured deliberations to address the unique aspects of IBD management within the Saudi population, healthcare infrastructure, and cultural considerations, ensuring the guidelines would be both evidence-based and locally applicable.

Selection of questions and outcomes’ prioritization

The panel examined local and international guidelines to classify the most critical key questions that should be covered.[14,15,16,17,18] The panel conferred on which Population, Intervention, Comparator, and Outcome (PICO) questions are most beneficial for clinical practice. The panel covered each of CD and UC separately. The panel issued a total of 41 questions; 22 questions focused on CD, while 19 questions focused on UC. The guideline panel thoroughly evaluated and endorsed the final set of PICO questions. Key outcomes were identified through a focused systematic review of relevant literature. The GRADE methodology systematically categorized outcomes as critical, important, or unimportant for each PICO question. These decisions were made during the initial meetings with respect to decision-making.[19,20] Next, critical outcomes for inclusion in the core outcome set were prioritized based on previous guidelines, key clinical trials, and their relative importance in clinical practice. Key prioritized outcomes for evaluation included the effectiveness of treatment approaches, disease progression indicators, and the incidence of adverse events (AEs). A list of the critical outcome measures for each PICO question is shown in Table S1.

S Table 1.

Critical Outcomes According to PICO Questions

PICO Question	Critical Outcomes (for decision- making)
Treatment Recommendations for Moderate-to-Severe Crohn’s Disease
1.Initial Treatments for Bio-Naïve Adults with Moderate-to-Severe CD
Q1. Should early initiation of biologic therapy vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?	Clinical remission - Clinical response
Q2. Should anti-TNF α [IFX, ADA, or certolizumab pegol (CZP)] vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?	Clinical remission- Clinical response- Safety
Q3. Should vedolizumab (VDZ) vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?	Clinical remission – Clinical response- Safety
Q4. Should ustekinumab vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?	Clinical remission - Clinical response- Safety
Q5. Should anti-IL-23 agents (risankizumab (RZB), guselkumab, and mirikizumab) vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?	Clinical remission - Stool frequency and abdominal pain score clinical remission – Endoscopic response- Safety
Q6. Should upadacitinib vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?	Clinical remission - Endoscopic response- Safety
Q7. Should SC IFX (CT-P13) vs. no treatment be used for maintenance of remission in bio-naïve patients with moderate-to-severe CD?	Clinical remission – Endoscopic response- Safety
Q8. Should treatment with biosimilars of anti-TNF agents or anti-IL-12/23 vs. no treatment be used to induce and maintain remission in conventional therapy-exposed patients with moderate-to-severe CD?	Clinical remission- Endoscopic response- Endoscopic remission- Safety
2.Treatment for Advanced Therapy Exposed Adults with Moderate-to-Severe CD
Q9. Should switching to another anti-TNF agent vs. no treatment be used to optimize the management of the disease in CD patients with secondary loss of response to anti-TNF therapy (and not primary treatment failure) due to developing Anti-Drug Antibodies (ADAs)?	Response rate- Remission rate
Q10. Should switching outside the anti-TNF class to another advanced therapy, vs. no treatment, be used for clinical remission in CD patients who do not respond to anti-TNF therapy, although having adequate serum drug levels and negative ADAs?	Clinical remission
Q11. Should anti-IL-23 vs. anti-IL 12/23 be used for induction and maintenance of remission in patients with moderate-to-severe CD who have previously failed anti-TNF therapy?	Clinical remission - Endoscopic remission- Endoscopic response- Safety
3.Combination Therapies for Adults with Moderate-to-Severe CD
Q12. Should combination therapy with an immunomodulator and IFX vs. IFX monotherapy be used for the induction of remission in patients with moderate-to-severe CD?	Corticosteroid-free remission - Mucosal healing- Clinical remission- Clinical response- Safety
Q13. Should the combination therapy of immunomodulators (thiopurine) with SC IFX (CT-P13) vs. SC IFX (CT-P13) without immunomodulators be used to maintain remission in patients with moderate-to-severe CD?	Clinical response- Mucosal healing - Immunogenicity
Q14. Should a combination of ADA with immunomodulators (thiopurine) vs. ADA monotherapy be used to induce and maintain remission in patients with moderate-to-severe CD?	Induction of response and remission- Maintenance of response and remission
4.Treatment Optimization Strategies for Adults with CD and Secondary Loss of Response to Advanced Therapy
Q15. Should adjusting the dose based on measured anti-TNF trough levels vs. empirically optimizing the dose without measuring anti-TNF trough levels be used for CD patients with secondary loss of response to anti-TNF therapy?	Clinical remission- Endoscopic remission- Clinical response
Q16. Should dose escalation (by shortening dosing interval to every 4 weeks) vs. no treatment be used for partial or secondary loss of response in patients with CD who are treated with standard 8-weekly anti-Integrins or anti-IL-12/23?	NA
5.Management of Complex Perianal Fistula among Adults with CD
Q17. Should combination therapy, including seton placement, antibiotics, and anti-TNF agents (e.g., IFX, ADA) vs. standard care or alternative treatments such as antibiotics alone, surgical drainage without Seton, or other immunosuppressive therapies be used for the induction of remission in patients with complicated perianal fistula associated with abscess?	Complete perianal remission- Maintenance of remission
Q18. Should a combination of immunomodulators & anti-TNF vs. anti-TNF monotherapy be used for fistula healing in patients with CD and complex perianal fistula?	Perianal fistula healing
Q19. Should anti-IL-12/23, anti-IL-23, anti-integrin, or selective Janus kinase Inhibitors (JAKIs) vs. no treatment be used for fistula healing in complex perianal fistulae in CD patients?	Resolution of drainage in draining perianal fistulas- Closure of external perianal fistula openings – Complete healing- Clinical remission- Endoscopic response- Safety
6.Switching Formulations for Maintenance of Remission in Adults with Stable Moderate-to-Severe CD
Q20. Should SC or IV IFX or SC or IV VDZ vs. no treatment be used to maintain remission for stable moderate-to-severe CD patients?	Clinical remission - Enhanced Clinical response- Safety
7.Prevention of Postoperative Recurrence (POR) among Adults with High-Risk CD
Q21. Should advanced therapy vs. no treatment be used for preventing the POR of high-risk CD?	Clinical remission- Endoscopic remission
Treatment Recommendations for Moderate-to-Severe UC.
1.Treatment of Advanced Therapy Exposed Adults with Moderate-to-Severe UC
Q22: Should treatment with anti-TNF agents [IFX, ADA, and golimumab] vs. no treatment be used for induction and maintenance of remission in patients with moderate-to-severe UC?	Clinical response- Clinical remission
Q23: Should treatment with anti-Integrins (VDZ) vs. no treatment be used for induction and maintenance of remission in patients with moderately to severely active UC?	Clinical response – Clinical remission- Mucosal healing- Safety
Q24. Should treatment with anti-IL-12/23 vs. no treatment be used for induction and maintenance of remission in patients with moderate-to-severe UC?	Clinical remission- Clinical response- Endoscopic improvement – Mucosal healing- Safety
Q25. Should Anti-IL-23 (RZB, Mirikizumab, Guselkumab) vs. no treatment be used for induction and maintenance of remission in patients with moderately-to-severely active UC?	Clinical remission- Clinical response- Endoscopic improvement- Mucosal healing- Safety
Q26. Should treatment with JAKIs (tofacitinib, upadacitinib, filgotinib) vs. no treatment be used for induction and maintenance of remission in patients with moderate-to-severe UC?	Clinical remission- Endoscopic remission- Histological remission- Endoscopic response- Safety
Q27. Should S1P-R modulator (Ozanimod, Etrasimod) vs. no treatment be used for induction and maintenance of remission in patients with moderate-to-severe UC?	Clinical remission- Clinical response- Endoscopic improvment- Histological remission- Safety
Q28. Should VDZ vs. ADA be used for induction and maintenance of remission in moderate-to-severe ambulatory UC patients bio-naïve to advanced therapies?	Clinical remission- Clinical response
Q29. Should treatment with biosimilars of anti-TNF agents or anti-IL-12/23 vs. no treatment be used for induction and maintenance of remission in patients with moderate-to-severe UC?	Clinical remission - Endoscopic–histologic mucosal improvement- Safety
Q30: Should combining IFX with AZA vs. IFX monotherapy be used to induce and maintain remission in patients with moderate-to-severe UC?	Clinical remission rate
2.Treatment Optimization Strategies for Adults with UC and Secondary Loss of Response to Advanced Therapy
Q31. Should adjusting the dose based on measured anti-TNF trough levels vs. empirically optimizing the dose without measuring anti-TNF trough levels be used for UC patients with secondary loss of response to anti-TNF therapy?	Clinical response
Q32. Should dose escalation (by shortening dosing intervals) be used for advanced therapies (VDZ and ustekinumab) vs. standard dose be used for maintaining the remission of patients with moderate-to-severe UC who demonstrated a partial response to standard 8-weekly dosing?	Clinical response- Endoscopic response
Q33. Should switching to a different class, such as anti-IL-12/23, anti-IL-23, anti-integrins, JAKIs, or S1P-R modulators vs. no treatment be used for optimizing the management of the disease in UC patients with secondary loss of response to anti-TNF therapy based on TDM?	Clinical remission – Clinical response- Mucosal healing- Safety
3.Management of Adults with Acute Severe UC
Q34. Should IFX or cyclosporine vs. no treatment be used for decreasing the risk of short-term colectomy in hospitalized adult patients with acute severe UC (ASUC) refractory to IV corticosteroids?	Colectomy rates- Safety
Q35. Should JAKIs vs. no treatment be used for remission induction in adults with ASUC who had an inadequate response or intolerance to at least one therapy, including IV corticosteroids, cyclosporine, or IFX?	Rate of response- Safety
Q36. Should Standard IFX dosing regimens vs. intensive IFX dosing regimens be used for decreasing the short-term risk of colectomy in hospitalized adult patients with ASUC being treated with IFX?	Clinical response – Clinical remission- Endoscopic remission- Risk of colectomy- Safety
4.Switching Formulations for Maintenance of Remission in Adults with Moderate-to-Severe UC
Q37. Should switching to SC formulation or continuing on IV formulations of IFX or VDZ vs. no treatment be used to maintain remission for stable moderate-to-severe UC patients on IV IFX or VDZ?	Clinical remission- Endoscopic improvement- Safety
Q38. Should switching to biosimilars vs. the originator version be used for maintaining the remission for stable moderate-to-severe UC patients on the originator biologic?	UC remission difference - Disease worsening Rates - Remission
5.Management of Adults with Complex/Refractory UC
Q39. Should advanced therapies vs. no treatment be used to treat recurrent pouchitis in patients with UC who have undergone IPAA and experience recurrent pouchitis that responds to antibiotics but relapses shortly after stopping the antibiotics?	mPDAI-Defined Remission - Safety
Treatment Recommendations for Moderate to Severe IBD with uncontrolled extraintestinal manifestations.
Q40. Should advanced combination therapy (e.g., biologic + small molecule, or biologic + biologic) vs. advanced monotherapy (e.g., biologic alone or small molecule alone) be used for adults with refractory IBD or those with uncontrolled extraintestinal manifestations (EIMs)?	NA

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Evidence synthesis

The methodology team performed an independent systematic literature review to support the guidelines. They conducted extensive searches across major medical databases (PubMed, EMBASE, and Cochrane Library) using question-specific search terms, with support from two research methodology experts. The complete search strategy is shown in Tables S2 and S3.

S Table 2.

Search Strategy for Crohn’s Disease Recommendations

Database	Search strategy
Category 1: Induction and Maintenance of Remission in Moderate-to-Severe CD (7 Qs)
PubMed (ALL)	("moderate-to-severe CD” OR “Crohn” OR “crohn’s disease” [MeSH])
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication]) AND (English[lang])
PubMed (Saudi)	("moderate-to-severe CD” OR “Crohn” OR “crohn’s disease” [MeSH])
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	AND ("2022/01/01"[Date - Publication] : "2025"[Date - Publication]) AND (English[lang])
SCOPUS (ALL)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")
SCOPUS (SAUDI)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
Embase (ALL)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)
Embase (SAUDI)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’ OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)
Category 2: Combination Therapies (6 Qs)
PubMed (ALL)	("moderate-to-severe CD” OR “Crohn” OR “crohn’s disease” [MeSH])
	AND (“combination therapy” OR “thiopurine” OR “subcutaneous” OR “methotrexate” OR “monotherapy” OR “biologics” OR “small molecule” OR “mucosal healing” OR “uncontrolled EIMs” OR “EIMs”)
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication]) AND (English[lang])
PubMed (Saudi)	("moderate-to-severe CD” OR “Crohn” OR “crohn’s disease” [MeSH])
	AND (“combination therapy” OR “thiopurine” OR “subcutaneous” OR “methotrexate” OR “monotherapy” OR “biologics” OR “small molecule” OR “mucosal healing” OR “uncontrolled EIMs” OR “EIMs”)
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	AND ("2022/01/01"[Date - Publication] : "2025"[Date - Publication]) AND (English[lang])
SCOPUS (ALL)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY (“combination therapy” OR “thiopurine” OR “subcutaneous” OR “methotrexate” OR “monotherapy” OR “biologics” OR “small molecule” OR “mucosal healing” OR “uncontrolled EIMs” OR “EIMs”)
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")
SCOPUS (SAUDI)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY (“combination therapy” OR “thiopurine” OR “subcutaneous” OR “methotrexate” OR “monotherapy” OR “biologics” OR “small molecule” OR “mucosal healing” OR “uncontrolled EIMs” OR “EIMs”)
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
Embase (ALL)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (‘combination therapy’ OR ‘thiopurine’ OR ‘subcutaneous’ OR ‘methotrexate’ OR ‘monotherapy’ OR ‘biologics’ OR ‘small molecule’ OR ‘mucosal healing’ OR ‘uncontrolled EIMs’ OR ‘EIMs’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)
Embase (SAUDI)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (‘combination therapy’ OR ‘thiopurine’ OR ‘subcutaneous’ OR ‘methotrexate’ OR ‘monotherapy’ OR ‘biologics’ OR ‘small molecule’ OR ‘mucosal healing’ OR ‘uncontrolled EIMs’ OR ‘EIMs’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’ OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)
Category 3: Sequencing Therapies (switching & dose escalation) (10 Qs)
PubMed (ALL)	("moderate-to-severe CD” OR “Crohn” OR “crohn’s disease” [MeSH])
	AND (“dose optimization” OR “dose escalation” OR “shortening the dosing interval” OR “shortening dosing interval” OR “escalation” OR “negative ADAs” OR “switching” OR “switch” OR “trough levels” OR “ADA” OR “TL” OR “secondary loss of response” OR ”proactive TDM” OR “TDM” OR “biologic agent” OR “primary non-response” OR “PNR” OR “low level ADA” OR “index score” OR “biologic naïve” OR “failed anti-TNF” OR “previously failed” OR “luminal Crohn” OR “second-line therapy” OR “partial or secondary loss of response”)
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication]) AND (English[lang])
PubMed (Saudi)	("moderate-to-severe CD” OR “Crohn” OR “crohn’s disease” [MeSH])
	AND (“dose optimization” OR “dose escalation” OR “shortening the dosing interval” OR “shortening dosing interval” OR “escalation” OR “negative ADAs” OR “switching” OR “switch” OR “trough levels” OR “ADA” OR “TL” OR “secondary loss of response” OR ”proactive TDM” OR “TDM” OR “biologic agent” OR “primary non-response” OR “PNR” OR “low level ADA” OR “index score” OR “biologic naïve” OR “failed anti-TNF” OR “previously failed” OR “luminal Crohn” OR “second-line therapy” OR “partial or secondary loss of response”)
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication]) AND (English[lang])
SCOPUS (ALL)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY (“dose optimization” OR “dose escalation” OR “shortening the dosing interval” OR “shortening dosing interval” OR “escalation” OR “negative ADAs” OR “switching” OR “switch” OR “trough levels” OR “ADA” OR “TL” OR “secondary loss of response” OR ”proactive TDM” OR “TDM” OR “biologic agent” OR “primary non-response” OR “PNR” OR “low level ADA” OR “index score” OR “biologic naïve” OR “failed anti-TNF” OR “previously failed” OR “luminal Crohn” OR “second-line therapy” OR “partial or secondary loss of response”)
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-
	ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")
SCOPUS (SAUDI)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY (“dose optimization” OR “dose escalation” OR “shortening the dosing interval” OR “shortening dosing interval” OR “escalation” OR “negative ADAs” OR “switching” OR “switch” OR “trough levels” OR “ADA” OR “TL” OR “secondary loss of response” OR ”proactive TDM” OR “TDM” OR “biologic agent” OR “primary non-response” OR “PNR” OR “low level ADA” OR “index score” OR “biologic naïve” OR “failed anti-TNF” OR “previously failed” OR “luminal Crohn” OR “second-line therapy” OR “partial or secondary loss of response”)
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
Embase (ALL)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (‘dose optimization’ OR ‘dose escalation’ OR ‘shortening the dosing interval’ OR ‘shortening dosing interval’ OR ‘escalation’ OR ‘negative ADAs’ OR ‘switching’ OR ‘switch’ OR ‘trough levels’ OR ‘ADA’ OR ‘TL’ OR ‘secondary loss of response’ OR ‘proactive TDM’ OR ‘TDM’ OR ‘biologic agent’ OR ‘primary non-response’ OR ‘PNR’ OR ‘low level ADA’ OR ‘index score’ OR ‘biologic naïve’ OR ‘failed anti-TNF’ OR ‘previously failed’ OR ‘luminal Crohn’ OR ‘second-line therapy’ OR ‘partial or secondary loss of response’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)
Embase (SAUDI)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (‘dose optimization’ OR ‘dose escalation’ OR ‘shortening the dosing interval’ OR ‘shortening dosing interval’ OR ‘escalation’ OR ‘negative ADAs’ OR ‘switching’ OR ‘switch’ OR ‘trough levels’ OR ‘ADA’ OR ‘TL’ OR ‘secondary loss of response’ OR ‘proactive TDM’ OR ‘TDM’ OR ‘biologic agent’ OR ‘primary non-response’ OR ‘PNR’ OR ‘low level ADA’ OR ‘index score’ OR ‘biologic naïve’ OR ‘failed anti-TNF’ OR ‘previously failed’ OR ‘luminal Crohn’ OR ‘second-line therapy’ OR ‘partial or secondary loss of response’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’ OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)
Category 4: Management of Complex Perianal Fistula (3 Qs)
PubMed (ALL)	("moderate-to-severe CD” OR “Crohn” OR “crohn disease” [MeSH])
	AND (“seton placement” OR “combination therapy” OR “combination” OR “antibiotics” OR “surgical drainage” OR “immunosuppressive” OR “complicated perianal fistula” OR “perianal fistula” OR “abscess” OR “immunomodulators” OR “Anti-TNF monotherapy” OR “fistula closure” OR “Fistula remission” OR “perianal sepsis” OR “stoma-free survival”)
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication]) AND (English[lang])
PubMed (Saudi)	("moderate-to-severe CD” OR “Crohn” OR “crohn’s disease” [MeSH])
	AND (“seton placement” OR “combination therapy” OR “combination” OR “antibiotics” OR “surgical drainage” OR “immunosuppressive” OR “complicated perianal fistula” OR “perianal fistula” OR “abscess” OR “immunomodulators” OR “Anti-TNF monotherapy” OR “fistula closure” OR “Fistula remission” OR “perianal sepsis” OR “stoma-free survival”)
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication]) AND (English[lang])
SCOPUS (ALL)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY (“seton placement” OR “combination therapy” OR “combination” OR “antibiotics” OR “surgical drainage” OR “immunosuppressive” OR “complicated perianal fistula” OR “perianal fistula” OR “abscess” OR “immunomodulators” OR “Anti-TNF monotherapy” OR “fistula closure” OR “Fistula remission” OR “perianal sepsis” OR “stoma-free survival”)
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")
SCOPUS (SAUDI)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY (“seton placement” OR “combination therapy” OR “combination” OR “antibiotics” OR “surgical drainage” OR “immunosuppressive” OR “complicated perianal fistula” OR “perianal fistula” OR “abscess” OR “immunomodulators” OR “Anti-TNF monotherapy” OR “fistula closure” OR “Fistula remission” OR “perianal sepsis” OR “stoma-free survival”)
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
Embase (ALL)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (‘seton placement’ OR ‘combination therapy’ OR ‘combination’ OR ‘antibiotics’ OR ‘surgical drainage’ OR ‘immunosuppressive’ OR ‘complicated perianal fistula’ OR ‘perianal fistula’ OR ‘abscess’ OR ‘immunomodulators’ OR ‘Anti-TNF monotherapy’ OR ‘fistula closure’ OR ‘Fistula remission’ OR ‘perianal sepsis’ OR ‘stoma-free survival’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)
Embase (SAUDI)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (‘seton placement’ OR ‘combination therapy’ OR ‘combination’ OR ‘antibiotics’ OR ‘surgical drainage’ OR ‘immunosuppressive’ OR ‘complicated perianal fistula’ OR ‘perianal fistula’ OR ‘abscess’ OR ‘immunomodulators’ OR ‘Anti-TNF monotherapy’ OR ‘fistula closure’ OR ‘Fistula remission’ OR ‘perianal sepsis’ OR ‘stoma-free survival’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’ OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)
Category 5: Managment of Post-operative High-risk CD (1 Qs)
PubMed (ALL)	("moderate-to-severe CD” OR “Crohn” OR “crohn disease” [MeSH])
	AND (“postoperative” OR “post-operative” OR “high-risk CD” OR “recurrence” OR “surgery” OR “clinical recurrence”)
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication]) AND (English[lang])
PubMed (Saudi)	("moderate-to-severe CD” OR “Crohn” OR “crohn’s disease” [MeSH])
	AND (“postoperative” OR “post-operative” OR “high-risk CD” OR “recurrence” OR “surgery” OR “clinical recurrence”)
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication]) AND (English[lang])
SCOPUS (ALL)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY (“postoperative” OR “post-operative” OR “high-risk CD” OR “recurrence” OR “surgery” OR “clinical recurrence”)
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")
SCOPUS (SAUDI)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY (“postoperative” OR “post-operative” OR “high-risk CD” OR “recurrence” OR “surgery” OR “clinical recurrence”)
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
Embase (ALL)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (‘postoperative’ OR ‘post-operative’ OR ‘high-risk CD’ OR ‘recurrence’ OR ‘surgery’ OR ‘clinical recurrence’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)
Embase (SAUDI)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (‘postoperative’ OR ‘post-operative’ OR ‘high-risk CD’ OR ‘recurrence’ OR ‘surgery’ OR ‘clinical recurrence’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’ OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)
Category 6: The Use of Biosimilars of Anti-TNFs and Anti-IL-12/23 (1 Qs)
PubMed (ALL)	("moderate-to-severe CD” OR “Crohn” OR “crohn disease” [MeSH])
	AND (“Biosimilar” OR “failure” OR “intolerance” OR “conventional” OR “advanced therapy” OR “advanced therapies” OR “inadequate response” OR “corticosteroids” OR “oral 5-ASA” OR “immunomodulator” OR “PRO response” OR “mucosal healing”)
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication]) AND (English[lang])
PubMed (Saudi)	("moderate-to-severe CD” OR “Crohn” OR “crohn disease” [MeSH])
	AND (“Biosimilar” OR “failure” OR “intolerance” OR “conventional” OR “advanced therapy” OR “advanced therapies” OR “inadequate response” OR “corticosteroids” OR “oral 5-ASA” OR “immunomodulator” OR “PRO response” OR “mucosal healing”)
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR “PRO remission”) AND (“biologic therapy” OR "anti-TNF" OR "infliximab" OR “infliximab biosimilars” OR “CT-P13” OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR " anti-IL-23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "biosimilars" OR “JAKIs” OR “Anti-IL-12/23”)
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication]) AND (English[lang])
SCOPUS (ALL)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY (“Biosimilar” OR “failure” OR “intolerance” OR “conventional” OR “advanced therapy” OR “advanced therapies” OR “inadequate response” OR “corticosteroids” OR “oral 5-ASA” OR “immunomodulator” OR “PRO response” OR “mucosal healing”)
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")
SCOPUS (SAUDI)	TITLE-ABS-KEY ("Crohn’s disease" OR "moderate-to-severe CD" OR "Crohn’s")
	AND TITLE-ABS-KEY (“Biosimilar” OR “failure” OR “intolerance” OR “conventional” OR “advanced therapy” OR “advanced therapies” OR “inadequate response” OR “corticosteroids” OR “oral 5-ASA” OR “immunomodulator” OR “PRO response” OR “mucosal healing”)
	AND TITLE-ABS-KEY ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission" OR "PRO remission")
	AND TITLE-ABS-KEY ("biologic therapy" OR "anti-TNF" OR "infliximab" OR "infliximab biosimilars" OR "CT-P13" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-23" OR "ustekinumab" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "biosimilars" OR "JAKIs" OR "Anti-IL-12/23")
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND NOT (TITLE-ABS-KEY("historical article") OR TITLE-ABS-KEY("cross-sectional studies") OR TITLE-ABS-KEY("cross-sectional") OR TITLE-ABS-KEY("case-control studies") OR TITLE-ABS-KEY("case-control") OR TITLE-ABS-KEY("epidemiologic studies") OR TITLE-ABS-KEY("review literature as topic") OR TITLE-ABS-KEY("erratum") OR TITLE-ABS-KEY("book chapter") OR TITLE-ABS-KEY("survey") OR TITLE-ABS-KEY("editorial") OR TITLE-ABS-KEY("letter") OR TITLE-ABS-KEY("case reports"))
	AND PUBYEAR > 2021 AND PUBYEAR < 2026
	AND LANGUAGE("English")AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
Embase (ALL)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (‘Biosimilar’ OR ‘failure’ OR ‘intolerance’ OR ‘conventional’ OR ‘advanced therapy’ OR ‘advanced therapies’ OR ‘inadequate response’ OR ‘corticosteroids’ OR ‘oral 5-ASA’ OR ‘immunomodulator’ OR ‘PRO response’ OR ‘mucosal healing’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)
Embase (SAUDI)	(’Crohn disease’/exp OR ’moderate-to-severe CD’ OR ’Crohn’)
	AND (‘Biosimilar’ OR ‘failure’ OR ‘intolerance’ OR ‘conventional’ OR ‘advanced therapy’ OR ‘advanced therapies’ OR ‘inadequate response’ OR ‘corticosteroids’ OR ‘oral 5-ASA’ OR ‘immunomodulator’ OR ‘PRO response’ OR ‘mucosal healing’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’ OR ’PRO remission’)
	AND (’biological therapy’ OR ’anti-TNF’ OR ’infliximab’ OR ’infliximab biosimilar’ OR ’CT-P13’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrin’ OR ’vedolizumab’ OR ’anti-IL-23’ OR ’ustekinumab’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitor’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitor’ OR ’ozanimod’ OR ’biosimilar’ OR ’JAKi’ OR ’anti-IL-12/23’)
	AND [2022-2025]/py
	AND [english]/lim
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’ OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
	NOT (’historical article’/it OR ’cross-sectional study’/exp OR ’cross sectional’:ti,ab OR ’case-control study’/exp OR ’case control’:ti,ab OR ’epidemiologic study’/exp OR ’review’/it OR ’erratum’:ti,ab OR ’book chapter’:ti,ab OR ’survey’:ti,ab OR ’editorial’/it OR ’letter’/it OR ’case report’/it)

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S Table 3.

Search Strategy for Ulcerative Colitis Recommendations

Database	Search strategy
Category 1: Induction and Maintenance of Remission in Moderate-to-Severe UC (9 Qs)
PubMed (ALL)	("Ulcerative Colitis"[MeSH] OR "moderate-to-severe UC" OR "ulcerative colitis") AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission") AND ("anti-TNF" OR "infliximab" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-12/23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "filgotinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "etrasimod" OR "biosimilars") AND ("Meta-Analysis"[Publication Type] OR "Network Meta-Analysis"[Title/Abstract] OR "Randomized Controlled Trial"[Publication Type] OR "Cohort Studies"[MeSH Terms]) AND ("2022/01/01"[Date - Publication] : "2025"[Date - Publication]) AND (English[lang])
PubMed (Saudi)	("Ulcerative Colitis"[MeSH] OR "moderate-to-severe UC" OR "ulcerative colitis")
	AND ("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission")
	AND ("anti-TNF" OR "infliximab" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-12/23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "filgotinib" OR "S1P1 inhibitors" OR "Sphingosine-1 phosphate" OR "ozanimod" OR "etrasimod" OR "biosimilars")
	AND ("Meta-Analysis"[Publication Type] OR "Network Meta-Analysis"[Title/Abstract] OR "Randomized Controlled Trial"[Publication Type] OR "Cohort Studies"[MeSH Terms])
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	AND ("2022/01/01"[Date - Publication] : "2025"[Date - Publication]) AND (English[lang])
SCOPUS (ALL)	(TITLE-ABS-KEY("Ulcerative Colitis" OR "moderate-to-severe UC" OR "ulcerative colitis"))
	AND (TITLE-ABS-KEY("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission"))
	AND (TITLE-ABS-KEY("anti-TNF" OR "infliximab" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-12/23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "filgotinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "etrasimod" OR "biosimilars"))
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND (PUBYEAR AFT 2021 AND PUBYEAR BEF 2026)
	AND (LANGUAGE("English"))
SCOPUS (SAUDI)	(TITLE-ABS-KEY("Ulcerative Colitis" OR "moderate-to-severe UC" OR "ulcerative colitis"))
	AND (TITLE-ABS-KEY("induction of remission" OR "maintenance of remission" OR "remission induction" OR "remission maintenance" OR "clinical remission" OR "biochemical remission" OR "steroid-free remission" OR "endoscopic remission"))
	AND (TITLE-ABS-KEY("anti-TNF" OR "infliximab" OR "adalimumab" OR "golimumab" OR "anti-integrins" OR "vedolizumab" OR "anti-IL-12/23" OR "ustekinumab" OR "anti-IL-23" OR "risankizumab" OR "mirikizumab" OR "guselkumab" OR "JAK inhibitors" OR "tofacitinib" OR "upadacitinib" OR "filgotinib" OR "Sphingosine-1 phosphate" OR "S1P1 inhibitors" OR "ozanimod" OR "etrasimod" OR "biosimilars"))
	AND (DOCTYPE("ar") OR TITLE-ABS-KEY("Meta-Analysis") OR TITLE-ABS-KEY("Network Meta-Analysis") OR TITLE-ABS-KEY("Randomized Controlled Trial") OR TITLE-ABS-KEY("Cohort Study"))
	AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
	AND (PUBYEAR AFT 2021 AND PUBYEAR BEF 2026)
Embase (ALL)	(’ulcerative colitis’ OR ’moderate-to-severe UC’ OR ’ulcerative colitis’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’)
	AND (’anti-TNF’ OR ’infliximab’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrins’ OR ’vedolizumab’ OR ’anti-IL-12/23’ OR ’ustekinumab’ OR ’anti-IL-23’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitors’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’filgotinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitors’ OR ’ozanimod’ OR ’etrasimod’ OR ’biosimilars’)
	AND ([meta analysis]/lim OR [randomized controlled trial]/lim OR ’cohort study’:ti,ab OR ’network meta-analysis’:ti,ab)
	AND ([2022-2025]/py)
	AND [english]/lim
Embase (SAUDI)	(’ulcerative colitis’ OR ’moderate-to-severe UC’ OR ’ulcerative colitis’)
	AND (’induction of remission’ OR ’maintenance of remission’ OR ’remission induction’ OR ’remission maintenance’ OR ’clinical remission’ OR ’biochemical remission’ OR ’steroid-free remission’ OR ’endoscopic remission’)
	AND (’anti-TNF’ OR ’infliximab’ OR ’adalimumab’ OR ’golimumab’ OR ’anti-integrins’ OR ’vedolizumab’ OR ’anti-IL-12/23’ OR ’ustekinumab’ OR ’anti-IL-23’ OR ’risankizumab’ OR ’mirikizumab’ OR ’guselkumab’ OR ’JAK inhibitors’ OR ’tofacitinib’ OR ’upadacitinib’ OR ’filgotinib’ OR ’Sphingosine-1 phosphate’ OR ’S1P1 inhibitors’ OR ’ozanimod’ OR ’etrasimod’ OR ’biosimilars’)
	AND ([meta analysis]/lim OR [randomized controlled trial]/lim OR ’cohort study’:ti,ab OR ’network meta-analysis’:ti,ab)
	AND ([2022-2025]/py)
	AND [english]/lim
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’ OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
Category 2: Treatment of Severe Hospitalized UC (ASUC) (5 Qs)
PubMed	("acute severe ulcerative colitis"[MeSH Terms] OR "acute severe UC" OR "ASUC" OR "hospitalized" OR "hospitalization")
	AND ("antibiotics" OR "adjunctive antibiotics" OR "colectomy risk" OR "short-term colectomy" OR "infliximab"[MeSH Terms] OR "cyclosporine"[MeSH Terms] OR "corticosteroid-refractory" OR "IV corticosteroids" OR "JAK inhibitors"[MeSH Terms] OR "JAKIs" OR "refractory to therapy" OR "inadequate response" OR "intensive infliximab dosing" OR "standard infliximab dosing" OR "colectomy risk" OR "exclusive enteral nutrition" OR "enteral nutrition" OR "EEN" OR "regular diet" OR “remission” OR “clinical remission”)
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication])
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND English[Language]
PubMed (SAUDI)	(("acute severe ulcerative colitis"[MeSH Terms] OR "acute severe UC" OR "severe ulcerative colitis" OR "ASUC") AND ("hospitalized adult patients" OR "adult patients" OR "hospitalized patients" OR "hospitalized"[Title/Abstract])) AND (("adjunctive antibiotics" OR "no antibiotics" OR "infliximab"[MeSH Terms] OR "cyclosporine"[MeSH Terms] OR "JAK inhibitors" OR "JAKIs" OR "intensive infliximab dosing" OR "standard infliximab dosing" OR "exclusive enteral nutrition" OR "regular diet" OR "no treatment")) AND (("short-term colectomy risk" OR "colectomy risk" OR "remission" OR "clinical remission")) AND (("refractory to intravenous corticosteroids" OR "inadequate response" OR "intolerance" OR "IV corticosteroids" OR "without gastrointestinal infections" OR "without extra-intestinal infections"))
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication])
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND English[Language]
SCOPUS	(TITLE-ABS-KEY("acute severe ulcerative colitis" OR "acute severe UC" OR "ASUC" OR "hospitalized" OR "hospitalization"))
	AND (TITLE-ABS-KEY("antibiotics" OR "adjunctive antibiotics" OR "colectomy risk" OR "short-term colectomy"
	OR "infliximab" OR "cyclosporine" OR "corticosteroid-refractory" OR "IV corticosteroids"
	OR "JAK inhibitors" OR "JAKIs" OR "refractory to therapy" OR "inadequate response"
	OR "intensive infliximab dosing" OR "standard infliximab dosing" OR "exclusive enteral nutrition"
	OR "enteral nutrition" OR "EEN" OR "regular diet" OR "remission" OR "clinical remission"))
	AND PUBYEAR AFT 2021 AND PUBYEAR BEF 2026
	AND (LIMIT-TO(LANGUAGE, "English"))
	AND NOT (TITLE-ABS-KEY("historical article" OR "cross-sectional" OR "cross sectional" OR "case-control"
	OR "case control" OR "epidemiologic studies" OR "review literature as topic" OR "erratum"
	OR "book chapter" OR "survey" OR "editorial" OR "letter" OR "case reports"))
SCOPUS (SAUDI)	(TITLE-ABS-KEY("acute severe ulcerative colitis" OR "acute severe UC" OR "ASUC" OR "hospitalized" OR "hospitalization"))
	AND (TITLE-ABS-KEY("antibiotics" OR "adjunctive antibiotics" OR "colectomy risk" OR "short-term colectomy"
	OR "infliximab" OR "cyclosporine" OR "corticosteroid-refractory" OR "IV corticosteroids"
	OR "JAK inhibitors" OR "JAKIs" OR "refractory to therapy" OR "inadequate response"
	OR "intensive infliximab dosing" OR "standard infliximab dosing" OR "exclusive enteral nutrition"
	OR "enteral nutrition" OR "EEN" OR "regular diet" OR "remission" OR "clinical remission"))
	AND PUBYEAR AFT 2021 AND PUBYEAR BEF 2026
	AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
	AND (LIMIT-TO(LANGUAGE, "English"))
	AND NOT (TITLE-ABS-KEY("historical article" OR "cross-sectional" OR "cross sectional" OR "case-control"
	OR "case control" OR "epidemiologic studies" OR "review literature as topic" OR "erratum"
	OR "book chapter" OR "survey" OR "editorial" OR "letter" OR "case reports"))
Embase	(’acute severe ulcerative colitis’/exp OR ’acute severe UC’ OR ’ASUC’ OR ’hospitalized’ OR ’hospitalization’)
	AND (’antibiotics’/exp OR ’adjunctive antibiotics’ OR ’colectomy risk’ OR ’short-term colectomy’ OR ’infliximab’/exp OR ’cyclosporine’/exp OR ’corticosteroid-refractory’ OR ’IV corticosteroids’ OR ’jak inhibitors’/exp OR ’jakis’ OR ’refractory to therapy’ OR ’inadequate response’
	OR ’intensive infliximab dosing’ OR ’standard infliximab dosing’ OR ’exclusive enteral nutrition’ OR ’enteral nutrition’ OR ’EEN’ OR ’regular diet’ OR ’remission’ OR ’clinical remission’)
	AND (’meta-analysis’/exp OR ’network meta-analysis’ OR ’randomized controlled trial’/exp OR ’cohort study’/exp)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/exp OR ’cross-sectional study’/exp OR ’case-control study’/exp OR ’epidemiologic study’/exp OR ’review’/exp OR ’erratum’/exp OR ’book’/exp OR ’survey’/exp OR ’editorial’/exp OR ’letter’/exp OR ’case report’/exp)
Embase (SAUDI)	(’acute severe ulcerative colitis’/exp OR ’acute severe UC’ OR ’severe ulcerative colitis’ OR ’ASUC’)
	AND (’hospitalized adult patients’ OR ’adult patients’ OR ’hospitalized patients’ OR ’hospitalized’)
	AND (’adjunctive antibiotics’ OR ’no antibiotics’ OR ’infliximab’/exp OR ’cyclosporine’/exp
	OR ’jak inhibitors’/exp OR ’jakis’ OR ’intensive infliximab dosing’ OR ’standard infliximab dosing’
	OR ’exclusive enteral nutrition’ OR ’regular diet’ OR ’no treatment’)
	AND (’short-term colectomy risk’ OR ’colectomy risk’ OR ’remission’ OR ’clinical remission’)
	AND (’refractory to intravenous corticosteroids’ OR ’inadequate response’ OR ’intolerance’
	OR ’IV corticosteroids’ OR ’without gastrointestinal infections’ OR ’without extra-intestinal infections’)
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’
	OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/exp OR ’cross-sectional study’/exp OR ’case-control study’/exp OR ’epidemiologic study’/exp OR ’review’/exp OR ’erratum’/exp OR ’book’/exp OR ’survey’/exp OR ’editorial’/exp OR ’letter’/exp OR ’case report’/exp)
Category 3: Management of Refractory UC or After Loss of Response (1 Qs)
PubMed	(“ulcerative colitis” OR “UC”) AND (“anti-TNF” OR “infliximab” OR “adalimumab” OR “golimumab” OR “certolizumab pegol” OR “loss of response” OR “secondary failure” OR “anti-IL-12/23” OR “Ustekinumab” OR “Risankizumab” OR “mirikizumab” OR “IL-23 inhibitor” OR “anti-integrin” OR “vedolizumab” OR “S1P1 inhibitor” OR “fingolimod” OR “ozanimod” OR “therapeutic drug monitoring”)
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication])
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND English[Language]
PubMed (Saudi)	(“ulcerative colitis” OR “UC”) AND (“anti-TNF” OR “infliximab” OR “adalimumab” OR “golimumab” OR “certolizumab pegol” OR “loss of response” OR “secondary failure” OR “anti-IL-12/23” OR “Ustekinumab” OR “Risankizumab” OR “mirikizumab” OR “IL-23 inhibitor” OR “anti-integrin” OR “vedolizumab” OR “S1P1 inhibitor” OR “fingolimod” OR “ozanimod” OR “therapeutic drug monitoring”)
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication])
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND English[Language]
SCOPUS	(TITLE-ABS-KEY (“ulcerative colitis” OR “UC”) AND (“anti-TNF” OR “infliximab” OR “adalimumab” OR “golimumab” OR “certolizumab pegol” OR “loss of response” OR “secondary failure” OR “anti-IL-12/23” OR “Ustekinumab” OR “Risankizumab” OR “mirikizumab” OR “IL-23 inhibitor” OR “anti-integrin” OR “vedolizumab” OR “S1P1 inhibitor” OR “fingolimod” OR “ozanimod” OR “therapeutic drug monitoring”))
	AND PUBYEAR AFT 2021 AND PUBYEAR BEF 2026
	AND (LIMIT-TO(LANGUAGE, "English"))
	AND NOT (TITLE-ABS-KEY("historical article" OR "cross-sectional" OR "cross sectional" OR "case-control" OR "case control" OR "epidemiologic studies" OR "review literature as topic" OR "erratum" OR "book chapter" OR "survey" OR "editorial" OR "letter" OR "case reports"))
SCOPUS (SAUDI)	(TITLE-ABS-KEY (“ulcerative colitis” OR “UC”) AND (“anti-TNF” OR “infliximab” OR “adalimumab” OR “golimumab” OR “certolizumab pegol” OR “loss of response” OR “secondary failure” OR “anti-IL-12/23” OR “Ustekinumab” OR “Risankizumab” OR “mirikizumab” OR “IL-23 inhibitor” OR “anti-integrin” OR “vedolizumab” OR “S1P1 inhibitor” OR “fingolimod” OR “ozanimod” OR “therapeutic drug monitoring”))
	AND PUBYEAR AFT 2021 AND PUBYEAR BEF 2026
	AND (LIMIT-TO(LANGUAGE, "English"))
	AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
	AND NOT (TITLE-ABS-KEY("historical article" OR "cross-sectional" OR "cross sectional" OR "case-control" OR "case control" OR "epidemiologic studies" OR "review literature as topic" OR "erratum" OR "book chapter" OR "survey" OR "editorial" OR "letter" OR "case reports"))
Embase	(‘ulcerative colitis ‘ OR ‘UC ‘) AND ( ‘anti-TNF ‘ OR ‘infliximab ‘ OR ‘adalimumab ‘ OR ‘golimumab ‘ OR ‘certolizumab pegol ‘ OR ‘loss of response ‘ OR ‘secondary failure ‘ OR ‘anti-IL-12/23 ‘ OR ‘Ustekinumab ‘ OR ‘Risankizumab ‘ OR ‘mirikizumab ‘ OR ‘IL-23 inhibitor ‘ OR ‘anti-integrin ‘ OR ‘vedolizumab ‘ OR ‘S1P1 inhibitor ‘ OR ‘fingolimod ‘ OR ‘ozanimod ‘ OR ‘therapeutic drug monitoring ‘)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/exp OR ’cross-sectional study’/exp OR ’case-control study’/exp OR ’epidemiologic study’/exp OR ’review’/exp OR ’erratum’/exp OR ’book’/exp OR ’survey’/exp OR ’editorial’/exp OR ’letter’/exp OR ’case report’/exp)
Embase (SAUDI)	(‘ulcerative colitis ‘ OR ‘UC ‘) AND ( ‘anti-TNF ‘ OR ‘infliximab ‘ OR ‘adalimumab ‘ OR ‘golimumab ‘ OR ‘certolizumab pegol ‘ OR ‘loss of response ‘ OR ‘secondary failure ‘ OR ‘anti-IL-12/23 ‘ OR ‘Ustekinumab ‘ OR ‘Risankizumab ‘ OR ‘mirikizumab ‘ OR ‘IL-23 inhibitor ‘ OR ‘anti-integrin ‘ OR ‘vedolizumab ‘ OR ‘S1P1 inhibitor ‘ OR ‘fingolimod ‘ OR ‘ozanimod ‘ OR ‘therapeutic drug monitoring ‘)
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’
	OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/exp OR ’cross-sectional study’/exp OR ’case-control study’/exp OR ’epidemiologic study’/exp OR ’review’/exp OR ’erratum’/exp OR ’book’/exp OR ’survey’/exp OR ’editorial’/exp OR ’letter’/exp OR ’case report’/exp)
Category 4: Pouchitis Management in UC Patients Post-IPAA (3 Qs)
PubMed	(“ulcerative colitis”) AND (“IPAA” OR “Ileal Pouch Anal Anastomosis” OR “pouchitis”) AND (“antibiotics” OR “Biologic Therapy” OR “advanced therapies” OR “probiotics” OR “recurrent pouchitis” OR “Recurrence” OR “clinical practice guidelines”)
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication])
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND English[Language]
PubMed (SAUDI)	(“ulcerative colitis”) AND (“IPAA” OR “Ileal Pouch Anal Anastomosis” OR “pouchitis”) OR (“antibiotics” OR “Biologic Therapy” OR “advanced therapies” OR “probiotics” OR “recurrent pouchitis” OR “Recurrence” OR “clinical practice guidelines”)
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication])
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND English[Language]
SCOPUS	(TITLE-ABS-KEY (“ulcerative colitis”) AND (“IPAA” OR “Ileal Pouch Anal Anastomosis” OR “pouchitis”) AND (“antibiotics” OR “Biologic Therapy” OR “advanced therapies” OR “probiotics” OR “recurrent pouchitis” OR “Recurrence” OR “clinical practice guidelines”))
	AND PUBYEAR AFT 2021 AND PUBYEAR BEF 2026
	AND (LIMIT-TO(LANGUAGE, "English"))
	AND NOT (TITLE-ABS-KEY("historical article" OR "cross-sectional" OR "cross sectional" OR "case-control" OR "case control" OR "epidemiologic studies" OR "review literature as topic" OR "erratum" OR "book chapter" OR "survey" OR "editorial" OR "letter" OR "case reports"))
SCOPUS (SAUDI)	(TITLE-ABS-KEY (“ulcerative colitis”) AND (“IPAA” OR “Ileal Pouch Anal Anastomosis” OR “pouchitis”) AND (“antibiotics” OR “Biologic Therapy” OR “advanced therapies” OR “probiotics” OR “recurrent pouchitis” OR “Recurrence” OR “clinical practice guidelines”))
	AND PUBYEAR AFT 2021 AND PUBYEAR BEF 2026
	AND (LIMIT-TO(LANGUAGE, "English"))
	AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
	AND NOT (TITLE-ABS-KEY("historical article" OR "cross-sectional" OR "cross sectional" OR "case-control" OR "case control" OR "epidemiologic studies" OR "review literature as topic" OR "erratum" OR "book chapter" OR "survey" OR "editorial" OR "letter" OR "case reports"))
Embase	( ‘ulcerative colitis ‘) AND ( ‘IPAA ‘ OR ‘Ileal Pouch Anal Anastomosis ‘ OR ‘pouchitis ‘) AND ( ‘antibiotics ‘ OR ‘Biologic Therapy ‘ OR ‘advanced therapies ‘ OR ‘probiotics ‘ OR ‘recurrent pouchitis ‘ OR ‘Recurrence ‘ OR ‘clinical practice guidelines ‘)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/exp OR ’cross-sectional study’/exp OR ’case-control study’/exp OR ’epidemiologic study’/exp OR ’review’/exp OR ’erratum’/exp OR ’book’/exp OR ’survey’/exp OR ’editorial’/exp OR ’letter’/exp OR ’case report’/exp)
Embase (SAUDI)	( ‘ulcerative colitis ‘) AND ( ‘IPAA ‘ OR ‘Ileal Pouch Anal Anastomosis ‘ OR ‘pouchitis ‘) AND ( ‘antibiotics ‘ OR ‘Biologic Therapy ‘ OR ‘advanced therapies ‘ OR ‘probiotics ‘ OR ‘recurrent pouchitis ‘ OR ‘Recurrence ‘ OR ‘clinical practice guidelines ‘)
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’
	OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/exp OR ’cross-sectional study’/exp OR ’case-control study’/exp OR ’epidemiologic study’/exp OR ’review’/exp OR ’erratum’/exp OR ’book’/exp OR ’survey’/exp OR ’editorial’/exp OR ’letter’/exp OR ’case report’/exp)
Category 5: Dose Optimization in UC Patients (2 Qs)
PubMed	(“ulcerative colitis” OR “moderate to severe UC”) AND (“anti-TNF therapy” OR “Tumor Necrosis Factor-alpha Antagonists”) AND (“dose optimization” OR “Drug Monitoring” OR “Dose-Response Relationship” OR “trough levels” OR “secondary loss of response” OR “dose escalation” OR “Drug Therapy” OR “Combination” OR “advanced therapies” OR “Vedolizumab” OR “Ustekinumab” OR “Risankizumab” OR “anti-integrin” OR “ IL-12/23 inhibitor” OR “IL-23 inhibitor” OR “dose interval” OR “clinical practice guidelines”)
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication])
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND English[Language]
PubMed (SAUDI)	(“ulcerative colitis” OR “moderate to severe UC”) AND (“anti-TNF therapy” OR “Tumor Necrosis Factor-alpha Antagonists”) AND (“dose optimization” OR “Drug Monitoring” OR “Dose-Response Relationship” OR “trough levels” OR “secondary loss of response” OR “dose escalation” OR “Drug Therapy” OR “Combination” OR “advanced therapies” OR “Vedolizumab” OR “Ustekinumab” OR “Risankizumab” OR “anti-integrin” OR “ IL-12/23 inhibitor” OR “IL-23 inhibitor” OR “dose interval” OR “clinical practice guidelines”)
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication])
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND English[Language]
SCOPUS	(TITLE-ABS-KEY(“ulcerative colitis” OR “moderate to severe UC”) AND (“anti-TNF therapy” OR “Tumor Necrosis Factor-alpha Antagonists”) AND (“dose optimization” OR “Drug Monitoring” OR “Dose-Response Relationship” OR “trough levels” OR “secondary loss of response” OR “dose escalation” OR “Drug Therapy” OR “Combination” OR “advanced therapies” OR “Vedolizumab” OR “Ustekinumab” OR “Risankizumab” OR “anti-integrin” OR “ IL-12/23 inhibitor” OR “IL-23 inhibitor” OR “dose interval” OR “clinical practice guidelines”))
	AND PUBYEAR AFT 2021 AND PUBYEAR BEF 2026
	AND (LIMIT-TO(LANGUAGE, "English"))
	AND NOT (TITLE-ABS-KEY("historical article" OR "cross-sectional" OR "cross sectional" OR "case-control" OR "case control" OR "epidemiologic studies" OR "review literature as topic" OR "erratum" OR "book chapter" OR "survey" OR "editorial" OR "letter" OR "case reports"))
SCOPUS (SAUDI)	(TITLE-ABS-KEY(“ulcerative colitis” OR “moderate to severe UC”) AND (“anti-TNF therapy” OR “Tumor Necrosis Factor-alpha Antagonists”) AND (“dose optimization” OR “Drug Monitoring” OR “Dose-Response Relationship” OR “trough levels” OR “secondary loss of response” OR “dose escalation” OR “Drug Therapy” OR “Combination” OR “advanced therapies” OR “Vedolizumab” OR “Ustekinumab” OR “Risankizumab” OR “anti-integrin” OR “ IL-12/23 inhibitor” OR “IL-23 inhibitor” OR “dose interval” OR “clinical practice guidelines”))
	AND PUBYEAR AFT 2021 AND PUBYEAR BEF 2026
	AND (LIMIT-TO(LANGUAGE, "English"))
	AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
	AND NOT (TITLE-ABS-KEY("historical article" OR "cross-sectional" OR "cross sectional" OR "case-control" OR "case control" OR "epidemiologic studies" OR "review literature as topic" OR "erratum" OR "book chapter" OR "survey" OR "editorial" OR "letter" OR "case reports"))
Embase	( ‘ulcerative colitis ‘ OR ‘moderate to severe UC ‘) AND ( ‘anti-TNF therapy ‘ OR ‘Tumor Necrosis Factor-alpha Antagonists ‘) AND ( ‘dose optimization ‘ OR ‘Drug Monitoring ‘ OR ‘Dose-Response Relationship ‘ OR ‘trough levels ‘ OR ‘secondary loss of response ‘ OR ‘dose escalation ‘ OR ‘Drug Therapy ‘ OR ‘Combination ‘ OR ‘advanced therapies ‘ OR ‘Vedolizumab ‘ OR ‘Ustekinumab ‘ OR ‘Risankizumab ‘ OR ‘anti-integrin ‘ OR ‘ IL-12/23 inhibitor ‘ OR ‘IL-23 inhibitor ‘ OR ‘dose interval ‘ OR ‘clinical practice guidelines ‘)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/exp OR ’cross-sectional study’/exp OR ’case-control study’/exp OR ’epidemiologic study’/exp OR ’review’/exp OR ’erratum’/exp OR ’book’/exp OR ’survey’/exp OR ’editorial’/exp OR ’letter’/exp OR ’case report’/exp)
Embase (SAUDI)	( ‘ulcerative colitis ‘ OR ‘moderate to severe UC ‘) AND ( ‘anti-TNF therapy ‘ OR ‘Tumor Necrosis Factor-alpha Antagonists ‘) AND ( ‘dose optimization ‘ OR ‘Drug Monitoring ‘ OR ‘Dose-Response Relationship ‘ OR ‘trough levels ‘ OR ‘secondary loss of response ‘ OR ‘dose escalation ‘ OR ‘Drug Therapy ‘ OR ‘Combination ‘ OR ‘advanced therapies ‘ OR ‘Vedolizumab ‘ OR ‘Ustekinumab ‘ OR ‘Risankizumab ‘ OR ‘anti-integrin ‘ OR ‘ IL-12/23 inhibitor ‘ OR ‘IL-23 inhibitor ‘ OR ‘dose interval ‘ OR ‘clinical practice guidelines ‘)
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’
	OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/exp OR ’cross-sectional study’/exp OR ’case-control study’/exp OR ’epidemiologic study’/exp OR ’review’/exp OR ’erratum’/exp OR ’book’/exp OR ’survey’/exp OR ’editorial’/exp OR ’letter’/exp OR ’case report’/exp)
Category 6: Switching from an Originator to a Bio Better or a Biosimilar (2 Qs)
PubMed	("ulcerative colitis" OR “moderate-severe UC”) AND ( “bio better” OR “Biobetters” OR "Biosimilar" OR “SC infliximab” OR “SC vedolizumab” OR “Subcutaneous") AND (“anti-TNFs” OR “IL 12/23” OR “Drug Substitution” OR "Combination" OR "Vedolizumab" OR “Injections” OR "Ustekinumab" OR "Risankizumab" OR "Infliximab" OR "Remission")
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication])
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR
	"letter"[publication type] OR "case reports"[publication type])
	AND English[Language]
PubMed (SAUDI)	("ulcerative colitis" OR “moderate-severe UC”) AND ( “bio better” OR “Biobetters” OR "Biosimilar" OR “SC infliximab” OR “SC vedolizumab” OR “Subcutaneous") AND (“anti-TNFs” OR “IL 12/23” OR “Drug Substitution” OR "Combination" OR "Vedolizumab" OR “Injections” OR "Ustekinumab" OR "Risankizumab" OR "Infliximab" OR "Remission")
	AND ("2022/01/01"[Date - Publication]: "2025"[Date - Publication])
	AND ("Saudi Arabia" OR "KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi")
	NOT ("historical article"[publication type] OR "cross-sectional studies"[mesh terms] OR "cross sectional"[ TIAB] OR "cross-sectional"[ TIAB] OR "case-control studies"[mesh terms] OR "case control"[ TIAB] OR "case-control"[ TIAB] OR "epidemiologic studies"[mesh terms] OR "review literature as topic"[mesh terms] OR "erratum"[TIAB] OR "book chapter"[TIAB] OR "survey"[TIAB] OR "editorial"[publication type] OR "letter"[publication type] OR "case reports"[publication type])
	AND English[Language]
SCOPUS	(TITLE-ABS-KEY ("ulcerative colitis" OR “moderate-severe UC”) AND (“bio better” OR “Biobetters” OR "Biosimilar" OR “SC infliximab” OR “SC vedolizumab” OR “Subcutaneous") AND (“anti-TNFs” OR “IL 12/23” OR “Drug Substitution” OR "Combination" OR "Vedolizumab" OR “Injections” OR "Ustekinumab" OR "Risankizumab" OR "Infliximab" OR "Remission"))
	AND PUBYEAR AFT 2021 AND PUBYEAR BEF 2026
	AND (LIMIT-TO(LANGUAGE, "English"))
	AND NOT (TITLE-ABS-KEY("historical article" OR "cross-sectional" OR "cross sectional" OR "case-control" OR "case control" OR "epidemiologic studies" OR "review literature as topic" OR "erratum" OR "book chapter" OR "survey" OR "editorial" OR "letter" OR "case reports"))
SCOPUS (SAUDI)	(TITLE-ABS-KEY ("ulcerative colitis" OR “moderate-severe UC”) AND (“bio better” OR “Biobetters” OR "Biosimilar" OR “SC infliximab” OR “SC vedolizumab” OR “Subcutaneous") AND (“anti-TNFs” OR “IL 12/23” OR “Drug Substitution” OR "Combination" OR "Vedolizumab" OR “Injections” OR "Ustekinumab" OR "Risankizumab" OR "Infliximab" OR "Remission"))
	AND PUBYEAR AFT 2021 AND PUBYEAR BEF 2026
	AND (LIMIT-TO(LANGUAGE, "English"))
	AND (AFFILCOUNTRY("Saudi Arabia") OR AFFIL("KSA" OR "Riyadh" OR "Jeddah" OR "Dammam" OR "Makkah" OR "Mecca" OR "Medina" OR "Al Khobar" OR "Khobar" OR "Abha" OR "Tabuk" OR "Qassim" OR "Al-Qassim" OR "Al Qassim" OR "Buraidah" OR "Al-Bahah" OR "Al Bahah" OR "Jizan" OR "Jazan" OR "Najran" OR "Al Ahsa" OR "Hofuf" OR "Hail" OR "Al Kharj" OR "Taif" OR "Yanbu" OR "Jubail" OR "Khamis Mushait" OR "Eastern Province" OR "Asir" OR "Hafar Al-Batin" OR "Qatif" OR "Dhahran" OR "Jubail Industrial City" OR "Saudi"))
	AND NOT (TITLE-ABS-KEY("historical article" OR "cross-sectional" OR "cross sectional" OR "case-control" OR "case control" OR "epidemiologic studies" OR "review literature as topic" OR "erratum" OR "book chapter" OR "survey" OR "editorial" OR "letter" OR "case reports"))
Embase	(‘ulcerative colitis ‘ OR ‘moderate-severe UC ‘) AND ( ‘bio better ‘ OR ‘Biobetters ‘ OR ‘Biosimilar ‘ OR ‘SC infliximab ‘ OR ‘SC vedolizumab ‘ OR ‘Subcutaneous ‘) AND ( ‘anti-TNFs ‘ OR ‘IL 12/23 ‘ OR ‘Drug Substitution ‘ OR ‘Combination ‘ OR ‘Vedolizumab ‘ OR ‘Injections ‘ OR ‘Ustekinumab ‘ OR ‘Risankizumab ‘ OR ‘Infliximab ‘ OR ‘Remission ‘)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/exp OR ’cross-sectional study’/exp OR ’case-control study’/exp OR ’epidemiologic study’/exp OR ’review’/exp OR ’erratum’/exp OR ’book’/exp OR ’survey’/exp OR ’editorial’/exp OR ’letter’/exp OR ’case report’/exp)
Embase (SAUDI)	(‘ulcerative colitis ‘ OR ‘moderate-severe UC ‘) AND ( ‘bio better ‘ OR ‘Biobetters ‘ OR ‘Biosimilar ‘ OR ‘SC infliximab ‘ OR ‘SC vedolizumab ‘ OR ‘Subcutaneous ‘) AND ( ‘anti-TNFs ‘ OR ‘IL 12/23 ‘ OR ‘Drug Substitution ‘ OR ‘Combination ‘ OR ‘Vedolizumab ‘ OR ‘Injections ‘ OR ‘Ustekinumab ‘ OR ‘Risankizumab ‘ OR ‘Infliximab ‘ OR ‘Remission ‘)
	AND (’Saudi Arabia’ OR ’KSA’ OR ’Riyadh’ OR ’Jeddah’ OR ’Dammam’ OR ’Makkah’ OR ’Mecca’ OR ’Medina’ OR ’Al Khobar’ OR ’Khobar’ OR ’Abha’ OR ’Tabuk’ OR ’Qassim’ OR ’Al-Qassim’ OR ’Al Qassim’ OR ’Buraidah’ OR ’Al-Bahah’ OR ’Al Bahah’ OR ’Jizan’ OR ’Jazan’ OR ’Najran’ OR ’Al Ahsa’ OR ’Hofuf’ OR ’Hail’ OR ’Al Kharj’ OR ’Taif’ OR ’Yanbu’ OR ’Jubail’
	OR ’Khamis Mushait’ OR ’Eastern Province’ OR ’Asir’ OR ’Hafar Al-Batin’ OR ’Qatif’ OR ’Dhahran’ OR ’Jubail Industrial City’ OR ’Saudi’)
	AND [2022-2025]/py
	AND [english]/lim
	NOT (’historical article’/exp OR ’cross-sectional study’/exp OR ’case-control study’/exp OR ’epidemiologic study’/exp OR ’review’/exp OR ’erratum’/exp OR ’book’/exp OR ’survey’/exp OR ’editorial’/exp OR ’letter’/exp OR ’case report’/exp)

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The review included meta-analyses, RCTs, nonrandomized studies, and pooled analyses published between 2015 and 2025. When insufficient evidence was found, the search was extended to include pre-2015 publications.

Two independent reviewers screened titles and abstracts to identify studies that met the inclusion criteria for each PICO question, and then assessed potentially eligible full-text articles. Recent systematic reviews were prioritized, but individual RCTs addressing the research questions were included when unavailable. Subsequently, the panelists assigned to each PICO question systematically reviewed and summarized the evidence for every outcome to create a Summary of Findings (SoF) table for each question. Quality assessment was conducted using standardized tools—the Cochrane risk of bias tool for RCTs[21] and the Newcastle–Ottawa scale for nonrandomized studies.[22]

Assessing the certainty of evidence

We employed the GRADEpro guideline development tool.[19] For each PICO question, comprehensive evidence profiles are generated. These profiles included data on critical and essential outcomes, presenting absolute and relative effects alongside certainty assessments.

Evidence certainty was evaluated using the five domains of the GRADE framework and classified into four distinct levels: very low, low, moderate, and high.[23] High certainty indicates strong confidence that the estimated effect accurately represents the true effect. Moderate certainty reflects reasonable confidence that the actual effect likely approximates the estimate. Low certainty suggests significant limitations in the effect estimate, indicating the actual effect may substantially differ. Very low certainty denotes considerable uncertainty, emphasizing the need for additional research to elucidate findings.

Five structured consultative sessions involving all panel members were held online, following a predefined agenda. These sessions facilitated focused discussions, expert feedback, and ongoing refinement to ensure the recommendations’ clarity, clinical relevance, and accuracy.

Recommendations were formulated based on thorough risk–benefit analyses conducted among panel members, a quality assessment of the available evidence, and the collective clinical expertise of the panel. The development process included virtual consultations to review and refine recommendations, which were subsequently presented to an expert panel for formal voting through the GRADEpro system. Formal approval required a minimum consensus threshold of 70%.

All results are reported in accordance with established epidemiological standards, with all point estimates accompanied by 95% confidence intervals to quantify statistical uncertainty and enhance the clinical relevance of the findings. This reporting approach aligns with current best practices in observational research and facilitates meta-analytical synthesis with future studies.

Each recommendation either endorsed or discouraged an intervention and was designated as either strong or conditional in strength. Understanding the strength classification is crucial for informed clinical decision-making (Table S4).

S Table 4.

Implications of the recommendation’s strength.

Strength of Recommendation	Definition	Implications for Stakeholders
Strong Recommendation	The benefits of the intervention clearly outweigh the risks, and the quality of evidence is high.	Clinicians should follow this recommendation in most situations. Patients can be confident in the benefits of the intervention.
Conditional Recommendation	The benefits of the intervention outweigh the risks, but the quality of evidence is lower, or there is uncertainty.	Clinicians should consider this recommendation, but individual patient circumstances and preferences should guide decision-making. Patients should be informed about the uncertainty and involved in the decision process.
No Recommendation (Good practice statement)	Evidence is insufficient to recommend for or against the intervention.	Clinicians should use their judgment and consider patient preferences. Further research is needed to clarify the intervention’s effectiveness.
Weak Recommendation Against	The risks of the intervention outweigh the benefits, but the quality of evidence is low.	Clinicians should generally avoid this intervention, but individual cases may warrant its use. Patients should be informed about the potential risks.
Strong Recommendation Against	The risks of the intervention clearly outweigh the benefits, and the quality of evidence is high.	Clinicians should not use this intervention. Patients should be made aware of the strong evidence against its use.

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TREATMENT RECOMMENDATIONS FOR MODERATE-TO-SEVERE CROHN’S DISEASE

Initial Treatments for Bio-Naïve Adults with Moderate-to-Severe CD

Q1. Should early initiation of biologic therapy vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?

Recommendation 1: For induction and maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend early initiation of biological therapy over no treatment. (Strong recommendation, moderate certainty evidence).

Rationale

A conventional or step-up therapeutic approach requires failure of corticosteroids, mesalamine, and thiopurines before initiating biologic therapy. On the other hand, there are several pieces of evidence that support the early initiation of biologics in disease, even without conventional therapy failure, allowing for improved patient outcomes. There is likely a window of opportunity during which timely and effective intervention, as part of a top-down strategy, can affect disease progression and decrease the risk of complications.[24]

This recommendation was developed based on SR and MA that evaluated the efficacy of biologic drugs compared to placebo in patients with IBD, for short and long durations (≤18 and >18 months).[25]

For the induction of remission, early initiation of biologic therapy was associated with significantly higher remission rates compared to placebo in both short (≤18 months) and long (>18 months) disease duration groups. The effect was observed in patients with short disease duration (Risk Ratio [RR] 1.47, [1.01 to 2.15]; moderate certainty, Table S5) and those with longer disease duration (RR 1.43, [1.19 to 1.72]; moderate certainty, Table S5). Notably, the proportion of patients who achieved remission was higher among those with short disease duration (41.4%) compared to those with longer disease duration (29.8%).[25]

S Table 5.

Early initiation of biologic therapy compared to no treatment for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD.

Bibliography: Berg DR, Colombel JF, Ungaro R. The Role of Early Biologic Therapy in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2019 Nov;25(12):1896–905.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	early initiation of biologic therapy	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	early initiation of biologic therapy	no treatment	Absolute (95% CI)
Remission during the induction period for treatment and control within patients with disease (assessed with: <18 months)
9	RCT	not serious	not serious	not serious	serious^a	none	117/319 (36.7%)	89/260 (34.2%)	RR 1.47 (1.01 to 2.15)	⨁⨁⨁◯ Moderate^a	CRITICAL
9	RCT	not serious	not serious	not serious	serious^a	none	117/319 (36.7%)	89/260 (34.2%)	161 more per 1,000 (from 3 more to 394 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Remission during the induction period for treatment and control within patients with disease (assessed with: >18 months)
11	RCT	serious^b	not serious	not serious	not serious^a	none	581/1682 (34.5%)	271/1172 (23.1%)	RR 1.43 (1.19 to 1.72)	⨁⨁⨁◯ Moderate^b	CRITICAL
11	RCT	serious^b	not serious	not serious	not serious^a	none	581/1682 (34.5%)	271/1172 (23.1%)	99 more per 1,000 (from 44 more to 166 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Clinical response during the induction period for treatment vs control within patients with disease (assessed with: =18 months)
9	RCTs	not serious	not serious	not serious	serious^a	none	178/317 (56.2%)	113/260 (43.5%)	RR 1.23 (1.00 to 1.51)	⨁⨁⨁◯ Moderate^a	CRITICAL
9	RCTs	not serious	not serious	not serious	serious^a	none	178/317 (56.2%)	113/260 (43.5%)	100 more per 1,000 (from 0 fewer to 222 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical response during the induction period for treatment vs control within patients with disease (assessed with: >18 months)
11	RCT	serious^b	not serious	not serious	not serious	none	878/1687 (52.0%)	422/1180 (35.8%)	RR 1.38 (1.23 to 1.56)	⨁⨁⨁◯ Moderate^b	CRITICAL
11	RCT	serious^b	not serious	not serious	not serious	none	878/1687 (52.0%)	422/1180 (35.8%)	136 more per 1,000 (from 82 more to 200 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Remission during the induction period for treatment vs control within patients without prior anti-TNF treatment
9	RCT	serious^b	not serious	not serious	not serious	none	621/1380 (45.0%)	306/890 (34.4%)	RR 1.39 (1.13 to 1.70)	⨁⨁⨁◯ Moderate^b	NOT IMPORTANT
9	RCT	serious^b	not serious	not serious	not serious	none	621/1380 (45.0%)	306/890 (34.4%)	134 more per 1,000 (from 45 more to 241 more)	⨁⨁⨁◯ Moderate^b	NOT IMPORTANT
Remission during the induction period for treatment vs control within patients with prior anti-TNF treatment
7	RCT	serious^b	not serious	not serious	not serious	none	165/687 (24.0%)	94/614 (15.3%)	RR 1.82 (1.25 to 2.66)	⨁⨁⨁◯ Moderate^b	NOT IMPORTANT
7	RCT	serious^b	not serious	not serious	not serious	none	165/687 (24.0%)	94/614 (15.3%)	126 more per 1,000 (from 38 more to 254 more)	⨁⨁⨁◯ Moderate^b	NOT IMPORTANT

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CI: confidence interval; RR: risk ratio; RCT, Randomized Controlled Trial.

Explanations:

^a.small sample size

^b.Blinding and allocation bias.

This was also in alignment with another SR and MA, which indicated that early initiation of biologic therapy is associated with lower surgery rates than late treatment.[26] The PROFILE study also supported the use of top-down therapy, which involves a combination of IFX and an immunomodulator, resulting in significantly better outcomes.[27]

In post hoc analyses of the SONIC and CHARM trials, early initiation of anti-tumor necrosis factor (TNF) therapy improved outcomes in patients. The SONIC trial demonstrated that early use of anti-TNF agents led to higher rates of remission and mucosal healing.[28] Additionally, a subgroup analysis of the CHARM trial demonstrated that ADA was superior to placebo in sustaining remission for patients with CD, irrespective of illness duration. Nonetheless, early beginning (within <2 years of diagnosis) demonstrated the best remission rates: 43% of ADA-treated patients attained remission at 1 year (19% on placebo, P = 0.024), with these benefits maintained over 3 years.[29]

The panel points out that the early initiation of biological therapy is both acceptable and feasible for implementation. We emphasized on structured monitoring and evaluation of short-term targets (clinical response within 6–12 weeks), intermediate targets (clinical remission, biochemical response/remission, and endoscopic response within 12–24 weeks), and long-term targets (endoscopic remission, radiological transmural remission, and normalization of QoL within 24–48 weeks) and encourage further research on predictive markers, preclinical phase of the disease, and disease prevention.[30] This recommendation is in alignment with British Society of Gastroenterology guidelines (BSG), which conditionally recommend advanced therapies for moderate to severe CD patients.[31] Several considerations should be taken for all patients with IBD starting advanced therapies, including receiving written information and undergoing safety checks, especially in low-risk patients. Vaccination history should be reviewed, with live vaccines only given at least 4 weeks before starting or 3 months after stopping therapy, and strictly contraindicated during immunosuppression or in patients with significant malnutrition. To reduce infection-related risks, patients should receive annual influenza, pneumococcal (with 5-year booster), SARS-CoV-2, and recombinant zoster vaccines. Female patients should adhere to national cervical screening recommendations and HPV vaccination programs to ensure long-term safety and optimal outcomes.[31]

Q2. Should anti-TNF α [IFX, ADA, or certolizumab pegol (CZP)] vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?

Recommendation 2: For induction and maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend using anti-TNF (such as IFX, ADA, or CZP) therapies over no treatment. (Strong recommendation, moderate certainty evidence)

Rationale

In addition, RCTs demonstrated that anti-TNF biologics, such as IFX and ADA, are more effective in inducing remission in patients with CD.

The CLASSIC I study evaluated the efficacy of ADA for inducing clinical remission in adults with CD who were anti-TNF biologic-naïve. Patients were randomized to receive varying doses of ADA (40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg) or placebo. Clinical remission was defined as a Crohn’s Disease Activity Index (CDAI) score of less than 150. The highest remission rate at week 4 was observed in the ADA 160/80 mg group, where 36% of patients achieved remission compared to 24% among those who received 80/40 mg and 12% in the placebo group (RR 1.97, [0.94 to 4.10], moderate certainty, Table S6) and (RR 2.92, [1.47 to 5.78], moderate certainty, Table S6), respectively. AEs were generally comparable between the ADA and placebo groups (RR 0.91, [0.74 to 1.12], moderate certainty, Table S6) and (RR 1.01, [0.84 to 1.21], moderate certainty, Table S6) for the 80/40 mg and 160/80 mg groups, respectively.[32]

S Table 6.

Anti-TNFα [infliximab (IFX), adalimumab (ADA), or certolizumab pegol (CZP)] compared to no treatment for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD.

Bibliography: Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al. Human Anti–Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in Crohn’s Disease: the CLASSIC-I Trial. Gastroenterology. 2006 Feb;130(2):323–33.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	anti-TNFα [IFX, IFX biosimilars, ADA, ADA biosimilars, or CZP]	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations		no treatment	Absolute (95% CI)
Clinical remission (ADA 80/40) (follow-up: 4 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	18/75 (24.0%)	9/74 (12.2%)	RR 1.97 (0.94 to 4.10)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a,b	none	18/75 (24.0%)	9/74 (12.2%)	118 more per 1,000 (from 7 fewer to 377 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
Clinical response (ADA 80/40) (follow-up: 4 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	30/75 (40.0%)	18/74 (24.3%)	RR 1.64 (1.00 to 2.67)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a,b	none	30/75 (40.0%)	18/74 (24.3%)	156 more per 1,000 (from 0 fewer to 406 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
Clinical remission (ADA 160/80) (follow-up: 4 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	27/76 (35.5%)	9/74 (12.2%)	RR 2.92 (1.47 to 5.78)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a,b	none	27/76 (35.5%)	9/74 (12.2%)	234 more per 1,000 (from 57 more to 581 more)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
Clinical rsponse (ADA 160/80)
1	RCT	not serious	not serious	not serious	serious^a,b	none	38/76 (50.0%)	18/74 (24.3%)	RR 2.05 (1.30 to 3.25)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a,b	none	38/76 (50.0%)	18/74 (24.3%)	255 more per 1,000 (from 73 more to 547 more)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
Any adverse events (ADA 80/40) (follow-up: 4 weeks)
1	RCT	not serious	not serious	not serious	serious^b	none	51/75 (68.0%)	55/74 (74.3%)	RR 0.91 (0.74 to 1.12)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	51/75 (68.0%)	55/74 (74.3%)	67 fewer per 1,000 (from 193 fewer to 89 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Any adverse events (ADA 160/80) (follow-up: 4 weeks)
1	RCT	not serious	not serious	not serious	serious^b	none	57/76 (75.0%)	55/74 (74.3%)	RR 1.01 (0.84 to 1.21)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	57/76 (75.0%)	55/74 (74.3%)	7 more per 1,000 (from 119 fewer to 156 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
infections (ADA 80/40) (follow-up: 4 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	13/75 (17.3%)	12/74 (16.2%)	RR 1.06 (0.52 to 2.18)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a,b	none	13/75 (17.3%)	12/74 (16.2%)	10 more per 1,000 (from 78 fewer to 191 more)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
infection (ADA 160/80) (follow-up: 4 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	16/76 (21.1%)	12/74 (16.2%)	RR 1.30 (0.66 to 2.55)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a,b	none	16/76 (21.1%)	12/74 (16.2%)	49 more per 1,000 (from 55 fewer to 251 more)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT

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CI: confidence interval; RR: risk ratio; RCT, Randomized Controlled Trial; ADA, Adalimumab; IFX, Infliximab; CZP, Certolizumab-Pegol.

Explanations

^a.Wide CI range

^b.small sample size

Only 1% of patients in the 80 mg/40 mg ADA group discontinued treatment due to AEs. Remarkably, the data revealed that among patients who were administered the highest induction dosing regimen (160 mg/80 mg), not a single individual required treatment discontinuation due to AEs, which stood in notable contrast to the placebo group, where 3% of participants had to cease therapy for the same reasons. Additionally, the rate of infection was low and comparable to the placebo in both ADA groups (RR 1.06, [0.52 to 2.18], moderate certainty, Table S6) and (RR 1.30, [0.66 to 2.55], moderate certainty, Table S6) for the 80/40 mg and 160/80 mg groups, respectively.[32]

In addition, the findings of ACCENT I RCT showed that patients with CD who responded to an IFX within 2 weeks were more probable to achieve remission at weeks 30 and 54, discontinue corticosteroids, and sustain their clinical response over time while maintained on IFX every 8 weeks.[33]

Furthermore, the CHARM trial has reported greater remission rates among CD patients treated with either ADA 40 mg weekly compared with the placebo at week 26 (40%, 47%, and 17%, respectively; P < 0.001).[34]

An SR and MA that included RCTs comparing CZP with placebo in patients with CD shows the superiority of CZP regarding efficacy and safety outcomes. A maintained clinical remission and clinical response at week 26 were reported in the CZP group (RR 0.73 and RR 0.58, respectively).[35] No difference in serious adverse events (SAEs) was reported for CZP when used as a remission maintenance treatment compared to placebo (RR 0.84, [0.40 to 1.78]).

Based on moderate certainty evidence, the guideline panel strongly recommends using anti-TNF therapies for the maintenance of CD. The panel indicates that anti-TNF agents have moderately desirable effects, such as improved clinical response, clinical remission, endoscopic remission, and QoL, with minor undesirable effects. The AGA and ACG guidelines strongly recommend using anti-TNF agents over no treatment for remission induction and maintenance.[15] However, IFX is conditionally recommended for the induction and maintenance of remission in patients with moderate to severe CD in the recent updates of the BSG guidelines, based on moderate certainty evidence.[31]

Q3. Should vedolizumab (VDZ) vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?

Recommendation 3: For induction and maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend using VDZ over no treatment (Strong recommendation, moderate certainty evidence).

Rationale

VDZ represents a targeted therapeutic approach as a humanized monoclonal antibody specifically engineered to bind to the α4β7 integrin receptor, demonstrating significant clinical efficacy in both achieving initial remission and maintaining long-term disease control in patients diagnosed with CD. The standardized treatment protocol involves administration through IV infusion utilizing a fixed dosing regimen of 300 mg during the induction phase, which is delivered at carefully timed intervals of weeks 0, 2, and 6 to optimize therapeutic response. Following successful induction, patients transition to a maintenance therapy schedule where they receive the same 300 mg dose via IV infusion every 8 weeks to sustain clinical remission and prevent disease relapse over the long term.[17,36,37]

This recommendation was developed based on an SR and MA that evaluated the efficacy of VDZ vs. placebo in CD treatment through 12 RCTs involving 4865 participants. The research findings clearly established that VDZ treatment exhibited statistically significant and clinically meaningful superiority over placebo in successfully inducing patient remission, with comprehensive follow-up evaluations conducted over variable timeframes ranging from 6 to 10 weeks for short-term assessment, while long-term maintenance efficacy was thoroughly evaluated across extended periods spanning from 52 to 60 weeks to ensure sustained therapeutic benefit.[38]

VDZ demonstrated a higher remission rate within 6 to 10 weeks (RR 1.95, [1.45 to 2.61], high certainty, Table S7). Maintenance of clinical remission within 52 to 60 weeks was superior in the VDZ group (RR, 1.59, [1.32 to 1.91]; high certainty, Table S7). Maintenance of clinical response within 6 to 10 weeks (RR 1.41, [1.16 to 1.73], moderate certainty, Table S7) and within 52 to 60 weeks (RR 1.38, [1.10 to 1.74], high certainty, Table S7) was also higher in the VDZ group.

S Table 7.

Vedolizumab compared to no treatment for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD.

Bibliography: Tang HJ, Bie CQ, Guo LL, Zhong LX, Tang SH. Efficacy and safety of vedolizumab in the treatment of patients with inflammatory bowel disease: A systematic review and metaanalysis of randomized controlled trials. Exp Ther Med [Internet]. 2023 May 5 [cited 2025 Apr 7];25(6). Available from: https://pubmed.ncbi.nlm.nih.gov/37229320/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	vedolizumab	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	vedolizumab	no treatment	Absolute (95% CI)
Induction of clinical remission (follow-up: range 6 weeks to 10 weeks)
5	RCT	not serious	not serious	not serious	not serious	None	637/738 (86.3%)	113/564 (20.0%)	RR 1.95 (1.45 to 2.61)	⨁⨁⨁⨁ High	CRITICAL
5	RCT	not serious	not serious	not serious	not serious	None	637/738 (86.3%)	113/564 (20.0%)	190 more per 1,000 (from 90 more to 323 more)	⨁⨁⨁⨁ High	CRITICAL
Maintenance of clinical response (follow-up: range 6 weeks to 10 weeks)
5	RCT	not serious	serious^a	not serious	not serious	None	674/738 (91.3%)	145/568 (25.5%)	RR 1.41 (1.16 to 1.73)	⨁⨁⨁◯ Moderate^a	CRITICAL
5	RCT	not serious	serious^a	not serious	not serious	None	674/738 (91.3%)	145/568 (25.5%)	105 more per 1,000 (from 41 more to 186 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Maintenance of clinical remission (follow-up: range 52 weeks to 60 weeks)
4	RCT	not serious	not serious	not serious	not serious	None	455/732 (62.2%)	105/456 (23.0%)	RR 1.59 (1.32 to 1.91)	⨁⨁⨁⨁ High	CRITICAL
4	RCT	not serious	not serious	not serious	not serious	None	455/732 (62.2%)	105/456 (23.0%)	136 more per 1,000 (from 74 more to 210 more)	⨁⨁⨁⨁ High	CRITICAL
Maintenance of clinical response (follow-up: range 52 weeks to 60 weeks)
4	RCT	not serious	not serious	not serious	not serious	None	499/732 (68.2%)	134/456 (29.4%)	RR 1.38 (1.10 to 1.74)	⨁⨁⨁⨁ High	CRITICAL
4	RCT	not serious	not serious	not serious	not serious	None	499/732 (68.2%)	134/456 (29.4%)	112 more per 1,000 (from 29 more to 217 more)	⨁⨁⨁⨁ High	CRITICAL
Safety (assessed with: Headache)
5	RCT	not serious	serious^b	serious^b	serious^c	None	0/738 (0.0%)	0/564 (0.0%)	RR 1.08 (0.63 to 1.86)	⨁◯◯◯ Very low^b,c	CRITICAL
5	RCT	not serious	serious^b	serious^b	serious^c	None	0/738 (0.0%)	0/564 (0.0%)	0 fewer per 1,000 (from 0 fewer to 0 fewer)	⨁◯◯◯ Very low^b,c	CRITICAL
Safety (assessed with: Nasopharyngitis)
3	RCT	not serious	not serious	not serious	not serious	None	377/468 (80.6%)	154/400 (38.5%)	RR 1.77 (1.01 to 3.10)	⨁⨁⨁⨁ High	IMPORTANT
3	RCT	not serious	not serious	not serious	not serious	None	377/468 (80.6%)	154/400 (38.5%)	296 more per 1,000 (from 4 more to 809 more)	⨁⨁⨁⨁ High	IMPORTANT
Safety (assessed with: Upper respiratory tract infection)
4	RCT	not serious	not serious	not serious	serious^c	None	695/732 (94.9%)	432/456 (94.7%)	RR 1.30 (0.81 to 2.09)	⨁⨁⨁◯ Moderate^c	NOT IMPORTANT
4	RCT	not serious	not serious	not serious	serious^c	None	695/732 (94.9%)	432/456 (94.7%)	284 more per 1,000 (from 180 fewer to 1,000 more)	⨁⨁⨁◯ Moderate^c	NOT IMPORTANT
Safety (assessed with: Arthralgia)
2	RCT	not serious	not serious	not serious	serious^c	None	266/275 (96.7%)	237/239 (99.2%)	RR 1.03 (0.57 to 1.84)	⨁⨁⨁◯ Moderate^c	IMPORTANT
2	RCT	not serious	not serious	not serious	serious^c	None	266/275 (96.7%)	237/239 (99.2%)	30 more per 1,000 (from 426 fewer to 833 more)	⨁⨁⨁◯ Moderate^c	IMPORTANT
Safety (assessed with: Abdominal pain)
3	RCT	not serious	not serious	not serious	serious^c	None	467/468 (99.8%)	388/400 (97.0%)	RR 0.95 (0.61 to 1.47)	⨁⨁⨁◯ Moderate^c	IMPORTANT
3	RCT	not serious	not serious	not serious	serious^c	None	467/468 (99.8%)	388/400 (97.0%)	49 fewer per 1,000 (from 378 fewer to 456 more)	⨁⨁⨁◯ Moderate^c	IMPORTANT
Safety (assessed with: Vomiting)
2	RCT	not serious	serious^d	not serious	serious^e	None	271/275 (98.5%)	236/239 (98.7%)	RR 0.86 (0.21 to 3.58)	⨁⨁◯◯ Low^d,e	IMPORTANT
2	RCT	not serious	serious^d	not serious	serious^e	None	271/275 (98.5%)	236/239 (98.7%)	138 fewer per 1,000 (from 780 fewer to 1,000 more)	⨁⨁◯◯ Low^d,e	IMPORTANT
Safety (assessed with: Serious adverse events)
5	RCT	not serious	not serious	not serious	serious^c	None	720/738 (97.6%)	555/564 (98.4%)	RR 0.76 (0.54 to 1.98)	⨁⨁⨁◯ Moderate^c	IMPORTANT
5	RCT	not serious	not serious	not serious	serious^c	None	720/738 (97.6%)	555/564 (98.4%)	236 fewer per 1,000 (from 453 fewer to 964 more)	⨁⨁⨁◯ Moderate^c	IMPORTANT

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CI: confidence interval; RR: risk ratio; RCT: Randomized Controlled Trial.

Explanations

^a.I2 = 45.3

^b.Moderate I2 index of heterogeneity

^c.Downgrade one level for crossing the line of no effect

^d.High I2 index of heterogeneity (more than 50%)

^e.Wide confidence interval

AEs were variable, while nasopharyngitis was more frequent in the VDZ group (RR 1.77, [1.01 to 3.10], high certainty, Table S7), SAEs (RR 0.76, [0.54 to 1.98], moderate certainty, Table S7), and arthralgia (RR 1.03, [0.57 to 1.84], moderate certainty, Table S7) were less common. Other AEs, such as upper respiratory infections (URIs) (RR 1.30, [0.81 to 2.09], moderate certainty, Table S7), abdominal pain (RR 0.95, [0.61 to 1.47], moderate certainty, Table S7), and vomiting (RR 0.86, [0.21 to 3.58], low certainty, Table S7), were comparable to placebo.

These results align with a previously published SR and MA that demonstrated the superior efficacy of VDZ compared to the placebo in inducing and maintaining clinical remission.[39]

Based on moderate certainty evidence and the targeting approach that anti-integrins offer, the guideline panel strongly recommends VDZ in patients with CD, demonstrating its efficacy in achieving clinical remission and response, alongside a favorable safety profile. The ECCO, ACG, and AGA guidelines strongly recommend using VDZ as induction and maintenance therapy for CD patients.[15,17] On the other hand, the recent BSG guideline updates concluded that VDZ shows a minimal effect in both biologic-naïve and biologic-exposed CD patients; therefore, its use is not recommended for CD. They indicated that it could be considered when other options are not appropriate or when induction is achieved through other modalities.[31]

Rationale

This recommendation emerged from a phase III clinical study (UNITI–IM-UNIT) that demonstrated ustekinumab, a monoclonal antibody designed to target IL-12/23, showed superior effectiveness for both achieving and maintaining remission vs. placebo in CD patients during an 8-week follow-up period.[40]

Q4. Should ustekinumab vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?

Recommendation 4: For induction and maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend using ustekinumab over no treatment (Strong recommendation, moderate certainty evidence).

A higher clinical response rate was observed with IV ustekinumab 130 mg (RR 1.50, [1.09 to 2.05], high certainty, Table S8) and IV ustekinumab 6 mg/kg (RR 1.60, [1.19 to 2.20], high certainty, Table S8) induction compared to placebo. Clinical remission rates were also higher with IV ustekinumab 130 mg (RR 2.02, [1.18 to 3.40], high certainty, Table S8) and with IV ustekinumab 6 mg/kg (RR 2.54, [1.52 to 4.20], moderate certainty, Table S8) compared to placebo. The safety profile was comparable in both the ustekinumab and placebo groups, whether with 130 mg ustekinumab (RR 1.00, [0.84 to 1.20], moderate certainty, Table S8) or with 6 mg/kg induction doses (RR 1.00, [0.85 to 1.19], moderate certainty, Table S8). These results align with a comprehensive SR and MA of 41 studies that found ustekinumab to be effective and safe in a real-world treatment setting for CD.[41]

S Table 8.

Ustekinumab compared to no treatment for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD.

Bibliography: Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med [Internet]. 2016 Nov 17 [cited 2025 Apr 5];375(20):1946–60. Available from: https://pubmed.ncbi.nlm.nih.gov/27959607/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	ustekinumab	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	ustekinumab	no treatment	Absolute (95% CI)
Patients with Clinical Response (follow-up: mean 8 weeks; assessed with: Ustekinumab, 130 mg)
1	RCT	not serious	not serious	not serious	not serious	None	83/245 (33.9%)	50/247 (20.2%)	RR 1.50 (1.09 to 2.05)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	None	83/245 (33.9%)	50/247 (20.2%)	101 more per 1,000 (from 18 more to 213 more)	⨁⨁⨁⨁ High	CRITICAL
Patients with Clinical Response (follow-up: mean 8 weeks; assessed with: Ustekinumab, 6 mg/kg)
1	RCT	not serious	not serious	not serious	not serious	None	94/249 (37.8%)	50/247 (20.2%)	RR 1.60 (1.19 to 2.20)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	None	94/249 (37.8%)	50/247 (20.2%)	121 more per 1,000 (from 38 more to 243 more)	⨁⨁⨁⨁ High	CRITICAL
Patients in Clinical Remission (follow-up: mean 8 weeks; assessed with: Ustekinumab, 130 mg)
1	RCT	not serious	not serious	not serious	not serious	None	39/245 (15.9%)	18/247 (7.3%)	RR 2.02 (1.18 to 3.40)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	None	39/245 (15.9%)	18/247 (7.3%)	74 more per 1,000 (from 13 more to 175 more)	⨁⨁⨁⨁ High	CRITICAL
Patients in Clinical Remission (follow-up: mean 8 weeks; assessed with: Ustekinumab, 6 mg/kg)
1	RCT	not serious	not serious	not serious	serious^a	None	52/249 (20.9%)	18/247 (7.3%)	RR 2.54 (1.52 to 4.20)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	None	52/249 (20.9%)	18/247 (7.3%)	112 more per 1,000 (from 38 more to 233 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Any adverse event (assessed with: Ustekinumab, 130 mg)
1	RCT	not serious	not serious	not serious	serious^b	None	159/246 (64.6%)	159/245 (64.9%)	RR 1.00 (0.84 to 1.20)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	None	159/246 (64.6%)	159/245 (64.9%)	0 fewer per 1,000 (from 104 fewer to 130 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Any adverse event (assessed with: Ustekinumab, 6 mg/kg)
1	RCT	not serious	not serious	not serious	serious^b	None	164/249 (65.9%)	159/245 (64.9%)	RR 1.00 (0.85 to 1.19)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	None	164/249 (65.9%)	159/245 (64.9%)	0 fewer per 1,000 (from 97 fewer to 123 more)	⨁⨁⨁◯ Moderate^b	CRITICAL

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CI: confidence interval; RR: risk ratio

Explanations

^a.Wide CI

^b.Downgrade one level for crossing line of no effect.

In the UNITI-1 subgroup analysis, among patients who responded to TNF antagonist therapy, 38.4% of those receiving ustekinumab 6 mg/kg achieved a clinical response, compared to 20.3% in the placebo group (odds ratio [OR] 2.5, P < 0.001). Patients who were intolerant to TNF antagonists had a response rate of 34.3% with ustekinumab 6 mg/kg compared to 24.1% with placebo (OR 1.6, [0.8 to 3.0]; P = 0.188). In patients who had failed at least two TNF antagonists, ustekinumab 6 mg/kg was also more effective, with a response rate of 34.9% compared to 19.4% in the placebo group (OR 2.1, [1.2 to 3.8], P = 0.008).[41]

Similarly, ustekinumab 130 mg demonstrated higher clinical response rates at week 6 compared to placebo in several patient subgroups with prior TNF antagonist exposure. Among patients with a prior response to TNF antagonists, 34.7% of those who received ustekinumab achieved clinical response vs. 20.3% with placebo (OR 2.3; [1.5 to 3.7; P < 0.001).[41]

Based on moderate certainty evidence, the guideline panel strongly recommends ustekinumab for CD patients for the induction and maintenance of remission. It highlights its moderate cost, efficacy in clinical response rate, and a manageable safety profile. The ECCO, ACG, and AGA guidelines strongly recommend using ustekinumab for CD patients.[15,17] However, BSG guidelines conditionally recommend its use in CD patients.[31]

Q5. Should anti-IL-23 agents (risankizumab (RZB), guselkumab, and mirikizumab) vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?

Recommendation 5: For induction and maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend using anti-IL-23 agents (RZB, guselkumab, and mirikizumab) over no treatment (Strong recommendation, moderate certainty evidence).

Rationale

This recommendation was developed from the phase 3 trials, which indicated that RZB (an IL-23 p19 inhibitor) at 600 mg or 1200 mg induction doses (weeks 0, 4, 8) followed by 180 or 360 mg subcutaneous (SC) maintenance doses achieved significantly higher rates of clinical remission and endoscopic response compared to placebo in CD patients.[42,43]

RZB demonstrated significantly higher clinical remission rates at both 600 mg and 1200 mg doses (RR 1.84, [1.38 to 2.45], high certainty, Table S9) and (RR 1.69, [1.27 to 2.26, high certainty, Table S9), respectively. Stool frequency (SF)/abdominal pain remission was also improved with both 600 mg and 1200 mg doses (RR 2.00, [1.47 to 2.72], high certainty, Table S9) and 1200 mg (RR 1.89, [1.39 to 2.57], high certainty, Table S9), respectively.[42,43]

S Table 9.

Anti-IL-23 agents (risankizumab (RZB), guselkumab, and mirikizumab) compared to no treatment for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	anti-IL-23 agents (RZB, guselkumab, and mirikizumab)	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	anti-IL-23 agents (RZB, guselkumab, and mirikizumab)	no treatment	Absolute (95% CI)
Clinical remission (Risankizumab 600 mg) (assessed with: CDAI <150)
2	RCT	not serious	not serious	not serious	not serious	none	152/336 (45.2%)	43/175 (24.6%)	RR 1.84 (1.38 to 2.45)	⨁⨁⨁⨁ High	CRITICAL
2	RCT	not serious	not serious	not serious	not serious	none	152/336 (45.2%)	43/175 (24.6%)	206 more per 1,000 (from 93 more to 356 more)	⨁⨁⨁⨁ High	CRITICAL
Stool frequency and abdominal pain score clinical remission (Risankizumab 600 mg)
2	RCT	not serious	not serious	not serious	not serious	none	146/336 (43.5%)	38/175 (21.7%)	RR 2.00 (1.47 to 2.72)	⨁⨁⨁⨁ High	CRITICAL
2	RCT	not serious	not serious	not serious	not serious	none	146/336 (43.5%)	38/175 (21.7%)	217 more per 1,000 (from 102 more to 373 more)	⨁⨁⨁⨁ High	CRITICAL
Endoscopic response (Risankizumab 600 mg)
2	RCT	not serious	not serious	not serious	not serious	none	135/336 (40.2%)	21/175 (12.0%)	RR 3.35 (2.20 to 5.11)	⨁⨁⨁⨁ High	CRITICAL
2	RCT	not serious	not serious	not serious	not serious	none	135/336 (40.2%)	21/175 (12.0%)	282 more per 1,000 (from 144 more to 493 more)	⨁⨁⨁⨁ High	CRITICAL
Clinical remission (Risankizumab 1200 mg) (assessed with: CDAI <150)
2	RCT	not serious	not serious	not serious	not serious	none	141/339 (41.6%)	43/175 (24.6%)	RR 1.69 (1.27 to 2.26)	⨁⨁⨁⨁ High	CRITICAL
2	RCT	not serious	not serious	not serious	not serious	none	141/339 (41.6%)	43/175 (24.6%)	170 more per 1,000 (from 66 more to 310 more)	⨁⨁⨁⨁ High	CRITICAL
Stool frequency and abdominal pain score clinical remission (Risankizumab 1200 mg)
2	RCT	not serious	not serious	not serious	not serious	none	139/339 (41.0%)	38/175 (21.7%)	RR 1.89 (1.39 to 2.57)	⨁⨁⨁⨁ High	CRITICAL
2	RCT	not serious	not serious	not serious	not serious	none	139/339 (41.0%)	38/175 (21.7%)	193 more per 1,000 (from 85 more to 341 more)	⨁⨁⨁⨁ High	CRITICAL
Endoscopic response (Risankizumab 1200 mg)
2	RCT	not serious	not serious	not serious	not serious	none	109/339 (32.2%)	21/175 (12.0%)	RR 2.68 (1.74 to 4.12)	⨁⨁⨁⨁ High	CRITICAL
2	RCT	not serious	not serious	not serious	not serious	none	109/339 (32.2%)	21/175 (12.0%)	202 more per 1,000 (from 89 more to 374 more)	⨁⨁⨁⨁ High	CRITICAL
Safety (Risankizumab 600 mg) (assessed with: Adverse events)
2	RCT	not serious	not serious	not serious	serious^a	none	210/373 (56.3%)	105/186 (56.5%)	RR 1.00 (0.85 to 1.16)	⨁⨁⨁◯ Moderate^a	CRITICAL
2	RCT	not serious	not serious	not serious	serious^a	none	210/373 (56.3%)	105/186 (56.5%)	0 fewer per 1,000 (from 85 fewer to 90 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Safety (Risankizumab 600 mg) (assessed with: Serious adverse events)
2	RCT	not serious	not serious	not serious	not serious	none	27/373 (7.2%)	28/186 (15.1%)	RR 0.48 (0.29 to 0.79)	⨁⨁⨁⨁ High	IMPORTANT
2	RCT	not serious	not serious	not serious	not serious	none	27/373 (7.2%)	28/186 (15.1%)	78 fewer per 1,000 (from 107 fewer to 32 fewer)	⨁⨁⨁⨁ High	IMPORTANT
Safety (Risankizumab 600 mg) (assessed with: Adverse events leading to discontinuation of study drug)
2	RCT	not serious	not serious	not serious	not serious	none	9/373 (2.4%)	14/186 (7.5%)	RR 0.32 (0.14 to 0.73)	⨁⨁⨁⨁ High	IMPORTANT
2	RCT	not serious	not serious	not serious	not serious	none	9/373 (2.4%)	14/186 (7.5%)	51 fewer per 1,000 (from 65 fewer to 20 fewer)	⨁⨁⨁⨁ High	IMPORTANT
Safety (Risankizumab 1200 mg) (assessed with: Adverse events)
2	RCT	not serious	not serious	not serious	serious^a	none	191/372 (51.3%)	105/186 (56.5%)	RR 0.91 (0.77 to 1.07)	⨁⨁⨁◯ Moderate^a	IMPORTANT
2	RCT	not serious	not serious	not serious	serious^a	none	191/372 (51.3%)	105/186 (56.5%)	51 fewer per 1,000 (from 130 fewer to 40 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Safety (Risankizumab 1200 mg) (assessed with: Serious adverse events)
2	RCT	not serious	not serious	not serious	not serious	none	14/372 (3.8%)	28/186 (15.1%)	RR 0.25 (0.13 to 0.46)	⨁⨁⨁⨁ High	IMPORTANT
2	RCT	not serious	not serious	not serious	not serious	none	14/372 (3.8%)	28/186 (15.1%)	113 fewer per 1,000 (from 131 fewer to 81 fewer)	⨁⨁⨁⨁ High	IMPORTANT
Safety (Risankizumab 1200 mg) (assessed with: Adverse events leading to discontinuation of study drug)
2	RCT	not serious	not serious	not serious	not serious	none	7/372 (1.9%)	14/186 (7.5%)	RR 0.25 (0.10 to 0.61)	⨁⨁⨁⨁ High	IMPORTANT
2	RCT	not serious	not serious	not serious	not serious	none	7/372 (1.9%)	14/186 (7.5%)	56 fewer per 1,000 (from 68 fewer to 29 fewer)	⨁⨁⨁⨁ High	IMPORTANT

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CI: confidence interval; RR: risk ratio; RZB, risankizumab.

Explanations

^a.Downgrade one level for crossing the line of no effect.

Additionally, RZB achieved significantly higher endoscopic responses at both 600 and 1200 mg doses (RR 3.35, [2.20 to 5.11], high certainty, Table S9) and (RR 2.68, [1.74 to 4.12], high certainty, Table S9), respectively. The safety profile was favorable in the anti-IL-23 group compared to placebo, with comparable AEs in both 600 and 1200 mg doses (RR 1.00, [0.85 to 1.16], Table S9) and (RR 0.91, [0.77 to 1.07], moderate certainty, Table S9), respectively.[42,43]

These results align with an SR and MA that found patients treated with IL-23 inhibitors achieved clinical remission more often than those treated with placebo, leading to higher clinical response and endoscopic remission rates.[44,45]

GALAXI-1 trial found IV and SC guselkumab maintenance in patients with CD, with no opportunistic infections, active tuberculosis, or deaths occurring.[46] Similarly, the phase 3 GRAVITI study found that SC guselkumab is effective for both induction and maintenance in treating those with CD.[47] Safety findings were comparable across treatment and placebo groups, consistent with those of guselkumab in approved indications, including UC.[47,48]

In the GALAXI 2 and 3 trials, guselkumab demonstrated higher efficacy compared to ustekinumab in achieving 90-day corticosteroid-free outcomes at week 48 in patients with CD. Higher proportions of guselkumab-treated patients achieved endoscopic response (100 mg q8w: +11.2%; 200 mg q4w: +14.5%), endoscopic remission (+9.5%, +11.9%), and composite endpoints of clinical remission with endoscopic response (+8.1%, +12.4%) or endoscopic remission (+8.0%, +10.9%), as well as clinical remission alone (+4.1%, +5.3%) compared to ustekinumab.[49] Another IL-23 inhibitor, mirikizumab, demonstrated efficacy as both induction and maintenance therapy in patients with CD who had experienced intolerance, inadequate response, or loss of response to standard treatments.[50] The VIVID-1 trial demonstrated that a significantly higher proportion of patients receiving mirikizumab achieved the composite endoscopic response compared to placebo (38.0% vs 9.0%; P < 0.0001). Additionally, CDAI clinical remission-composite was achieved in 45.4% of patients who received mirikizumab, 19.6% of those in the placebo group (P < 0.0001).[50]

Based on moderate-certainty evidence, the guideline panel strongly recommends anti-IL-23 therapy for the induction and maintenance of remission. It highlights its moderate cost and ability to strengthen the treatment approach through demonstrated efficacy. This recommendation aligns with the ECCO guideline in using IL-23 inhibitor therapy among CD patients.[51] Regarding ACG guidelines, they specifically strongly recommend RZB and guselkumab for induction and maintenance of remission among CD patients.[52] The guidelines gave the option for SC induction based on the GRAVITI.

Q6. Should upadacitinib vs. no treatment be used for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD?

Recommendation 6: For induction and maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend using upadacitinib over no treatment (Strong recommendation, Moderate certainty evidence).

Rationale

This recommendation is based on a Phase III study involving two induction trials and one maintenance trial with upadacitinib. This oral selective JAK inhibitor demonstrated its effectiveness in achieving higher rates of induction and maintenance of clinical remission compared to placebo in patients with CD.[53]

Within 12 weeks of follow-up, upadacitinib 45 mg daily revealed a higher clinical remission assessed by CDAI of <150 (RR 1.77, [1.44 to 2.16], high certainty, Table S10), endoscopic response (assessed by SES-CD) (RR 4.80, [3.35 to 6.89], moderate certainty, Table S10), and clinical remission assessed by SF and abdominal pain score (SF to APS), which required both SF ≤2.8 and abdominal pain score ≤1.0 (RR 2.50, [1.97 to 3.17], moderate certainty, Table S10). At week 52, upadacitinib (15 and 30 mg daily) also demonstrated a higher CDAI clinical remission (RR 2.06, [1.35 to 3.14], Table S10), endoscopic response (RR 3.21, [1.76 to 5.85], Table S10), and SF-APS clinical remission (RR 2.44, [1.60 to 3.72], moderate certainty, Table S10).[53]

S Table 10.

Upadacitinib compared to no treatment for induction and maintenance of remission in bio-naive patients with moderate-to-severe CD.

Bibliography: Loftus E V., Panés J, Lacerda AP, Peyrin-Biroulet L, D’Haens G, Panaccione R, et al. Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med [Internet]. 2023 May 25 [cited 2025 Apr 5];388(21):1966–80. Available from: https://pubmed.ncbi.nlm.nih.gov/37224198/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Upadacitinib	no treatment	Relative (95% CI)	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Upadacitinib	no treatment	Absolute (95% CI)
Clinical remission (follow-up: mean 12 weeks; assessed with: Crohn’s Disease Activity Index (CDAI) )
1	RCT	not serious	not serious	not serious	not serious	none	299/674 (44.4%)	87/347 (25.1%)	RR 1.77 (1.44 to 2.16)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	299/674 (44.4%)	87/347 (25.1%)	193 more per 1,000 (from 110 more to 291 more)	⨁⨁⨁⨁ High	CRITICAL
Endoscopic response (follow-up: mean 12 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	271/674 (40.2%)	29/347 (8.4%)	RR 4.80 (3.35 to 6.89)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	271/674 (40.2%)	29/347 (8.4%)	318 more per 1,000 (from 196 more to 492 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical remission (follow-up: mean 12 weeks; assessed with: Stool frequency and abdominal pain score (SF–APS) )
1	RCT	not serious	not serious	not serious	serious^a	none	306/674 (45.4%)	63/347 (18.2%)	RR 2.50 (1.97 to 3.17)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	306/674 (45.4%)	63/347 (18.2%)	272 more per 1,000 (from 176 more to 394 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
CDAI clinical remission (follow-up: mean 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	63/169 (37.3%)	25/165 (15.2%)	RR 2.06 (1.35 to 3.14)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	63/169 (37.3%)	25/165 (15.2%)	161 more per 1,000 (from 53 more to 324 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Endoscopic response (follow-up: mean 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	47/169 (27.8%)	12/165 (7.3%)	RR 3.21 (1.76 to 5.85)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	47/169 (27.8%)	12/165 (7.3%)	161 more per 1,000 (from 55 more to 353 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
SF–APS clinical remission (follow-up: mean 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	60/169 (35.5%)	24/165 (14.5%)	RR 2.44 (1.60 to 3.72)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	60/169 (35.5%)	24/165 (14.5%)	209 more per 1,000 (from 87 more to 396 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Safety (assessed with: Any adverse event)
1	RCT	not serious	not serious	not serious	serious^b	none	219/350 (62.6%)	103/176 (58.5%)	RR 1.042 (0.866 to 1.255)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	219/350 (62.6%)	103/176 (58.5%)	25 more per 1,000 (from 78 fewer to 149 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Safety (assessed with: Serious adverse event)
1	RCT	not serious	not serious	not serious	serious^b	none	24/350 (6.9%)	12/176 (6.8%)	RR 1.005 (0.514 to 1.966)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	24/350 (6.9%)	12/176 (6.8%)	0 fewer per 1,000 (from 33 fewer to 66 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Safety (assessed with: Adverse event leading to discontinuation of trial agent)
1	RCT	not serious	not serious	not serious	serious^b	none	15/350 (4.3%)	10/176 (5.7%)	RR 0.760 (0.350 to 1.668)	⨁⨁⨁◯ Moderate^b	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^b	none	15/350 (4.3%)	10/176 (5.7%)	14 fewer per 1,000 (from 37 fewer to 38 more)	⨁⨁⨁◯ Moderate^b	IMPORTANT
Safety (assessed with: Anemia)
1	RCT	not serious	not serious	not serious	serious^a	none	28/350 (8.0%)	8/176 (4.5%)	RR 1.704 (0.792 to 3.660)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	28/350 (8.0%)	8/176 (4.5%)	32 more per 1,000 (from 9 fewer to 121 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.Wide confidence interval range

^b.Downgrade one level as the confidence interval crosses 1 and includes both the possibility of no effect and a meaningful benefit or harm.

During the induction phase, patients receiving 45 mg upadacitinib most commonly experienced acne (6.9%) and anemia (6.3%) in the U-EXCEL trial, and nasopharyngitis (7.1%), headache (6.2%), worsening of CD (5.9%), and upper respiratory tract infections (5.2%) in U-EXCEED. Serious infections occurred in 1.1% (U-EXCEL) and 2.8% (U-EXCEED) of patients receiving upadacitinib, compared to 1.7% and 1.8% in the placebo groups, respectively. Opportunistic infections were rare, reported in 0.6% of patients in U-EXCEED. Cutaneous and nonserious herpes zoster infections occurred only in the upadacitinib groups (2.9% in U-EXCEL, 1.5% in U-EXCEED). Gastrointestinal perforation was reported in one patient (0.3%) in the U-EXCEED study. No cases of active tuberculosis, malignancies, or major cardiovascular or thromboembolic events were reported. Neutropenia and creatine kinase elevations were more frequent with upadacitinib. One death due to infectious shock occurred 159 days after premature discontinuation from U-EXCEED.[53]

The guideline panel strongly recommends upadacitinib for induction and maintenance or remission either as first-line therapy or after exposure to biologics based on moderate certainty evidence. This recommendation is attributed to the drug’s rapid onset of action, convenient oral administration, manageable safety profile, appropriate patient selection, moderate cost, and the practicality of monitoring.

Caution is advised when using the treatment for the elderly, high-risk groups, and patients with cardiovascular risk. Females of childbearing potential should use effective contraception. Additional studies on local predictive data markers or tools, safety data in real-world contexts (pharmacovigilance), local cost-effectiveness studies, and local or regional real-world evidence are warranted.

In comparison with ACG guidelines, they strongly recommend upadacitinib for the induction and maintenance of remission in patients with anti-TNF agents exposed to moderate-to-severe CD.[52] On the other hand, BSG indicated that upadacitinib, the first oral agent shown to induce and maintain remission in CD, is suggested after anti-TNF failure, intolerance, or contraindication, while its use requires caution due to safety concerns in high-risk patients and infection risks.[31]

Q7. Should SC IFX (CT-P13) vs. no treatment be used for maintenance of remission in bio-naïve patients with moderate-to-severe CD?

Recommendation 7: For maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend using SC IFX (CT-P13) over no treatment (Strong recommendation, moderate certainty evidence).

Rationale

The recommendation was developed based on phase 3 trials (LIBERTY-CD) for SC IFX (CT-P13 SC) as maintenance therapy for patients with CD over 52 weeks.[54]

The clinical remission, as assessed by the CDAI Score, was higher in the SC IFX group (RR 1.94, [1.46 to 2.58], high certainty, Table S11). Clinical remission assessed with SES-CD, SF, and abdominal pain was also greater in the IFX group (RR 1.98, [1.35 to 2.89], high certainty, Table S11). Additionally, the corticosteroid-free remission rate was higher in the SC IFX group (RR 1.77, [0.98 to 3.22], moderate certainty, Table S11). The endoscopic response, defined as a 50% decrease in SES-CD from baseline, was higher in the SC IFX group (RR 2.86, [1.89 to 4.34], high certainty, Table S11). SC IFX was effective in reducing symptom severity, achieving a CDAI-100 response compared to placebo (RR, 1.71, [1.33 to 2.20]; high certainty, Table S11).

S Table 11.

Subcutaneous infliximab (CT-P13) compared to no treatment for maintenance of remission in bio-naïve patients with moderate-to-severe CD.

Bibliography: Hanauer SB, Sands BE, Schreiber S, Danese S, Kłopocka M, Kierkuś J, et al. Subcutaneous Infliximab (CT-P13 SC) as Maintenance Therapy for Inflammatory Bowel Disease: Two Randomized Phase 3 Trials (LIBERTY). Gastroenterology [Internet]. 2024 Oct 1 [cited 2025 Apr 7];167(5):919–33. Available from: https://pubmed.ncbi.nlm.nih.gov/38788861/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	subcutaneous IFX (CT-P13)	no treatment	Relative (95% CI)	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	subcutaneous IFX (CT-P13)	no treatment	Absolute (95% CI)
Clinical remission (CDAI Score) (follow-up: 54 weeks)
2	RCT	not serious	not serious	not serious	not serious^a	none	144/231 (62.3%)	36/112 (32.1%)	302 more per 1,000 (from 148 more to 508 more)	⨁⨁⨁⨁ High^a	CRITICAL
2	RCT	not serious	not serious	not serious	not serious^a	none	144/231 (62.3%)	36/112 (32.1%)	302 more per 1,000 (from 148 more to 508 more)	⨁⨁⨁⨁ High^a	CRITICAL
Endoscopic response (follow-up: 54 weeks)
2	RCT	not serious	not serious	not serious	not serious^a	none	118/231 (51.1%)	20/112 (17.9%)	RR 2.86 (1.89 to 4.34)	⨁⨁⨁⨁ High^a	CRITICAL
2	RCT	not serious	not serious	not serious	not serious^a	none	118/231 (51.1%)	20/112 (17.9%)	332 more per 1,000 (from 159 more to 596 more)	⨁⨁⨁⨁ High^a	CRITICAL
Severity of symptoms in patients with Crohn’s disease (follow-up: 54 weeks; assessed with: CADI-100 response )
2	RCT	not serious	not serious	not serious	not serious^a	none	152/231 (65.8%)	43/112 (38.4%)	RR 1.71 (1.33 to 2.20)	⨁⨁⨁⨁ High^a	IMPORTANT
2	RCT	not serious	not serious	not serious	not serious^a	none	152/231 (65.8%)	43/112 (38.4%)	273 more per 1,000 (from 127 more to 461 more)	⨁⨁⨁⨁ High^a	IMPORTANT
Corticosteroids free remission (follow-up: 54 weeks)
2	RCT	not serious	not serious	not serious	serious^b	none	40/99 (40.4%)	10/44 (22.7%)	RR 1.77 (0.98 to 3.22)	⨁⨁⨁◯ Moderate^b	IMPORTANT
2	RCT	not serious	not serious	not serious	serious^b	none	40/99 (40.4%)	10/44 (22.7%)	175 more per 1,000 (from 5 fewer to 505 more)	⨁⨁⨁◯ Moderate^b	IMPORTANT
Clinical remission (assessed with: Simplified Endoscopic Activity Score for Crohn’s Disease (SF) and Abdominal pain)
2	RCT	not serious	not serious	not serious	not serious^a	none	131/231 (56.7%)	35/112 (31.3%)	RR 1.98 (1.35 to 2.89)	⨁⨁⨁⨁ High^a	IMPORTANT
2	RCT	not serious	not serious	not serious	not serious^a	none	131/231 (56.7%)	35/112 (31.3%)	306 more per 1,000 (from 109 more to 591 more)	⨁⨁⨁⨁ High^a	IMPORTANT
Patients with 1 or more treatment-emergent adverse event (TEAE)
2	RCT	not serious	not serious	not serious	serious^c	none	172/238 (72.3%)	65/105 (61.9%)	RR 1.0970 (0.8780 to 1.3705)	⨁⨁⨁◯ Moderate^c	CRITICAL
2	RCT	not serious	not serious	not serious	serious^c	none	172/238 (72.3%)	65/105 (61.9%)	60 more per 1,000 (from 76 fewer to 229 more)	⨁⨁⨁◯ Moderate^c	CRITICAL
Patients with 1 or more treatment-emergent serious adverse event
2	RCT	not serious	not serious	not serious	serious^a	none	16/238 (6.7%)	8/105 (7.6%)	RR 0.890 (0.392 to 2.019)	⨁⨁⨁◯ Moderate^a	IMPORTANT
2	RCT	not serious	not serious	not serious	serious^a	none	16/238 (6.7%)	8/105 (7.6%)	8 fewer per 1,000 (from 46 fewer to 78 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Patients with one or more TEAE leading to study drug discontinuation
2	RCT	not serious	not serious	not serious	serious^c	none	9/238 (3.8%)	5/105 (4.8%)	RR 0.453 (0.134 to 1.532)	⨁⨁⨁◯ Moderate^c	IMPORTANT
2	RCT	not serious	not serious	not serious	serious^c	none	9/238 (3.8%)	5/105 (4.8%)	26 fewer per 1,000 (from 41 fewer to 25 more)	⨁⨁⨁◯ Moderate^c	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.Wide confidence interval range

^b.small sample size

^c.Downgrade one level for crossing the line of no effect

The safety profile was comparable between both groups for patients with one or more treatment-emergent adverse events (TEAE) (RR 1.0970, [0.8780 to 1.3705, moderate certainty, Table S11), for patients with one or more TEAE (RR 0.890, [0.392 to 2.019, moderate certainty, Table S11), and for patients with one or more TEAE leading to study drug discontinuation (RR 0.453, [0.134 to 1.532, moderate certainty, Table S11).

Based on moderate certainty evidence, the guideline panel strongly recommends using SC IFX (CT-P13) to maintain remission in CD. This recommendation underscores the advantageous balance between beneficial effects and potential AEs and its cost-effectiveness, which is enhanced by moderate savings compared to IV alternatives.[55] Similarly, ACG guidelines strongly recommend SC IFX as a treatment option for maintenance of remission among those with moderately to severely active CD who respond to IV induction with IFX.[52]

Q8. Should treatment with biosimilars of anti-TNF agents or anti-IL-12/23 vs. no treatment be used to induce and maintain remission in conventional therapy-exposed patients with moderate-to-severe CD?

Recommendation 8: For induction and maintenance of remission in conventional therapy-exposed adults with moderate-to-severe CD, we recommend using biosimilars of TNF agents or anti-IL-12/23 over no treatment (Strong recommendation, moderate certainty evidence).

Rationale

This recommendation was supported by an RCT (the LIBERTY trial), which evaluated the superior efficacy of a biosimilar of IFX (CT-P13) as maintenance therapy compared to a placebo, among 396 active CD patients with low response to corticosteroids and immunomodulatory therapy. It demonstrated the superiority of CS CT-P13 for clinical and endoscopic remission at week 54, assessed by CDAI <150.[54]

The clinical remission rate, assessed by a CDAI score of <150, significantly differed between the two groups (RR 1.93, [1.45 to 2.58], Table S12). The proportion of patients with a decrease in CDAI score of ≥ 100 points from baseline was higher among patients receiving CT-P13 than among those receiving placebo (RR 1.94, [1.45 to 2.58], moderate certainty, Table S12).[54]

S Table 12.

Treatment with biosimilars of anti-tumor necrosis factor [TNF] agents or Anti-IL-12/23 compared to no treatment for inducing and maintaining remission in conventional therapy-exposed patients with moderate-to-severe CD.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	treatment with biosimilars of [TNF] agents or Anti-IL-12/23	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	treatment with biosimilars of [TNF] agents or Anti-IL-12/23	no treatment	Absolute (95% CI)
Clinical remission (follow-up: 54 weeks; assessed with: CDAI)
1	RCT	not serious	not serious	not serious	serious^a,b	none	144/231 (62.3%)	36/112 (32.1%)	RR 1.93 (1.45 to 2.58)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a,b	none	144/231 (62.3%)	36/112 (32.1%)	299 more per 1,000 (from 145 more to 508 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
CDAI-100 response (follow-up: 54 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	152/231 (65.8%)	43/112 (38.4%)	RR 1.94 (1.45 to 2.58)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a,b	none	152/231 (65.8%)	43/112 (38.4%)	361 more per 1,000 (from 173 more to 607 more)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
Endoscopic response (follow-up: 54 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	118/231 (51.1%)	20/112 (17.9%)	RR 2.86 (1.88 to 4.34)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a,b	none	118/231 (51.1%)	20/112 (17.9%)	332 more per 1,000 (from 157 more to 596 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
clinical remission (follow-up: 54 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	131/231 (56.7%)	35/112 (31.3%)	RR 1.81 (1.35 to 2.44)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a,b	none	131/231 (56.7%)	35/112 (31.3%)	253 more per 1,000 (from 109 more to 450 more)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
Endoscopic remission (follow-up: 54 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	80/231 (34.6%)	12/112 (10.7%)	RR 3.23 (1.84 to 5.67)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a,b	none	80/231 (34.6%)	12/112 (10.7%)	239 more per 1,000 (from 90 more to 500 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
Corticosteroid-free remission (follow-up: 54 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	40/99 (40.4%)	10/44 (22.7%)	RR 1.78 (0.98 to 3.22)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a,b	none	40/99 (40.4%)	10/44 (22.7%)	177 more per 1,000 (from 5 fewer to 505 more)	⨁⨁⨁◯ Moderate^a,b	IMPORTANT
Treatment-emergent adverse event
1	RCT	not serious	not serious	not serious	serious^a	none	172/238 (72.3%)	65/105 (61.9%)	RR 1.16 (0.98 to 1.38)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	172/238 (72.3%)	65/105 (61.9%)	99 more per 1,000 (from 12 fewer to 235 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Treatment-emergent serious adverse event
1	RCT	not serious	not serious	not serious	serious^a	none	16/238 (6.7%)	8/105 (7.6%)	RR 0.88 (0.38 to 1.99)	⨁⨁⨁◯ Moderate^a	⨁⨁⨁◯ Moderate^a
1	RCT	not serious	not serious	not serious	serious^a	none	16/238 (6.7%)	8/105 (7.6%)	9 fewer per 1,000 (from 47 fewer to 75 more)	⨁⨁⨁◯ Moderate^a	⨁⨁⨁◯ Moderate^a

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CI: confidence interval; RR: risk ratio

Explanations

^a.small sample size

^b.Wide CI

Additionally, endoscopic response and remission were superior in the SC CT-P13 group (RR 2.86, [1.88 to 4.34], Table S12) and the SC CT-P13 group (RR 3.23, [1.84 to 5.67], Table S12), respectively. Moreover, 40.4% of patients receiving SC CT-P13 achieved corticosteroid-free clinical remission, compared to 22.7% of patients in the placebo group (RR 1.78, [0.98–3.22], moderate certainty, Table S12). Treatment-emergent serious adverse events (TESAEs) were lower with SC CT-P13 (RR 1.16, [0.98 to 1.38], moderate certainty, Table S12) and (RR 0.88, [0.38 to 1.99], moderate certainty, Table S12), respectively.[54]

In another RCT, CT-P13 was not inferior to the originator IFX regarding CDAI-70 response, clinical remission, CDAI-100 response, and steroid-free remission. Furthermore, both drugs were well tolerated throughout the study, with no clinically meaningful differences in immunogenicity.[56] Several ustekinumab biosimilars have been introduced recently.[57] Their approvals in various jurisdictions were primarily based on phase III clinical trials conducted in patients with psoriasis, which demonstrated safety and efficacy profiles comparable to the reference product.[58,59] However, real-world evidence on their use in IBD remains limited.

The guideline panel strongly recommends using biosimilars of anti-TNF agents or anti-IL-12/23 therapies for patients with CD. These options provide significant clinical benefits while considering cost-effectiveness, feasibility, acceptability, and the balance of desirable vs. minor undesirable effects. Comparative studies examining these therapeutic approaches against a no-treatment control group are crucial for establishing their clinical benefits, optimizing treatment strategies, and enhancing long-term outcomes for individuals with CD.

ACG guidelines mention that biosimilars, such as IFX, ADA, and ustekinumab, are effective options for patients with moderate-to-severe CD, which can be used for both de novo induction and maintenance therapy.[52] BSG guidelines issued a strong recommendation for IFX and ADA biosimilars and a conditional recommendation for ustekinumab among patients with moderate-to-severe CD.[31]

Treatment for Advanced Therapy Exposed Adults with Moderate-to-Severe CD

Q9. Should switching to another anti-TNF agent vs. no treatment be used to optimize the management of the disease in CD patients with secondary loss of response to anti-TNF therapy (and not primary treatment failure) due to developing Anti-Drug Antibodies (ADAs)?

Recommendation 9: In CD patients with secondary loss of response to anti-TNF therapy (not primary treatment failure) due to developing ADAs, we suggest switching to another anti-TNF agent over switching to another class of medications to optimize the disease control (Conditional recommendation, very low certainty evidence).

Rationale

A recent SR and MA examining 46 studies provided the evidence base for this recommendation by assessing the efficacy and safety outcomes when CD patients with prior anti-TNF treatment failure were switched to alternative anti-TNF agents like IFX, ADA, or CZP.[60]

A high remission rate was observed in patients with CD who switched to ADA or CZP after secondary failure of IFX (relative remission rate 0.45, [0.34 to 0.57], very low certainty, Table S13). The study also evaluated the impact of the ADA induction dose on response and remission rates, reporting that the remission rate for switching from IFX to the ADA dose of 160/80 was 51% (relative remission rate, 0.51; [0.32 to 0.70]; very low certainty, Table S13).

S Table 13.

Switching to another anti-TNF agent compared to no treatment for optimizing the management of the disease in CD patients with secondary loss of response to anti-TNF therapy (and not primary treatment failure) due to developing Anti-Drug Antibodies (ADAs)

Bibliography: Gisbert JP, Marín AC, McNicholl AG, Chaparro M. Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed. Aliment Pharmacol Ther [Internet]. 2015 Apr 1 [cited 2025 Apr 6];41(7):613–23. Available from: https://pubmed.ncbi.nlm.nih.gov/25652884/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	switching to another anti-TNF agent	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	switching to another anti-TNF agent	no treatment	Absolute (95% CI)
Pooled remission rate (Switch to adalimumab (ADA) and certolizumab-pegol (CZP) after secondary failure of infliximab (IFX))
11	non-RCT	very serious^a	serious^b	serious^c	serious^d	none	367/814 (45.1%)		Remission rate 0.45 (0.34 to 0.57)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
11	non-RCT	very serious^a	serious^b	serious^c	serious^d	none	367/814 (45.1%)		-- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
Remission rate (infliximab (IFX) switch to Adalimumab (ADA) dose of 160/80)
6	non-RCT	very serious^a	serious^b	serious^c	serious^d	dose response gradient	249/488 (51.0%)		Remission rate 0.51 (0.32 to 0.70)	⨁◯◯◯ Very low^a,b,c,d	CRITCAL
6	non-RCT	very serious^a	serious^b	serious^c	serious^d	dose response gradient	249/488 (51.0%)		-- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b,c,d	CRITCAL
Remission rate (infliximab (IFX) switch to Adalimumab (ADA) dose of 80/40)
3	non-RCT	very serious^a	not serious	serious^c	serious^d	dose response gradient	47/107 (43.9%)		Remission rate 0.44 (0.30 to 0.58)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
3	non-RCT	very serious^a	not serious	serious^c	serious^d	dose response gradient	47/107 (43.9%)		-- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
Response rates (switching from IFX to ADA)
8	non-RCT	very serious^a	serious^b	serious^c	serious^d	none	172/246 (69.9%)		Response rate 0.70 (0.49 to 0.91)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
8	non-RCT	very serious^a	serious^b	serious^c	serious^d	none	172/246 (69.9%)		-- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
Response rates (switching from IFX to certolizumab-pegol (CZP))
3	non-RCT	very serious^a	serious^b	serious^c	not serious	none	421/1026 (41.0%)		Response rate 0.41 (0.07 to 0.76)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
3	non-RCT	very serious^a	serious^b	serious^c	not serious	none	421/1026 (41.0%)		-- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
Response rate with 160/80 ADA dose
2	non-RCT	very serious^a	not serious	serious^c	serious^d	none	73/90 (81.1%)		Response rate 0.81 (0.72 to 0.90)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
2	non-RCT	very serious^a	not serious	serious^c	serious^d	none	73/90 (81.1%)		-- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
Response rate with 80/40 ADA dose
2	non-RCT	very serious^a	serious^e	serious^c	serious^d	none	23/35 (65.7%)		Response rate 0.66 (0.44 to 0.87)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
2	non-RCT	very serious^a	serious^e	serious^c	serious^d	none	23/35 (65.7%)		-- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
Remission rate (infliximab (IFX) switch to Adalimumab (ADA) (long-term) (follow-up: range 41 weeks to 52 weeks)
11	non-RCT	very serious^a	serious^f	serious^c	serious^d	none			remission rate 0.6 (0.4 to 0.8)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
11	non-RCT	very serious^a	serious^f	serious^c	serious^d	none			-- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
Remission rate (infliximab (IFX) switch to Adalimumab (ADA) (medium-term) (follow-up: range 9 weeks to 40 weeks)
11	non-RCT	very serious^a	not serious	serious^c	serious^d	none			remission rate 0.38 (0.30 to 0.45)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
11	non-RCT	very serious^a	not serious	serious^c	serious^d	none			-- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
Remission rate (infliximab (IFX) switch to Adalimumab (ADA) (short-term) (follow-up: range 4 weeks to 8 weeks)
11	non-RCT	very serious^a	serious^e	serious^c	serious^d	none			remission rate 0.41 (0.20 to 0.61)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL
11	non-RCT	very serious^a	serious^e	serious^c	serious^d	none			-- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b,c,d	CRITICAL

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CI: confidence interval

Explanations

^a.Most studies are retrospective cohorts with potential detection, misclassification, or confounding bias.

^b.Substantial heterogeneity

^c.No comparator

^d.Number of events below 400

^e.I2=87%

^f.I2=48%

Response rates for switching from IFX to ADA (relative response rate 0.70, [0.49 to 0.91], very low certainty, Table S13) were higher than those obtained after switching to CZP (relative response rate 0.41, [0.07 to 0.76], very low certainty, Table S13).[60]

Based on the follow-up periods, higher remission rates were reported in the longer follow-ups (41–52 weeks) (relative remission rate 0.60, [0.40 to 0.80], very low certainty, Table S13) compared to short-term (4–8 weeks) (relative remission rate 0.41, [0.20 to 0.61], very low certainty, Table S13) and medium-term periods (9–40 weeks) (relative remission rate 0.38, [0.30 to 0.45], very low certainty, Table S13).[60]

The expert guideline panel strongly advocates for the implementation of combination therapy by incorporating an immunosuppressive agent when clinicians decide to switch patients to a second anti-TNF medication, as this therapeutic strategy significantly reduces the likelihood of patients developing subsequent immunogenicity reactions against the newly introduced anti-TNF agent. Supporting this recommendation, a well-designed RCT specifically investigated the comparative effectiveness of switching to a second anti-TNF therapy while simultaneously adding azathioprine to the treatment regimen, with comprehensive patient monitoring conducted over an extended 2-year follow-up period among IBD patients who had previously experienced immune-mediated loss of therapeutic response to their initial anti-TNF treatment. The trial results clearly demonstrated that this combination therapy approach was directly associated with significantly more favorable clinical outcomes and sustained therapeutic response rates following the switch to anti-TNF medication.[61]

The very low certainty evidence, combined with moderate desirable effects with minor undesirable effects, and the balance of effects likely favoring the intervention, were the reasons for conditionally recommending switching to another anti-TNF agent over switching to another class, for CD patients with secondary loss of response to anti-TNF therapy.

The guideline panel highlights that switching to a biologic or a small molecule with an alternative mechanism of action can be appropriate in certain settings, particularly where a combination of immunomodulators and anti-TNF is not desirable. This recommendation aligns with the AGA guideline, which recommends using ADA or ustekinumab after secondary nonresponse to IFX, depending on the literature and therapeutic drug monitoring (TDM).[15]

Q10. Should switching outside the anti-TNF class to another advanced therapy, vs. no treatment, be used for clinical remission in CD patients who do not respond to anti-TNF therapy, although having adequate serum drug levels and negative ADAs?

Recommendation 10: For induction and maintenance of clinical remission in adult patients with moderate-to-severe CD who do not respond to anti-TNF therapy despite adequate serum drug levels and negative ADAs, we suggest switching to an advanced therapy outside the anti-TNF class over switching to another anti-TNF agent (Conditional recommendation, low certainty evidence).

Rationale

Anti-TNF agents are effective in the management of CD. However, about 10% to 30% of patients are not responsive to initial therapy, and 23% to 46% of patients may gradually lose their response.[62] A previous prospective study has found that patients with adequate trough levels at the time of loss or response may not benefit from dose intensification or switching to another anti-TNF agent, and switching outside the anti-TNF class may be beneficial.[63] In such cases, switching to drugs with different mechanisms of action may be considered.[64]

Patients with primary or secondary nonresponse to anti-TNF agents or those experiencing unacceptable side effects had significantly higher response rates when treated with IV ustekinumab. Clinical response rates demonstrated significant therapeutic superiority for ustekinumab treatment, with the two active dosing regimens achieving response rates of 34.3% and 33.7%, respectively, both substantially outperforming the placebo group’s 21.5% response rate, with statistical significance confirmed for both comparisons (P ≤ 0.003). During the extended maintenance phase evaluation at week 44, patients receiving ustekinumab maintenance therapy administered every 8 weeks achieved a remission rate of 53.1%, while those on the 12-week dosing schedule demonstrated a 48.8% remission rate, both significantly superior to the placebo cohort’s 35.9% remission rate, with statistical significance established at P = 0.005 and P = 0.04, respectively, indicating sustained therapeutic benefit across both maintenance dosing intervals.[40]

An updated meta-analysis of the CERTIFI and UNITI-1 clinical trials has confirmed the superior efficacy of ustekinumab over placebo regarding clinical response and clinical remission, with a comparable safety profile among CD patients experiencing primary or secondary failure to anti-TNF agents or intolerance.[65,66]

The recommendation was supported by a phase 3 RCT (GEMINI 3) that investigated the efficacy and safety of switching to VDZ after anti-TNF failure as induction therapy compared to placebo in CD, revealing that switching to another advanced therapy, such as VDZ, demonstrates more clinical remission over a more extended induction period at 10 weeks.[67]

The clinical remission rate was significantly higher after switching to VDZ in week 10 (RR 2.2, [1.3 to 3.6], low certainty, Table S14). Although the effect was lower at 6 weeks, it still had a marginally higher clinical remission rate than no treatment (RR 1.2, [0.7 to 2.2], low certainty, Table S14).[67]

S Table 14.

Switching outside the anti-TNF class to another advanced therapy compared to no treatment for clinical remission in CD patients who do not respond to anti-TNF therapy, although having adequate serum drug levels and negative ADAs.

Bibliography: Marsal J, Barreiro-de Acosta M, Blumenstein I, Cappello M, Bazin T, Sebastian S. Management of Non-response and Loss of Response to Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Front Med. 2022 Jun;9.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	switching outside the anti-TNF class to another advanced therapy	no treatment	Relative (95% CI)	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations		no treatment	Absolute (95% CI)
Clinical remission at week 6
1	RCT	not serious	not serious	not serious	very serious^a	none	24/158 (15.2%)	19/157 (12.1%)	RR 1.2 (0.7 to 2.2)	⨁⨁◯◯ Low^a	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a	none	24/158 (15.2%)	19/157 (12.1%)	24 more per 1,000 (from 36 fewer to 145 more)	⨁⨁◯◯ Low^a	CRITICAL
Clinical remission at week 10
1	RCT	not serious	not serious	not serious	very serious^a	none	42/158 (26.6%)	19/157 (12.1%)	RR 2.2 (1.3 to 3.6)	⨁⨁◯◯ Low^a	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a	none	42/158 (26.6%)	19/157 (12.1%)	145 more per 1,000 (from 36 more to 315 more)	⨁⨁◯◯ Low^a	CRITICAL
Crohn’s Disease Activity Index (CDAI-100) response at week 6
1	RCT	not serious	not serious	not serious	very serious^a	none	62/158 (39.2%)	35/157 (22.3%)	RR 1.8 (1.2 to 2.5)	⨁⨁◯◯ Low^a	IMPORTANT
1	RCT	not serious	not serious	not serious	very serious^a	none	62/158 (39.2%)	35/157 (22.3%)	178 more per 1,000 (from 45 more to 334 more)	⨁⨁◯◯ Low^a	IMPORTANT
CDAI-100 response at week 10
1	RCT	not serious	not serious	not serious	very serious^a	none	74/158 (46.8%)	39/157 (24.8%)	RR 1.9	⨁⨁◯◯ Low^a	IMPORTANT
1	RCT	not serious	not serious	not serious	very serious^a	none	74/158 (46.8%)	39/157 (24.8%)	224 more per 1,000 (from 99 more to 397 more)	⨁⨁◯◯ Low^a	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.Total number of events is below 400

A separate prospective registry investigation conducted a comparative efficacy analysis between ustekinumab and VDZ therapies, specifically among patients with CD who had previously experienced failure of anti-TNF treatment. The study findings revealed that patients receiving ustekinumab therapy demonstrated significantly enhanced likelihood of achieving sustained corticosteroid-free clinical remission compared to those treated with VDZ, suggesting superior therapeutic outcomes for ustekinumab in this challenging patient population with prior biologic treatment resistance (OR 2.58; [1.36 to 4.90]; P = 0.004) and biochemical remission (OR: 2.34, [1.10 to 4.96], P = 0.027), compared with those treated with VDZ, with a comparable safety profile.[68]

A local retrospective study found that the clinical response rate among ustekinumab-treated CD patients was 76.7%, with 70% achieving remission at week 52 measured by the Harvey–Bradshaw Index (HBI) score. The corticosteroid-free remission rates were 76.7% at week 12 and 86.7% at week 52.[69]

Upadacitinib is another out-of-class alternative for CD patients with anti-TNF failure. A recent retrospective study reported clinical remission rates of 58% in week 12, 43% in week 24, and 52% in the last observation.[70]

Anti-TNF agents effectively induce and maintain remission, reducing the need for surgery and hospitalizations.[71,72,73] In cases of primary nonresponse to anti-TNF therapy, the panel recommends switching to an alternative anti-TNF or opting for an out-of-class switch, which has been shown to restore clinical remission.

While long-term data continue to evolve, current evidence supports this approach as an effective strategy for improving outcomes in refractory cases. Given the moderately desirable effects, moderate resource implications, and likely favorable cost-effectiveness, the panel issued a conditional recommendation for switching to another advanced therapy outside the anti-TNF class in cases of primary nonresponse. This recommendation aligns with the AGA guideline, which strongly recommends ustekinumab and conditionally recommends switching to VDZ among adults with CD and primary anti-TNF nonresponse.[15]

The panel emphasizes that in some patients, anti-TNF therapy may not be effective, due to either a primary nonresponse or a subsequent loss of response. TDM, which measures serum drug levels and anti-drug antibodies, can help guide adjustments in treatment.

For patients with low drug concentrations and minimal or absent anti-drug antibodies, dose escalation is recommended. If the response remains inadequate after dose escalation, clinicians should switch to another drug with a different treatment mechanism.

Q11. Should anti-IL-23 vs. anti-IL 12/23 be used for induction and maintenance of remission in patients with moderate-to-severe CD who have previously failed anti-TNF therapy?

Recommendation 11: For induction and maintenance of remission in adults with moderate-to-severe CD who have previously failed anti-TNF therapy, we recommend using anti-IL-23 over anti-IL-12/23 (Strong recommendation, moderate certainty evidence).

Rationale

This recommendation was based on a phase 3b open-label RCT (SEQUENCE).[74]

RZB demonstrated superior efficacy outcomes compared to ustekinumab after 24 and 48 weeks of follow-up. The clinical remission rate at 24 weeks was better (RR 1.47, [1.23 to 1.76], high certainty, Table S15), which remained favorable at 48 weeks (RR 1.49, [1.25 to 1.77], high certainty, Table S15) in the RZB group. Endoscopic outcomes, including remission at 48 weeks (RR 1.95, [1.41 to 2.70], moderate certainty, Table S15), response at 24 weeks (RR 1.70, [1.39 to 2.17], high certainty, Table S15), and 48 weeks (RR 2.06, [1.58 to 2.68], moderate certainty, Table S15) were also higher in the RZB group.

S Table 15.

Anti-IL23 compared to anti-IL 12/23 for induction and maintenance of remission in patients with moderate-to-severe CD who have previously failed anti-TNF therapy.

Bibliography: Peyrin-Biroulet L, Chapman JC, Colombel JF, Caprioli F, D’Haens G, Ferrante M, et al. Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease. N Engl J Med [Internet]. 2024 Jul 18 [cited 2025 Apr 6];391(3):213–23. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2314585

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	anti-IL23	anti-IL 12/23	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	anti-IL23	anti-IL 12/23	Absolute (95% CI)
Clinical remission (follow-up: 24 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	149/255 (58.4%)	105/265 (39.6%)	RR 1.47 (1.23 to 1.76)	High ⨁⨁⨁⨁	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	149/255 (58.4%)	105/265 (39.6%)	186 more per 1,000 (from 91 more to 301 more)	High ⨁⨁⨁⨁	CRITICAL
Endoscopic remission (follow-up: 48 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	81/255 (31.8%)	43/265 (16.2%)	154 more per 1,000 (from 67 more to 276 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	81/255 (31.8%)	43/265 (16.2%)	154 more per 1,000 (from 67 more to 276 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Endoscopic response (follow-up: 48 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	115/255 (45.1%)	58/265 (21.9%)	RR 2.06 (1.58 to 2.68)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	115/255 (45.1%)	58/265 (21.9%)	232 more per 1,000 (from 127 more to 368 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Glucocorticoid-free endoscopic remission (follow-up: 48 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	80/255 (31.4%)	41/265 (15.5%)	RR 2.00 (1.45 to 2.83)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	80/255 (31.4%)	41/265 (15.5%)	155 more per 1,000 (from 70 more to 283 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Glucocorticoid-free clinical remission (follow-up: 24 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	155/255 (60.8%)	107/265 (40.4%)	RR 1.50 (1.26 to 1.79)	High ⨁⨁⨁⨁	IMPORTANT
1	RCT	not serious	not serious	not serious	not serious	none	155/255 (60.8%)	107/265 (40.4%)	202 more per 1,000 (from 105 more to 319 more)	High ⨁⨁⨁⨁	IMPORTANT
Clinical remission (follow-up: 48 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	155/255 (60.8%)	108/265 (40.8%)	RR 1.49 (1.25 to 1.77)	High ⨁⨁⨁⨁	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	155/255 (60.8%)	108/265 (40.8%)	200 more per 1,000 (from 102 more to 314 more)	High ⨁⨁⨁⨁	CRITICAL
Endoscopic response (follow-up: 24 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	115/255 (45.1%)	70/265 (26.4%)	RR 1.70 (1.39 to 2.17)	High ⨁⨁⨁⨁	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	115/255 (45.1%)	70/265 (26.4%)	185 more per 1,000 (from 103 more to 309 more)	High ⨁⨁⨁⨁	CRITICAL
Any adverse events
1	RCT	not serious	not serious	not serious	not serious	none	223/262 (85.1%)	219/265 (82.6%)	RR 1.029 (0.950 to 1.110)	High ⨁⨁⨁⨁	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	223/262 (85.1%)	219/265 (82.6%)	24 more per 1,000 (from 41 fewer to 91 more)	High ⨁⨁⨁⨁	CRITICAL

Open in a new tab

CI: confidence interval; RR: risk ratio

Explanations

^a.Wide confidence interval

The safety profile was comparable, with no significant difference in AEs between both groups (RR 1.03, [0.95 to 1.11], high certainty, Table S15).

The pooled analysis of the Phase 3 GALAXI 2 and 3 studies revealed that guselkumab demonstrated greater efficacy than ustekinumab in patients with moderately to severely active CD. At week 48, both guselkumab dosing regimens (100 mg SC q8w and 200 mg SC q4w) demonstrated statistical superiority over ustekinumab across critical endpoints, including endoscopic response (10.6% and 15.6%, respectively), endoscopic remission (8.5% and 12.3%), deep remission (7.4% and 11.3%), and the composite of clinical remission plus endoscopic response (7.8% and 13.6%). The observed differences were clinically substantial and statistically significant (P < 0.001), but the safety profiles of guselkumab and ustekinumab were equivalent. The results indicate that GUS may serve as a more efficacious therapeutic alternative for CD, demonstrating superior mucosal healing and improved long-term outcomes compared to UST.[48]

A recent meta-analysis has compared different anti-IL-23, including RZB, guselkumab, and mirikizumab, with ustekinumab. The study revealed that anti-IL-23 agents were more effective among patients with prior biologic exposure (clinical remission: RR 1.31, [1.16 to 1.48]; endoscopic remission: RR 1.61, [1.27 to 2.05]). They were also associated with a lower risk of SAEs than ustekinumab (RR 0.79, [0.61 to 1.02]).[75]

The VIVID-1 trial demonstrated that mirikizumab was noninferior to ustekinumab in achieving clinical remission, as measured by CDAI, at week 52. Additionally, mirikizumab did not show superiority over ustekinumab in terms of endoscopic response at the same timepoint. However, a higher percentage of patients in the mirikizumab group reached the combined endpoints at week 52 compared to those receiving ustekinumab. Since both endpoints are important for patients and clinicians, achieving both simultaneously is critical.[50]

Furthermore, mirikizumab exhibited a numerical trend toward higher response rates compared to ustekinumab, particularly among patients who had previously failed biologics.[50] These findings further confirm the favorable benefit–risk profile of anti-IL-23 over anti-IL-12/23 among patients with moderate-to-severe CD, regardless of previous failure to biologics.

Based on moderate certainty evidence, along with moderate desirable effects, minor undesirable effects, achieving effect balance favoring anti-IL-23, and moderate cost, the guideline strongly recommends using anti-IL-23 over anti-IL-12/23 for induction and maintenance of remission in CD patients, especially those with previously failed anti-TNF therapy.

Similarly, BSG guidelines suggest the use of RZB in patients with moderate-to-severe CD with an inadequate response or loss of response to a prior advanced therapy, intolerance to other advanced therapies, or for whom anti-TNF therapy is not appropriate.[31] They also indicated that Ustekinumab can be used after failure of anti-TNF failure.[31]

Combination Therapies for Adults with Moderate-to-Severe CD

Q12. Should combination therapy with an immunomodulator and IFX vs. IFX monotherapy be used for the induction of remission in patients with moderate-to-severe CD?

Recommendation 12: For the induction of remission in adults with moderate-to-severe CD, we suggest combination therapy with immunomodulators and IFX over IFX monotherapy (Conditional recommendation, Moderate certainty evidence).

Rationale

This recommendation was based on an RCT (the SONIC trial), which compared the efficacy and safety of IFX plus thiopurine (azathioprine) with those of IFX and azathioprine monotherapy in patients with CD who have not previously received any biologics or immunomodulators.[76]

Combination therapy with IFX-azathioprine demonstrated higher corticosteroid-free remission rates compared to IFX monotherapy in CD patients (RR 1.15, [0.89 to 1.47], moderate certainty, Table S16) and mucosal healing (RR 1.55, [1.06 to 2.27], moderate certainty, Table S16). Clinical remission and clinical response, assessed by a reduction of ≥100 points in the CDAI score, were also more significant in the IFX-azathioprine group compared to IFX alone (RR 1.52, [0.97 to 1.60], moderate certainty, Table S16) and (RR 1.21, [0.96 to 1.53], moderate certainty, Table S16), respectively. Furthermore, the rate of AEs was comparable between both groups (RR 1.00, [0.94 to 1.08], moderate certainty, Table S16).[76]

S Table 16.

Combination therapy with an immunomodulator and IFX compared to IFX monotherapy for the induction of remission in patients with moderate-to-severe CD.

Bibliography: Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. Infliximab, Azathioprine, or Combination Therapy for Crohn’s Disease. N Engl J Med. 2010 Apr;362(15):1383–95.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	combination with an immune modulator and IFX	IFX alone	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	combination with an immune modulator and IFX	IFX alone	Absolute (95% CI)
Adverse events (Infliximab + azathioprine vs Infliximab)
3	RCT	not serious	not serious	not serious	serious^a	none			OR 0.56 (0.33 to 0.97)	⨁⨁⨁◯ Moderate^b	IMPORTANT
3	RCT	not serious	not serious	not serious	serious^a	none			1 fewer per 1,000 (from 1 fewer to 0 fewer)	⨁⨁⨁◯ Moderate^b	IMPORTANT
Corticosteroid-free remission (follow-up: 42 weeks)
1	RCT	not serious	not serious	not serious	serious^b	none	77/169 (45.6%)	67/169 (39.6%)	RR 1.15 (0.89 to 1.47)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	77/169 (45.6%)	67/169 (39.6%)	59 more per 1,000 (from 44 fewer to 186 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Mucosal healing
1	RCT	not serious	not serious	not serious	serious^b	none	47/107 (43.9%)	28/99 (28.3%)	RR 1.55 (1.06 to 2.27)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	47/107 (43.9%)	28/99 (28.3%)	156 more per 1,000 (from 17 more to 359 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Any adverse events
1	RCT	not serious	not serious	not serious	serious^b	none	161/179 (89.9%)	145/163 (89.0%)	RR 1.00 (0.94 to 1.08)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	161/179 (89.9%)	145/163 (89.0%)	0 fewer per 1,000 (from 53 fewer to 71 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Clinical remission (follow-up: 50 weeks)
1	RCT	not serious	not serious	not serious	serious^b	none	80/169 (47.3%)	64/169 (37.9%)	RR 1.52 (0.97 to 1.60)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	80/169 (47.3%)	64/169 (37.9%)	197 more per 1,000 (from 11 fewer to 227 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Clinical response (follow-up: 50 weeks; assessed with: Reuction of more than 100 point in CDAI score)
1	RCT	not serious	not serious	not serious	serious^b	none	85/169 (50.3%)	70/169 (41.4%)	RR 1.21 (0.96 to 1.53)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	85/169 (50.3%)	70/169 (41.4%)	87 more per 1,000 (from 17 fewer to 220 more)	⨁⨁⨁◯ Moderate^b	CRITICAL

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CI: confidence interval; OR: odds ratio; RR: risk ratio

Explanations

^a.Findings are based on network meta-analysis and the number of patients in each group is not reported

^b.small sample size

The combination therapy of IFX plus azathioprine increased serious and opportunistic infections compared with IFX monotherapy (HR, 1.23, [1.05 to 1.45]) and (HR, 1.96, [1.32 to 2.91]), respectively.[77] The meta-analysis by Siegel et al.[78] and the nationwide cohort study by Lemaitre et al.[79] found a higher risk of lymphoma with combination therapy (anti-TNF + thiopurines) compared to monotherapy. The combination therapy had a standardized incidence ratio of 3.23 for lymphoma compared to the general population, exceeding the risk with immunomodulators alone.[78]

MTX is a safer option than azathioprine for individuals who are intolerant to azathioprine or at high risk of azathioprine-related adverse effects, especially young males with an increased risk of hepatosplenic T-cell lymphoma (HSTCL).[80] In contrast to thiopurines, MTX is not associated with HSTCL, rendering it a more favorable choice for this population; however, its teratogenic effects require stringent contraception for women of reproductive potential. MTX necessitates folate supplementation and consistent liver monitoring due to possible hepatotoxicity; however, it circumvents azathioprine-related concerns, including pancreatitis and severe myelosuppression.[81]

Based on moderate certainty of evidence, the guideline panel conditionally recommends IFX-azathioprine combination therapy for remission induction in biologic-bio-naïve CD patients. This recommendation aligns with the ECCO, ACG, and BSG guidelines that strongly recommend the IFX-thiopurine combination for at least 6 to 12 months.[17] It also aligns with AGA guidelines recommending combining over monotherapy.[15]

Q13. Should the combination therapy of immunomodulators (thiopurine) with SC IFX (CT-P13) vs. SC IFX (CT-P13) without immunomodulators be used to maintain remission in patients with moderate-to-severe CD?

Recommendation 13: For maintenance of remission in adults with moderate-to-severe CD, we suggest SC IFX (CT-P13) monotherapy over SC IFX (CT-P13) in combination with immunomodulators (thiopurine) (Conditional recommendation, very low certainty evidence).

Rationale

A post hoc analysis of the pivotal trial comparing the combination therapy of SC IFX with immunosuppressants (azathioprine, 6-mercaptopurine, or methotrexate) to SC IFX monotherapy demonstrated that the combination therapy may offer comparable efficacy and safety to monotherapy in CD patients.[82]

Combination therapy yields marginally higher clinical remission rates (RR 1.10, [0.69 to 1.76], very low certainty, Table S17), but lower mucosal healing rates (RR 0.95, [0.62 to 1.47], very low certainty, Table S17). Efficacy was assessed with CDAI-100 response (a reduction in the CDAI score of 100 points or more from the baseline), and the score was higher in combination therapy (RR 1.14, [0.56 to 2.33], very low certainty, Table S17). In contrast, CDAI-100 nonresponse was lower in the combination therapy (RR 0.67, [0.19 to 2.39], very low certainty, Table S17).[82]

S Table 17.

Combination therapy with immunomodulators (thiopurine) with subcutaneous (SC) infliximab (CT-P13) compared to subcutaneous infliximab (CT-P13) without immunomodulators for maintaining remission in patients with moderate-to-severe CD.

Bibliography: D’Haens G, Reinisch W, Schreiber S, Cummings F, Irving PM, Ye BD, et al. Subcutaneous Infliximab Monotherapy Versus Combination Therapy with Immunosuppressants in Inflammatory Bowel Disease: A Post Hoc Analysis of a Randomised Clinical Trial. Clin Drug Investig [Internet]. 2023 Apr 1 [cited 2025 Apr 5];43(4):277–88. Available from: https://link.springer.com/article/10.1007/s40261-023-01252-z

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Combination with immune modulators (thiopurine) with SC IFX (CT-P13)	SC IFX (CT-P13) without immune modulators	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations		SC IFX (CT-P13) without immune modulators	Absolute (95% CI)
Clinical remission
1	RCT	serious^a	not serious	not serious	very serious^b	None	20/27 (74.1%)	22/35 (62.9%)	RR 1.1020 (0.6915 to 1.7577)	⨁◯◯◯ Very low^a,b	CRITICAL
1	RCT	serious^a	not serious	not serious	very serious^b	None	20/27 (74.1%)	22/35 (62.9%)	64 more per 1,000 (from 194 fewer to 476 more)	⨁◯◯◯ Very low^a,b	CRITICAL
Mucosal healing
1	RCT	serious^a	not serious	serious^c	very serious^b	None	20/27 (74.1%)	28/35 (80.0%)	RR 0.9500 (0.6216 to 1.4747)	⨁◯◯◯ Very low^a,b,c	CRITICAL
1	RCT	serious^a	not serious	serious^c	very serious^b	None	20/27 (74.1%)	28/35 (80.0%)	40 fewer per 1,000 (from 303 fewer to 380 more)	⨁◯◯◯ Very low^a,b,c	CRITICAL
Efficacy (a reduction in the CDAI score of 100 points or more from the baseline score which indicates a significant improvement in disease activity) (assessed with: CDAI-100 response)
1	RCT	serious^a	not serious	not serious	very serious^b	None	10/13 (76.9%)	8/13 (61.5%)	RR 1.140 (0.557 to 2.330)	⨁◯◯◯ Very low^a,b	IMPORANT
1	RCT	serious^a	not serious	not serious	very serious^b	None	10/13 (76.9%)	8/13 (61.5%)	86 more per 1,000 (from 273 fewer to 818 more)		IMPORANT
Efficacy (assessed with: CDAI-100 non-response)
1	RCT	serious^a	not serious	not serious	very serious^b	None	3/13 (23.1%)	5/13 (38.5%)	RR 0.670 (0.191 to 2.390)	⨁◯◯◯ Very low^a,b	IMPORTANT
1	RCT	serious^a	not serious	not serious	very serious^b	None	3/13 (23.1%)	5/13 (38.5%)	127 fewer per 1,000 (from 311 fewer to 535 more)	⨁◯◯◯ Very low^a,b	IMPORTANT
Safety (assessed with: Injection-site reaction)
1	RCT	serious^a	not serious	serious^c	very serious^b	None	8/29 (27.6%)	7/37 (18.9%)	RR 1.36 (0.54 to 3.39)	⨁◯◯◯ Very low^a,b,c	IMPORTANT
1	RCT	serious^a	not serious	serious^c	very serious^b	None	8/29 (27.6%)	7/37 (18.9%)	68 more per 1,000 (from 87 fewer to 452 more)	⨁◯◯◯ Very low^a,b,c	IMPORTANT
Safety (assessed with: Infection)
1	RCT	serious^a	not serious	serious^c	very serious^c	None	12/29 (41.4%)	12/37 (32.4%)	RR 1.195	⨁◯◯◯ Very low^a,c	IMPORTANT
1	RCT	serious^a	not serious	serious^c	very serious^c	None	12/29 (41.4%)	12/37 (32.4%)	63 more per 1,000 (from 129 fewer to 444 more)	⨁◯◯◯ Very low^a,c	IMPORTANT
Safety (assessed with: Malignancy)
1	RCT	serious^a	not serious	serious^c	very serious^b	None	0/29 (0.0%)	1/37 (2.7%)	RR 0.434 (0.018 to 10.260)	⨁◯◯◯ Very low^a,b,c	IMPORTANT
1	RCT	serious^a	not serious	serious^c	very serious^b	None	0/29 (0.0%)	1/37 (2.7%)	15 fewer per 1,000 (from 27 fewer to 250 more)	⨁◯◯◯ Very low^a,b,c	IMPORTANT
Immunogenicity (assessed with: anti-drug antibody positive)
1	RCT	serious^a	not serious	serious^c	very serious^b	None	12/25 (48.0%)	19/29 (65.5%)	RR 0.820 (0.458 to 1.470)	⨁◯◯◯ Very low^a,b,c	CRITICAL
1	RCT	serious^a	not serious	serious^c	very serious^b	None	12/25 (48.0%)	19/29 (65.5%)	118 fewer per 1,000 (from 355 fewer to 308 more)	⨁◯◯◯ Very low^a,b,c	CRITICAL
Immunogenicity (assessed with: Neutralising antibody positive)
1	RCT	serious^a	not serious	serious^c	very serious^b	None	2/12 (16.7%)	2/19 (10.5%)	RR 1.500 (0.238 to 9.440)	⨁◯◯◯ Very low^a,b,c	IMPORTANT
1	RCT	serious^a	not serious	serious^c	very serious^b	None	2/12 (16.7%)	2/19 (10.5%)	53 more per 1,000 (from 80 fewer to 888 more)	⨁◯◯◯ Very low^a,b,c	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.Blinding and allocation ROB.

^b.Small sample size.

^c.The outcome includes UC and CD patient.

Safety outcomes were mixed between the two groups, with marginally higher injection site reactions and infections associated with combination therapy (RR 1.36, [0.54 to 3.39], very low certainty, Table S17) and (RR 1.20, [0.60 to 2.37], very low certainty, Table S17), respectively. Immunogenicity outcomes showed variability. There was a nonsignificant trend toward lower anti-drug antibody positivity in the combination therapy group (RR 0.82; [0.46 to 1.47]; very low certainty, Table S17). In contrast, neutralizing antibody positivity appeared higher in this group, though this difference was also not statistically significant (RR 1.50; [0.24 to 9.44]; very low certainty, Table S17).[82]

In another post hoc analysis of the LIBERTY study, there was no clinically meaningful difference in the efficacy of a combination of SC CT-P13 and immunosuppressants compared to SC CT-P13 alone. However, serious infection rates were higher in the combination group during the maintenance period (4.7% vs 1.3%).[83]

Although the thiopurine-IFX combination therapy may increase clinical remission rates and reduce immunogenicity, it has potential risks and higher costs when compared with monotherapy. Based on very low certainty evidence, the guideline panel recommends against the thiopurine-IFX combination and conditionally recommends SC IFX monotherapy for maintaining remission. This is in alignment with BSG guidelines recommendation.[31]

Q14. Should a combination of ADA with immunomodulators (thiopurine) vs. ADA monotherapy be used to induce and maintain remission in patients with moderate-to-severe CD?

Recommendation 14: For induction and maintenance of remission in adults with moderate-to-severe CD, we suggest against using a combination of ADA with immunomodulators (thiopurine) rather than ADA monotherapy (Conditional recommendation, moderate certainty evidence).

Remarks: Combining ADA with thiopurine should not be considered routinely for advanced therapy-naive CD. However, it should be considered in high-risk groups, including those with prior immunogenic failure to other anti-TNF agents.

Rationale

This recommendation was based on an SR and MA of 24 studies involving 3096 patients that compared the efficacy and safety of ADA-thiopurine combination therapy vs. ADA monotherapy.[84] The study found no superiority between the combination of ADA and immunomodulators and ADA monotherapy in inducing and maintaining remission in CD.

There was no significant difference between patients who received ADA-thiopurine combination therapy and ADA monotherapy regarding induction of remission (OR 0.86, [0.70 to 1.06], moderate certainty, Table S18) and clinical response (OR 1.01, [0.62 to 1.65], low certainty, Table S18). Additionally, the maintenance of remission and response was similar with ADA-thiopurine combination therapy compared to ADA monotherapy (OR 0.97, [0.79 to 1.19], moderate certainty, Table S18).

S Table 18.

Combination of adalimumab with immunomodulators (thiopurine) compared to adalimumab monotherapy for inducing and maintaining remission in patients with moderate-to-severe CD.

Bibliography: Chalhoub JM, Rimmani HH, Gumaste V V., Sharara AI. Systematic Review and Meta-analysis: Adalimumab Monotherapy Versus Combination Therapy with Immunomodulators for Induction and Maintenance of Remission and Response in Patients with Crohn’s Disease. Inflamm Bowel Dis [Internet]. 2017 Aug 1 [cited 2025 Apr 6];23(8):1316–27. Available from: https://pubmed.ncbi.nlm.nih.gov/28719541/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	combination of ADA with immune modulators (thiopurine)	ADA alone	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	combination of ADA with immune modulators (thiopurine)	ADA alone	Absolute (95% CI)
Induction of remission
12	RCT	serious^a	not serious	not serious	not serious	none	628/1400 (44.9%)	560/1696 (33.0%)	OR 0.86 (0.70 to 1.06)	⨁⨁⨁◯ Moderate^a	CRITICAL
12	RCT	serious^a	not serious	not serious	not serious	none	628/1400 (44.9%)	560/1696 (33.0%)	32 fewer per 1,000 (from 74 fewer to 13 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Induction of response
7	RCT	serious^a	serious^b	not serious	not serious	none	330/477 (69.2%)	388/563 (68.9%)	OR 1.01 (0.62 to 1.65)	⨁⨁◯◯ Low^a,b	CRITICAL
7	RCT	serious^a	serious^b	not serious	not serious	none	330/477 (69.2%)	388/563 (68.9%)	2 more per 1,000 (from 110 fewer to 96 more)	⨁⨁◯◯ Low^a,b	CRITICAL
Maintenance of remission
9	RCT	serious^a	serious^c	not serious	not serious	none	356/859 (41.4%)	408/1026 (39.8%)	OR 0.97 (0.79 to 1.19)	⨁⨁◯◯ Low^a,c	CRITICAL
9	RCT	serious^a	serious^c	not serious	not serious	none	356/859 (41.4%)	408/1026 (39.8%)	7 fewer per 1,000 (from 55 fewer to 42 more)	⨁⨁◯◯ Low^a,c	CRITICAL
Maintenance of response
7	RCT	serious^a	very serious^c	not serious	not serious	none	519/745 (69.7%)	603/935 (64.5%)	OR 0.91 (0.54 to 1.54)	⨁⨁◯◯ Low^a,c	CRITICAL
7	RCT	serious^a	very serious^c	not serious	not serious	none	519/745 (69.7%)	603/935 (64.5%)	22 fewer per 1,000 (from 150 fewer to 92 more)	⨁⨁◯◯ Low^a,c	CRITICAL
serious/severe AEs
8	RCT	serious^a	not serious^d	not serious	not serious	none	101/1531 (6.6%)	128/1743 (7.3%)	OR 1.15 (0.77 to 1.73)	⨁⨁⨁◯ Moderate^a,d	IMPORTANT
8	RCT	serious^a	not serious^d	not serious	not serious	none	101/1531 (6.6%)	128/1743 (7.3%)	10 more per 1,000 (from 16 fewer to 47 more)	⨁⨁⨁◯ Moderate^a,d	IMPORTANT
Rate of opportunistic infections
6	RCT	serious^a	not serious	not serious	not serious	none	16/843 (1.9%)	10/1047 (1.0%)	OR 0.49 (0.22 to 1.08)	⨁⨁⨁◯ Moderate^a	IMPORTANT
6	RCT	serious^a	not serious	not serious	not serious	none	16/843 (1.9%)	10/1047 (1.0%)	5 fewer per 1,000 (from 7 fewer to 1 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Rate of antibodies to adalimumab
3	RCT	serious^a	not serious	not serious	not serious	none	3/245 (1.2%)	17/334 (5.1%)	OR 0.24 (0.07 to 0.82)	⨁⨁⨁◯ Moderate^a	IMPORTANT
3	RCT	serious^a	not serious	not serious	not serious	none	3/245 (1.2%)	17/334 (5.1%)	38 fewer per 1,000 (from 47 fewer to 9 fewer)	⨁⨁⨁◯ Moderate^a	IMPORTANT

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CI: confidence interval; OR: odds ratio

Explanations

^a.Blinding and allocation ROB.

^b.I2=51%. ^c. I2=80%.

^c.I2=39%.

The safety profile was comparable for serious/severe AEs (OR 1.15, [0.77 to 1.73], moderate certainty, Table S18) and opportunistic infections (OR 0.49, [0.22 to 1.08], moderate certainty, Table S18). Notably, combination therapy was associated with lower immunogenicity; the rate of developing antibodies to ADA was lower in the ADA-thiopurine combination therapy (OR 0.24, [0.07 to 0.82], moderate certainty, Table S18).[84] Although overall rates were low, combination therapy was associated with an increased risk of malignancies, including lymphoma and urinary bladder cancer, with less than one event per 100 person-years reported. These findings suggest that while combination therapy may reduce immunogenicity, it may also carry a higher long-term malignancy risk that warrants careful consideration, particularly in patients requiring prolonged immunosuppression.

A single open-label RCT (DIAMOND study) compared a combination of ADA and azathioprine to ADA monotherapy in bio-naïve patients for 52 weeks.[85] A nonsignificant difference was found between the two groups in the induction of remission (RR 1.31, [0.80 to 2.14]) or the maintenance of remission (RR 1.13, [0.72 to 1.78]).[85]

On the other side, in an SR and MA that included anti-TNF-experienced patients, there were higher odds of successful induction in a combination group compared to those who received a monotherapy (OR 1.26; [1.06–1.49], P = 0.008).[84] Similarly, an RCT concluded that combination therapy is associated with benefits among patients with prior experience with anti-TNF.[61]

Based on moderate certainty evidence, the guideline panel conditionally recommends against the ADA-thiopurine combination for induction or maintenance of remission in CD patients. ADA monotherapy should remain the standard for most patients. However, they indicated that combination therapy should be considered in high-risk groups, including those with prior immunogenic failure to previous anti-TNF agents. The AGA guideline suggests using ADA-thiopurine over ADA monotherapy for remission induction and maintenance among biologics-bio-naïve patients.[15] Meanwhile, the ECCO guideline recommends ADA monotherapy over the combination.[17] Both guidelines also acknowledge the importance of combination therapy in the subgroups of patients who have developed secondary non-response to anti-TNF agents.[15,17]

Treatment Optimization Strategies for Adults with CD and Secondary Loss of Response to Advanced Therapy

Q15. Should adjusting the dose based on measured anti-TNF trough levels vs. empirically optimizing the dose without measuring anti-TNF trough levels be used for CD patients with secondary loss of response to anti-TNF therapy?

Recommendation 15: For adults with CD and secondary loss of response to anti-TNF therapy, we suggest measurement of anti-TNF trough levels and dose optimization based on these levels over maintaining the standard anti-TNF dose without trough level monitoring or optimizing the dose empirically (Conditional recommendation, very low certainty evidence).

Rationale

This recommendation was based on a retrospective cohort study of 312 active IBD patients that compared the effect of IFX dose adjustment through guided TDM vs. clinical decision alone.[86]

Very low certainty evidence for adjusting the anti-TNF dose through TDM-guided indicated that TDM before dose adjustment is associated with higher rates of endoscopic remission (63% TDM vs. 48% non-TDM, P <0.05, very low certainty, Table S19). In addition, TDM was associated with favorable outcomes, including improved clinical response (69% TDM vs. 57% non-TDM, P <0.01, very low certainty, Table S19) and fewer hospitalization rates (22% TDM vs. 35% non-TDM, P = 0.025).[86]

S Table 19.

Adjusting the dose based on measured anti-TNF trough levels compared to empirically optimizing the dose without measuring anti-TNF trough levels for CD patients with secondary loss of response to anti-TNF therapy.

Bibliography: Kelly OB, O’Donnell S, Stempak JM, Steinhart AH, Silverberg MS. Therapeutic Drug Monitoring to Guide Infliximab Dose Adjustment is Associated with Better Endoscopic Outcomes than Clinical Decision Making Alone in Active Inflammatory Bowel Disease. Inflamm Bowel Dis [Internet]. 2017 Jul 1 [cited 2025 Apr 6];23(7):1202–9. Available from: https://pubmed.ncbi.nlm.nih.gov/28498155/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	adjusting the dose based on measured anti-TNF trough levels	empirically optimizing the dose without measuring anti-TNF trough levels	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	adjusting the dose based on measured anti-TNF trough levels		Absolute (95% CI)
Endoscopic remission
1	non-RCT	very serious^a	not serious	very serious^b	very serious^c	none	99/149 (66.4%)		not estimable	⨁◯◯◯ Very low^a,b,c	CRITICAL
Clinical response
1	non-RCT	very serious^a	not serious	very serious^b	very serious^c	none	103/149 (69.1%)		not estimable	⨁◯◯◯ Very low^a,b,c	CRITICAL
Clinical remission
1	non-RCT	very serious^a	not serious	very serious^b	very serious^c	none	77/149 (51.7%)		not estimable	⨁◯◯◯ Very low^a,b,c	CRITICAL
Steroid use
1	non-RCT	very serious^a	not serious	very serious^b	very serious^c	none	22/149 (14.8%)		not estimable	⨁◯◯◯ Very low^a,b,c	IMPORTANT

Open in a new tab

CI: confidence interval

Explanations

a.Retrospective data collection, no blinding and population bias.

b.The included patients were the IBD patients not CD only

c.Total events below 400

A systematic review of 503 studies concluded that measuring anti-TNF trough levels and anti-drug antibody levels through TDM should be considered in evaluating the underlying cause of primary nonresponse and secondary loss of response. This approach could also guide clinicians in determining which patients are most likely to benefit from anti-TNF therapy and optimizing drug therapy for patients who do not respond to anti-TNF therapy.[87] Moreover, an RCT found that targeting IFX trough concentrations of 3–7 μg/mL resulted in more efficient drug use and fewer disease flares than clinically based dosing.[88]

Based on a local cross-sectional study from Saudi Arabia, the IFX trough levels were subtherapeutic in 58%, therapeutic in 29%, and supratherapeutic in 13% of IBD patients. Only 33.3% of patients had undergone treatment optimization following TDM, highlighting the need for a dashboard to facilitate clinical decision-making.[89]

Based on the very low certainty evidence, the guideline panel conditionally recommends TDM-guided dose adjustment with loss of response to anti-TNF therapy in CD patients. However, if the trough levels are unavailable, empirical optimization of the anti-TNF dose can be adapted. The panel emphasizes limitations, such as a lack of data, and recommends that prospective local and regional studies are warranted to fill evidence gaps.

Q16. Should dose escalation (by shortening the dosing interval to every 4 weeks) vs. no treatment be used for partial or secondary loss of response in patients with CD who are treated with standard 8-weekly anti-Integrins or anti-IL-12/23?

Recommendation 16: For treating partial or secondary loss of response in adults with CD who are treated with standard 8-weekly anti-integrins or anti-IL-12/23 inhibitors, we suggest dose escalation (by shortening the dosing interval to every 4 weeks) over no escalation (Good practice statement).

Rationale

This good practice statement is based on limited data and expert opinion due to the lack of direct evidence. A previous SR and MA of 15 cohort studies investigates the effectiveness of reinduction and/or dose escalation (shortening the dosing interval to every 4 weeks) of ustekinumab in 925 adult patients with CD.[90]

The clinical response rate was 57%, and corticosteroid-free remission was observed in 37.3%. The endoscopic response rate was 61%, and the endoscopic remission rate was 29%. Biochemical remission was observed in 21.1% of cases.

Similarly, a study by Rehman and his colleagues found that dose escalation of ustekinumab among IBD patients resulted in pooled prevalence rates of clinical response and clinical remission of 55% and 51%, respectively.[91]

However, the STARDUST trial found no significant differences in the proportion of patients reaching endoscopic, clinical, and biomarker endpoints at week 48 between those treated with ustekinumab every 8 weeks and those whose treatment was escalated to every 4 weeks. This result contrasts with the real-world treatment practices observed in KSA.[92] Furthermore, the study has several limitations, including being open-label, notable selection bias, and a reduction in the sample size for the endoscopic endpoint over time in the treat-to-target group, thus limiting its generalizability.

Based on a good practice statement, high cost, and potential AEs, the guideline panel conditionally suggests dose escalation for partial or secondary loss of response in adults with CD who are treated with standard 8-weekly anti-integrins or anti-IL-12/23. Additional real-world data are needed to support this recommendation. Similarly, the BSG guidelines issued a good practice statement noting that dose escalation may improve outcomes in patients with partial response or loss of response; however, there is insufficient evidence to support TDM for VDZ or Ustekinumab.[31]

Management of Complex Perianal Fistula among Adults with CD

Q17. Should combination therapy, including seton placement, antibiotics, and anti-TNF agents (e.g. IFX, ADA) vs. standard care or alternative treatments such as antibiotics alone, surgical drainage without Seton, or other immunosuppressive therapies be used for the induction of remission in patients with complicated perianal fistula associated with abscess?

Recommendation 17: For induction of remission in adults with complicated perianal fistula associated with an abscess, we recommend the use of combination therapy, including seton placement, antibiotics, and anti-TNF agents (e.g. IFX, ADA), over standard care or alternative treatments such as antibiotics alone, surgical drainage without seton, or other immunosuppressive therapies (Strong recommendation, moderate certainty evidence).

Rationale

Few data are available on the role of combination therapy among CD patients with complicated perianal fistula associated with abscess. This recommendation was based on a retrospective cohort study of 78 CD patients with perianal fistulas, demonstrating the effectiveness of a multimodal approach for treating high perianal fistulas, which included seton drainage, anti-TNF agents, and a short course of antibiotics for 2 weeks. The study found that combination therapy achieved clinical healing in 52.6% of patients (rate 0.526, [0.29 to 0.55], very low certainty, Table S20). After 4 years of follow-up, 97% of the patients maintained perianal complete remission (rate 0.97, [0.28 to 0.54], very low certainty, Table S20), and the recurrence rate was very low (rate 0.098, [0.07 to 1.88], very low certainty, Table S20).[93] The PISA-II trial involved randomizing patients with CD and an active high perianal fistula to receive either a combination of 4 months of anti-TNF therapy and surgical closure or anti-TNF therapy alone for 1 year following seton insertion. After 18 months, radiological healing was significantly more common in the combination group compared to the anti-TNF monotherapy group, with rates of 32% vs. 9%, respectively. Additionally, fewer patients in the combination group required reintervention compared to those in the anti-TNF monotherapy group, with rates of 13% vs. 43%. However, the two groups showed no significant differences in surgical closure rates, recurrence rates, or AEs.[94]

S Table 20.

Combination therapy including seton placement, antibiotics, and anti-TNF agents (e.g., infliximab, adalimumab) compared to Standard care or alternative treatments such as antibiotics alone, surgical drainage without seton, or other immunosuppressive therapies for the induction of remission in patients with complicated perianal fistula associated with abscess.

Bibliography: Kotze PG, de Albuquerque IC, Da Luz Moreira A, Tonini WB, Olandoski M, Coy CSR. Perianal complete remission with combined therapy (seton placement and anti-TNF agents) in Crohn’s disease: a Brazilian multicenter observational study. Arq Gastroenterol. 2014;51(4):283–9.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other consideration	combination therapy including seton placement, antibiotics, and anti-TNF agents (e.g., IFX, ADA)	Standard care or alternative treatments such as antibiotics alone, surgical drainage without seton, or other immunosuppressive therapies	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other consideration			Absolute (95% CI)
complete perianal remission
1	non-RCT	serious^a	not serious	not serious	very serious^b	None	41/78 (52.6%)	0/0	rate 0.526 (0.290 to 0.550) -- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b	CRITICAL
Maintained remission (follow-up: 4 years)
1	non-RCT	serious^a	not serious	not serious	very serious^b	None	40/41 (97.6%)	0/0	rate 0.97 (0.28 to 0.54) -- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b	CRITICAL
Recurrence
1	non-RCT	serious^a	not serious	not serious	very serious^b	None	4/41 (9.8%)	0/0	rate 0.098 (0.070 to 0.188) -- per 1,000 (from -- to --)	⨁◯◯◯ Very low^a,b	IMPORTANT

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CI: confidence interval

Explanations

^a.Retrospective single-arm study

^b.very small sample size

Similarly, combining ciprofloxacin and IFX enhanced clinical response and endoanal ultrasonography more effectively than IFX alone.[95] Additionally, a combination of seton placement, IFX, and immunomodulators has achieved complete fistula healing in 67% of patients with CD and partial healing in 19% of patients with perianal fistula. Relapses were effectively treated with repeated IFX infusions.[96]

Among 61 Saudi patients with perianal fistulizing CD, treatment with anti-TNF agents resulted in a full response in 44.4% of the patients, and partial and no response in 16.3% and 39.3%, respectively. There was a significant association between poor response and low BMI, rectal involvement, fistulae classification, and the presence of an abscess, and low BMI was an independent predictor for poor disease outcomes.[97]

The evidence indicating moderate certainty, along with the balanced effects between beneficial outcomes such as improved fistula healing and minor undesirable effects, as well as considerations of cost-effectiveness, feasibility, and acceptability, has resulted in a strong recommendation for prioritizing combination therapy for the induction of remission in CD patients with complicated perianal fistulas associated with abscess.

Q18. Should a combination of immunomodulators and anti-TNF vs. anti-TNF monotherapy be used for fistula healing in patients with CD and complex perianal fistula?

Recommendation 18: For complex perianal fistula healing in adults with CD, we suggest using a combination of immunomodulators and anti-TNF over anti-TNF monotherapy. (Conditional recommendation, Moderate certainty evidence).

Rationale

This recommendation was based on a network meta-analysis (NMA) of 15 studies comparing combination approaches, including antibiotics, immunomodulators, or surgical drainage to anti-TNF monotherapy. Combination therapy of anti-TNF agents and immunomodulators demonstrated a higher fistula healing rate compared with anti-TNF monotherapy (RR 0.92, [0.78 to 1.08], moderate certainty, Table S21).[98]

S Table 21.

combination of immunomodulators & anti-TNF compared to anti-TNF monotherapy for fistula healing in patients with CD and complex perianal fistula.

Bibliography: Tandon P, Rhee GG, Schwartz D, McCurdy JD. Strategies to Optimize Anti-tumor Necrosis Factor Therapy for Perianal Fistulizing Crohn’s Disease: A Systematic Review. Dig Dis Sci [Internet]. 2019 Nov 1 [cited 2025 Apr 7];64(11):3066–77. Available from: pubmed.ncbi.nlm.nih.gov/31030304/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	a combination of immunomodulators & anti-TNF	anti-TNF alone	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	a combination of immunomodulators & anti-TNF	anti-TNF alone	Absolute (95% CI)
Perianal fistula healing
5	RCT	serious^a	not serious	not serious	not serious^b	none	75/121 (62.0%)	171/253 (67.6%)	RR 0.92 (0.78 to 1.08) 54 fewer per 1,000 (from 149 fewer to 54 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL

Open in a new tab

CI: confidence interval; RR: risk ratio

Explanations

^a.allocation ROB

The study also emphasized an exposure–response relationship between anti-TNF agents and fistula healing, suggesting that optimizing the dose may be a potential approach to enhance fistula healing.[98]

In a prospective open interventional study, a combination of anti-TNF agents and thiopurine showed sustained benefits for patients with CD who had perianal fistulas. The study also found that an early clinical response was linked to a later clinical remission. Additionally, it was observed that radiological healing occurred more slowly than clinical healing, with a time lag of approximately 1 year.[99] Notably, it was shown that targeting higher trough levels of anti-TNF agents among patients with perianal fistulizing CD was positively associated with fistula closure and healing. Therefore, higher levels than those reported for mucosal healing may be necessary to achieve therapeutic success.[100,101]

Based on moderate certainty evidence, balanced effects favor the combination of immunomodulators and anti-TNF therapy, and given its cost-effectiveness, the guideline panel conditionally recommends combination therapy over monotherapy.

The panel indicates that adding azathioprine to ADA may offer additional benefits in complex fistulizing CD; however, it does not appear to significantly impact the clinical remission rate, with very low certainty compared to IFX.

Q19. Should anti-IL-12/23, anti-IL-23, anti-integrin, or selective Janus kinase Inhibitors (JAKIs) vs. no treatment be used for fistula healing in complex perianal fistulae in CD patients?

Recommendation 19: For complex perianal fistula healing in adults with CD, we suggest using anti-IL-12/23, anti-IL-23, anti-integrin, or JAKIs over no treatment (Conditional recommendation, moderate certainty evidence).

Rationale

This recommendation was based on a post hoc analysis of three phase 3 RCTs (U-EXCEL, U-EXCEED, and U-ENDURE) that compared the efficacy and safety of upadacitinib, an oral JAKi, to placebo among 143 patients with fistulizing CD. It demonstrated the effectiveness of upadacitinib 45 mg once daily during induction compared to placebo.[102]

Upadacitinib demonstrated higher rates of drainage resolution (RR 0.17, [0.02 to 1.19], moderate certainty, Table S22) and closure of external perianal fistula opening (RR 0.25, [0.06 to 1.03], moderate certainty, Table S22).

S Table 22.

Anti-IL-12/23, anti-IL23, anti-integrin, or selective JAKi compared to no treatment for fistula healing in complex perianal fistulae in CD patients.

Bibliography: Colombel JF, Lacerda AP, Irving PM, Panaccione R, Reinisch W, Rieder F, et al. Efficacy and Safety of Upadacitinib for Perianal Fistulizing Crohn’s Disease: A Post Hoc Analysis of 3 Phase 3 Trials. Clin Gastroenterol Hepatol [Internet]. 2024 Sep 24 [cited 2025 Apr 7]; Available from: https://pubmed.ncbi.nlm.nih.gov/39326583/

Certainty assessment							№ of patients		Effect		Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Anti-IL-12/23, anti-IL23, anti-integrin, or selective JAKi	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Anti-IL-12/23, anti-IL23, anti-integrin, or selective JAKi	no treatment	Absolute (95% CI)
Resolution of drainage in draining perianal fistulas (Upadacitinib)
1	RCT	not serious	not serious	not serious	serious^a	none	17/38 (44.7%)	1/18 (5.6%)	RR 0.1700 (0.0243 to 1.1947)		⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	17/38 (44.7%)	1/18 (5.6%)	46 fewer per 1,000 (from 54 fewer to 11 more)		⨁⨁⨁◯ Moderate^a	CRITICAL
Closure of external perianal fistula openings (Upadacitinib)
1	RCT	not serious	not serious	not serious	serious^a	none	19/86 (22.1%)	2/42 (4.8%)	RR 0.2512 (0.0611 to 1.0329)		⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	19/86 (22.1%)	2/42 (4.8%)	36 fewer per 1,000 (from 45 fewer to 2 more)		⨁⨁⨁◯ Moderate^a	CRITICAL
Recurrence rates (Upadacitinib)
1	RCT	not serious	not serious	not serious	serious^a	none	2/47 (4.3%)	4/96 (4.2%)	RR 0.510 (0.133 to 1.956)		⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	2/47 (4.3%)	4/96 (4.2%)	20 fewer per 1,000 (from 36 fewer to 40 more)		⨁⨁⨁◯ Moderate^a	IMPORTANT
Clinical remission (Upadacitinib) (follow-up: 12 weeks; assessed with: Crohn’s Disease Activity Index (CDAI <150))
1	RCT	not serious	not serious	not serious	serious^a	none	14/38 (36.8%)	3/32 (9.4%)	RR 3.4000 (0.9739 to 10.1307)		⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	14/38 (36.8%)	3/32 (9.4%)	225 more per 1,000 (from 2 fewer to 856 more)		⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical remission (Upadacitinib) (assessed with: SF/APS)
1	RCT	not serious	not serious	not serious	serious^a	none	51/96 (53.1%)	10/47 (21.3%)	RR 0.5000 (0.2762 to 0.9260)		⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	51/96 (53.1%)	10/47 (21.3%)	106 fewer per 1,000 (from 154 fewer to 16 fewer)		⨁⨁⨁◯ Moderate^a	CRITICAL
Endoscopic response (Upadacitinib) (follow-up: 52; assessed with: Crohn’s Disease Activity Index (CDAI <150))
1	RCT	not serious	not serious	not serious	serious^a	none	12/38 (31.6%)	0/32 (0.0%)	RR 16.1700 (0.9910 to 264.0634)		⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	12/38 (31.6%)	0/32 (0.0%)	0 fewer per 1,000 (from 0 fewer to 0 fewer)		⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical remission (Upadacitinib) (follow-up: 52 weeks; assessed with: Crohn’s Disease Activity Index (CDAI <150))
1	RCT	not serious	not serious	not serious	serious^a	none	14/38 (36.8%)	3/32 (9.4%)	RR 3.1400 (0.9739 to 10.1307)	201 more per 1,000 (from 2 fewer to 856 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	14/38 (36.8%)	3/32 (9.4%)			⨁⨁⨁◯ Moderate^a	CRITICAL
Any adverse events (Upadacitinib)
1	RCT	not serious	not serious	not serious	serious^a	none	43/96 (44.8%)	31/47 (66.0%)	RR 0.7700 (0.5380 to 1.1261)		⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	43/96 (44.8%)	31/47 (66.0%)	152 fewer per 1,000 (from 305 fewer to 83 more)		⨁⨁⨁◯ Moderate^a	CRITICAL
Complete healing (vedolizumab)
4	RCT	serious^b	serious^c	not serious	serious^a	none	52/198 (26.3%)		Pooled rate 0.276 (0.188 to 0.373)		⨁◯◯◯ Very low^a,b,c	CRITICAL
4	RCT	serious^b	serious^c	not serious	serious^a	none	52/198 (26.3%)		-- per 1,000 (from -- to --)		⨁◯◯◯ Very low^a,b,c	CRITICAL
Partial healing (vedolizumab)
4	RCT	serious^b	serious^d	not serious	serious^a	none	71/198 (35.9%)		Pooled rate 0.349 (0.232 to 0.477)		⨁◯◯◯ Very low^a,b,d	CRITICAL
4	RCT	serious^b	serious^d	not serious	serious^a	none	71/198 (35.9%)		-- per 1,000 (from -- to --)		⨁◯◯◯ Very low^a,b,d	CRITICAL

Open in a new tab

CI: confidence interval; RR: risk ratio

Explanations

^a.small sample size

^b.1 study was moderate quality and 1 study was low quality

^c.I2= 49.4%

^d.I2= 67.1%

In clinical practice, VDZ, an anti-integrin, is mainly utilized as a second- or third-line treatment for fistulizing CD, influenced by payer considerations and limited efficacy data compared to anti-TNF agents.[103] The ENTERPRISE randomized, double-blind, phase 4 trial demonstrated that 53.6% of patients with fistulizing CD (15 out of 28) achieved ≥50% reduction in the number of draining perianal fistulae by week 30, with 64.3% in the standard VDZ regimen and 42.9% in the regimen with an additional dose at week 10.[104]

In an SR and MA of four studies, including 198 patients with perianal fistulizing CD who previously failed previous anti-TNF therapy, VDZ resulted in complete and partial healing of perianal fistulas in 27.6% (pooled rate 0.276, [0.188 to 0.373], certainty, Table S22) and 34.9% (pooled rate 0.349, [0.232 to 0.474], certainty, Table S22) of the patients, respectively.[105] It is important to emphasize that the existing evidence about VDZ is limited due to a scarcity of data, a small number of studies, and their varying sample sizes. Additionally, the significant heterogeneity among these studies highlights the need for future prospective research on fistula healing in patients undergoing anti-integrin therapy.

The HEAL study has shown that the remission rates for perianal fistulas were 54% for the ustekinumab group and 46% for the VDZ group. Additionally, the relapse rates were 27% for ustekinumab and 20% for VDZ. The incidence rate of relapse was 11% per patient-year in the ustekinumab group, compared to 7% in the VDZ group. Furthermore, the rates of AEs were similar between the two groups, with 6% in the ustekinumab group and 8% in the VDZ group.[106] However, this study was retrospective in nature, with a modest sample size and restricted MRI evaluation to less than half of the patients. Thus, definitive conclusions could not be drawn from the study, and prospective studies are necessary to validate these findings.

Furthermore, patients treated with RZB, a humanized monoclonal antibody that inhibits IL-23, exhibited an absence of draining fistulas by week 12 of induction, irrespective of whether they were in the RZB 600 mg group or the 1200 mg group.[43] This analysis was constrained by the small number of patients and the fact that only Asian patients were included limited the precision in estimating treatment effects.

According to the available evidence, upadacitinib has shown greater efficacy compared to other advanced therapies, including IL-23 inhibitors, ustekinumab, and VDZ, which is supported by higher-certainty evidence and more rigorous study designs.

The guideline panel conditionally recommends upadacitinib, IL-23 inhibitors, ustekinumab, or VDZ for healing perianal fistulas in CD patients, based on moderate-certainty evidence, moderate cost, and a balance of benefits and risks, along with probable feasibility and acceptability. This recommendation aligns with the AGA guideline, recommending the use of anti-IL-12 or anti-IL-23 in fistulizing CD patients.[15]

Switching Formulations for Maintenance of Remission in Adults with Stable Moderate-to-Severe CD

Q20. Should SC or IV IFX or SC or IV VDZ vs. no treatment be used to maintain remission for stable moderate-to-severe CD patients?

Recommendation 20: For maintenance of remission in stable moderate-to-severe CD patients, we recommend treatment with either SC or IV formulations of IFX or VDZ over no treatment (Strong recommendation, moderate certainty evidence).

Rationale

This recommendation was based on the VISIBLE 2 trial involving 410 CD patients over 52 weeks, which indicated that SC VDZ is as effective and safe as maintenance treatment.[107]

SC VDZ demonstrated higher clinical remission and corticosteroid-free remission rates (OR 1.76, [1.15 to 2.71], moderate certainty, Table S23) and (OR 3.70, [1.56 to 8.84], low certainty, Table S23), respectively. Similarly, the enhanced clinical response was greater in the SC VDZ group (OR 1.34, [0.88 to 2.00], moderate certainty, Table S23). The safety profile was comparable, with no differences between the two groups in total AEs (RR 0.96, [0.86 to 1.09], moderate certainty, Table S23) and a marginally lower number of SAEs observed with SC VDZ (RR 0.8, [0.4 to 1.5], moderate certainty, Table S23).

S Table 23.

Subcutaneous or IV infliximab or subcutaneous or IV vedolizumab compared to no treatment for maintaining remission for stable moderate-to-severe CD patients.

Bibliography: Vermeire S, D’Haens G, Baert F, Danese S, Kobayashi T, Loftus E V., et al. Efficacy and Safety of Subcutaneous Vedolizumab in Patients With Moderately to Severely Active Crohn’s Disease: Results From the VISIBLE 2 Randomised Trial. J Crohns Colitis [Internet]. 2021 Jan 1 [cited 2025 Apr 7];16(1):27. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8797168/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	SC or IV IFX or SC or IV VDZ	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	SC or IV IFX or SC or IV VDZ	no treatment	Absolute (95% CI)
Clinical remission (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	132/275 (48.0%)	46/134 (34.3%)	OR 1.76 (1.15 to 2.71)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	132/275 (48.0%)	46/134 (34.3%)	136 more per 1,000 (from 63 fewer to 52 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Enhanced Clinical response (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	143/275 (52.0%)	60/134 (44.8%)	OR 1.34 (0.88 to 2.00)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	143/275 (52.0%)	60/134 (44.8%)	73 more per 1,000 (from 31 fewer to 171 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Corticosteroid free remssion (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	43/95 (45.3%)	8/44 (18.2%)	OR 3.70 (1.56 to 8.84)	⨁⨁◯◯ Low^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	very serious^a,b	none	43/95 (45.3%)	8/44 (18.2%)	269 more per 1,000 (from 76 more to 481 more)	⨁⨁◯◯ Low^a,b	IMPORTANT
Any adverse event (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	202/275 (73.5%)	102/134 (76.1%)	RR 0.960 (0.860 to 1.086)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	202/275 (73.5%)	102/134 (76.1%)	30 fewer per 1,000 (from 107 fewer to 65 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Serious adverse events (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	23/275 (8.4%)	14/134 (10.4%)	RR 0.8 (0.4 to 1.5)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	23/275 (8.4%)	14/134 (10.4%)	21 fewer per 1,000 (from 63 fewer to 52 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT

Open in a new tab

CI: confidence interval; OR: odds ratio; RR: risk ratio

Explanations

^a.small sample size

^b.Wide CI

Based on a recent NMA, clinical remission rates were significantly higher than those of the placebo for IFX and VDZ, regardless of the dose and route of administration. SC IFX 120 mg Q2W exhibited the highest OR for clinical remission during the maintenance phase (OR 5.90; [1.90 to 18.2]), while SC VDZ 108 mg Q2W had the lowest OR (OR 1.28; [0.69 to 2.42]).[108]

In the rankings of treatments for achieving clinical remission, SC IFX 120 mg Q2W was rated the highest, followed by IFX IV 10 mg/kg Q8W. Next was VDZ IV 300 mg Q8W, while SC VDZ 108 mg Q2W ranked the lowest. Furthermore, the rates of endoscopic remission were higher with SC IFX 120 mg Q2W than with IV IFX 5 mg/kg Q8W (OR 0.51, [0.21 to 0.81], and OR 0.38, [0.24 to 0.52], respectively).[108]

Switching from IV to SC IFX (120 mg every 2 weeks) is safe and effective for maintaining remission in patients who are stable on standard IV IFX (5 mg/kg every 8 weeks) as demonstrated by the REMSWITCH study.[109] However, special consideration, close clinical and biochemical monitoring, is strongly recommended for patients receiving high-intensity IV regimens (10 mg/kg every 4 weeks) as they may require dose escalation to SC 240 mg every 2 weeks to maintain therapeutic efficacy and minimize relapse risk.[109,110]

The guideline panel strongly recommends SC or IV IFX or VDZ over no treatment for maintaining remission in stable CD patients. The recommendation is supported by moderate certainty evidence and moderate desirable effects, such as improved clinical remission and corticosteroid-free remission rates, with trivial undesirable effects. This recommendation aligns with the ECCO guidelines that strongly recommend using IFX and VDZ as maintenance therapy among CD patients.[17]

Prevention of Postoperative Recurrence (POR) among Adults with High-Risk CD

Q21. Should advanced therapy vs. no treatment be used for preventing the POR of high-risk CD?

Recommendation 21: To prevent the POR of high-risk CD, we suggest using advanced therapy over no treatment (Conditional recommendation, moderate certainty evidence).

Remarks: The strongest evidence supports using anti-TNFs, followed by VDZ.

Rationale

A recent meta-analysis demonstrated that anti-TNF agents were more effective in preventing clinical, endoscopic, and severe endoscopic and histological POR than conventional therapies. IFX and ADA effectively prevented endoscopic POR.[111]

This recommendation was supported by the phase 3 PREVENT trial, which compared the efficacy of IFX vs. placebo among 297 CD patients. It demonstrated that although IFX therapy did not meet the primary endpoint of clinical remission, there was a significant decrease in endoscopic recurrence, as assessed by a Rutgeerts score of <i2.[112]

Advanced IFX therapy demonstrated a similar clinical remission rate (RR 0.99, [0.66 to 1.49], moderate certainty, Table S24). In contrast, IFX exhibited a decreased endoscopic recurrence rate (RR 0.54, [0.38 to 0.77], moderate certainty, Table S24).

S Table 24.

Advanced therapy compared to no treatment for preventing the postoperative recurrence for high-risk CD.

Bibliography: Regueiro M, Feagan BG, Zou B, Johanns J, Blank MA, Chevrier M, et al. Infliximab Reduces Endoscopic, but Not Clinical, Recurrence of Crohn’s Disease After Ileocolonic Resection. Gastroenterology [Internet]. 2016 Jun 1 [cited 2025 Apr 7];150(7):1568–78. Available from: https://pubmed.ncbi.nlm.nih.gov/26946343/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	advanced therapy	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	advanced therapy	no treatment	Absolute (95% CI)
Clinical remission (follow-up: 104; assessed with: CDAI score <’200 and evidence of endoscopic recurrence defined by a Rutgeerts score <12)
1	RCT	not serious	not serious	not serious	serious^a	none	38/150 (25.3%)	37/147 (25.2%)	RR 0.9900 (0.6639 to 1.4908)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	38/150 (25.3%)	37/147 (25.2%)	3 fewer per 1,000 (from 85 fewer to 124 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Endoscopic remission (follow-up: 104 weeks; assessed with: CDAI score <200 and evidence of endoscopic recurrence defined by a Rutgeerts score <’12)
1	RCT	not serious	not serious	not serious	serious^a	none	33/147 (22.4%)	77/150 (51.3%)	RR 0.5400 (0.3779 to 0.7730)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	33/147 (22.4%)	77/150 (51.3%)	236 fewer per 1,000 (from 319 fewer to 117 fewer)	⨁⨁⨁◯ Moderate^a	CRITICAL
Infusion reactions adverse event
1	RCT	not serious	not serious	not serious	serious^a	none	29/147 (19.7%)	12/150 (8.0%)	RR 2.2200 (1.1753 to 4.2102)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	29/147 (19.7%)	12/150 (8.0%)	98 more per 1,000 (from 14 more to 257 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.small sample size

It was also shown that advanced therapy with VDZ administered within 4 weeks of ileocolonic resection was more effective in preventing endoscopic recurrence than placebo among high-risk CD patients. The authors observed that the probability of achieving a lower modified Rutgeerts score with VDZ was 77% compared to the placebo. Additionally, the rate of endoscopic recurrence was 23.3% in the VDZ group vs. 62.2% in the placebo group (difference –38%, [–56 to –17; P = 0.0004), indicating that VDZ is a promising option for the postoperative management of high-risk CD patients.[113]

The guideline panel conditionally recommends advanced therapy for high-risk CD patients within 4 weeks postoperatively to prevent POR. The recommendation is based on moderate certainty evidence and moderate desirable effects, such as significant reductions in endoscopic recurrence, with trivial undesirable effects. The panel considers the intervention acceptable and feasible, with monitoring focusing on clinical and endoscopic remission. Therefore, they advocate for decision-making that considers the efficacy, safety, patient preferences, individual patient and disease characteristics, and the cost and accessibility of these therapies.

The updated ACG guidelines strongly recommend anti-TNF and VDZ therapies for preventing postoperative endoscopic recurrence in patients with high-risk CD [Table 1].[52]

Table 1.

Treatment recommendations for Crohn’s disease

Final recommendation	Strength of recommendation	Certainty of evidence	Percentage of panel agreement
Initial Treatments for Bio-Naïve Adults with Moderate-to-Severe CD
For induction and maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend early initiation of biological therapy over no treatment.	Strong	Moderate	100%
For induction and maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend using anti-TNF (such as IFX, ADA, or CZP) therapies over no treatment.	Strong	Moderate	93%
For induction and maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend using VDZ over no treatment.	Strong	Moderate	93%
For induction and maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend using ustekinumab over no treatment.	Strong	Moderate	100%
For induction and maintenance of remission in Bio-Naïve adults with moderate-to-severe CD, we recommend using anti-IL-23 agents (RZB, guselkumab, and mirikizumab) over no treatment.	Strong	Moderate	87%
For induction and maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend using upadacitinib over no treatment.	Strong	Moderate	100%
For maintenance of remission in bio-naïve adults with moderate-to-severe CD, we recommend using SC IFX (CT-P13) over no treatment.	Strong	Moderate	100%
For induction and maintenance of remission in advanced therapy-exposed adults with moderate-to-severe CD, we recommend using biosimilars of TNF agents or anti-IL-12/23 over no treatment.	Strong	Moderate	100%
Treatment for Advanced Therapy Exposed Adults with Moderate-to-Severe CD
In CD patients with secondary loss of response to anti-TNF therapy (not primary treatment failure) due to developing ADAs, we suggest switching to another anti-TNF agent over switching to another class of medications to optimize disease control.	Conditional	Very low	100%
For induction and maintenance of clinical remission in adult patients with moderate-to-severe CD who do not respond to anti-TNF therapy despite adequate serum drug levels and negative ADAs, we suggest switching to an advanced therapy outside the anti-TNF class over switching to another anti-TNF agent.	Conditional	Low	93%
For induction and maintenance of remission in adults with moderate-to-severe CD who have previously failed anti-TNF therapy, we recommend using anti-IL-23 over anti-IL-12/23.	Strong	Moderate	87%
Combination Therapies for Adults with Moderate-to-Severe CD
For the induction of remission in adults with moderate-to-severe CD, we suggest combination therapy with immunomodulators and IFX over IFX monotherapy.	Conditional	Moderate	80%
For maintenance of remission in adults with moderate-to-severe CD, we suggest SC IFX (CT-P13) monotherapy over SC IFX (CT-P13) in combination with immunomodulators (thiopurine).	Conditional	Very low	93%
For induction and maintenance of remission in adults with moderate-to-severe CD, we suggest against using a combination of ADA with immunomodulators (thiopurine) rather than ADA monotherapy. Remarks: Combining ADA with thiopurine should not be considered routinely for advanced therapy-naive CD. However, it should be considered in high-risk groups, including those with prior immunogenic failure to other anti-TNF agents.	Conditional	Moderate	93%
Treatment Optimization Strategies for Adults with CD and Secondary Loss of Response to Advanced Therapy
For adults with CD and secondary loss of response to anti-TNF therapy, we suggest measurement of anti-TNF trough levels and dose optimization based on these levels, over maintaining the standard anti-TNF dose without trough level monitoring or optimizing the dose empirically.	Conditional	Very low	100%
For treating partial or secondary loss of response in adults with CD who are treated with standard 8-weekly anti-integrins or anti-IL-12/23 inhibitors, we suggest dose escalation (by shortening the dosing interval to every 4 weeks) over no escalation.	(Good practice statement).		93%
Management of Complex Perianal Fistula among Adults with CD
For induction of remission in adults with CD and complicated perianal fistula, we recommend the use of combination therapy, including seton placement, antibiotics, and anti-TNF agents (e.g., IFX, ADA, biosimilars) over standard care or alternative treatments such as antibiotics alone, surgical drainage without seton, or other immunosuppressive therapies.	Strong	Moderate	87%
For complex perianal fistula healing in adults with CD, we suggest using a combination of immunomodulators and anti-TNF over anti-TNF monotherapy.	Conditional	Moderate	100%
For complex perianal fistula healing in adults with CD, we suggest using anti-IL-12/23, anti-IL-23, anti-integrin, or JAKIs over no treatment.	Conditional	Moderate	100%
Switching Formulations for Maintenance of Remission in Adults with Stable Moderate-to-Severe CD
For maintenance of remission in stable moderate-to-severe CD patients, we recommend treatment with either SC or IV formulations of IFX or VDZ over no treatment.	Strong	Moderate	87%
Prevention of Postoperative Recurrence among Adults with High-Risk CD
To prevent the POR of high-risk CD, we suggest using advanced therapy over no treatment. Remarks: The strongest evidence supports using anti-TNFs followed by VDZ.	Conditional	Moderate	87%

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ADA=Adalimumab, ADAs=Anti-drug antibodies, ASM=Antiseizure medication, CD=Crohn’s disease, CS=Corticosteroid, CZP=Certolizumab pegol, EIMs=Extraintestinal manifestations, IFX=Infliximab, IV=Intravenous, JAK=Janus kinase, POR=postoperative recurrence, RZB=Risankizumab, SC=Subcutaneous, TNF=Tumor necrosis factor, UST=Ustekinumab, VDZ=Vedolizumab

TREATMENT RECOMMENDATIONS FOR MODERATE TO SEVERE UC

Treatment of Advanced Therapy Exposed Adults with Moderate-to-Severe UC

Q22: Should treatment with anti-TNF agents [IFX, ADA, and golimumab] vs. no treatment be used for induction and maintenance of remission in patients with moderate-to-severe UC?

Recommendation 22: For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend anti-TNF agents (IFX, ADA, golimumab) over no treatment. (Strong recommendation, moderate certainty evidence).

Remarks: IFX is the favored anti-TNF agent in terms of efficacy in moderate-to-severe UC.

Rationale

This recommendation was supported by an NMA investigating the comparative effectiveness of anti-TNF agents for inducing and maintaining clinical response based on the Mayo score among UC patients.[114]

The analysis revealed that anti-TNF agents resulted in a 2.45 and 1.65-fold higher likelihood of inducing remission and response compared to placebo (RR 2.45, [1.72 to 3.47], moderate certainty, Table S25) and (RR 1.65, [1.37 to 1.99], moderate certainty, Table S25), respectively. Moreover, anti-TNF agents demonstrated a 2 and 1.76-fold higher likelihood of inducing remission and response compared to placebo (RR 2, [1.52 to 2.62], high certainty, Table S25) and (RR 1.76, [1.46 to 2.14], high certainty, Table S25), respectively. The authors observed an increasing trend in remission and response rates associated with IFX.[114]

S Table 25.

Treatment with anti-tumor necrosis factor [TNF] agents [IFX, adalimumab, and golimumab] compared to no treatment for induction and maintenance of remission in patients with moderate-to-severe UC.

Bibliography: Stidham RW, Lee TCH, Higgins PDR, Deshpande AR, Sussman DA, Singal AG, et al. Systematic review with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis. Aliment Pharmacol Ther. 2014 Apr;39(7):660.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision (95% CI)	Other considerations	treatment with TNF agents [IFX, ADA, and golimumab	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision (95% CI)	Other considerations	treatment with TNF agents [IFX, ADA, and golimumab	no treatment	Absolute (95% CI)
Induction of remission endpoint (assessed with: Mayo Score)
6	RCT	not serious^a	serious^b	not serious	not serious	None	210/911 (23.1%)	82/912 (9.0%)	RR 2.45 (1.72 to 3.47)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
6	RCT	not serious^a	serious^b	not serious	not serious	None	210/911 (23.1%)	82/912 (9.0%)	130 more per 1,000 (from 65 more to 222 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
Indication of response (assessed with: Mayo Score)
4	RCT	not serious^a	serious^c	not serious	not serious	None	491/888 (55.3%)	300/892 (33.6%)	RR 1.65 (1.37 to 1.99)	⨁⨁⨁◯ Moderate^a,c	CRITICAL
4	RCT	not serious^a	serious^c	not serious	not serious	None	491/888 (55.3%)	300/892 (33.6%)	219 more per 1,000 (from 124 more to 333 more)	⨁⨁⨁◯ Moderate^a,c	CRITICAL
Maintenance of remission (assessed with: Mayo Score)
3	RCT	not serious	not serious	not serious	not serious	None	129/533 (24.2%)	65/537 (12.1%)	RR 2.00 (1.52 to 2.62)	⨁⨁⨁⨁ High	CRITICAL
3	RCT	not serious	not serious	not serious	not serious	None	129/533 (24.2%)	65/537 (12.1%)	121 more per 1,000 (from 63 more to 196 more)	⨁⨁⨁⨁ High	CRITICAL
Maintenance of response endpoint (assessed with: Mayo Score)
3	RCT	not serious	not serious	not serious	not serious	None	208/533 (39.0%)	118/537 (22.0%)	RR 1.76 (1.46 to 2.14)	⨁⨁⨁⨁ High	CRITICAL
3	RCT	not serious	not serious	not serious	not serious	None	208/533 (39.0%)	118/537 (22.0%)	167 more per 1,000 (from 101 more to 251 more)	⨁⨁⨁⨁ High	CRITICAL

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CI: confidence interval; RR: risk ratio

Explanations

^a.blinding and allocation concealment ROB

^b.I2= 50.3

^c.I2=64.5

These results are supported by PURSUIT induction and maintenance trials, which found that SC golimumab significantly improved clinical response rates, remission, and mucosal healing among UC patients by week 6, with efficacy detected as early as week 2.[115] The clinical response was effectively maintained through week 54, with the 100 mg dose exhibiting superior remission and mucosal healing at weeks 30 and 54. Additionally, the safety profile was consistent in both trials.[116] ACT 1 and ACT 2 RCTs demonstrated that patients with UC treated with IFX were more likely to have a clinical response at weeks 8, 30, and 54 than those receiving a placebo.[117]

Based on moderate certainty evidence, along with balanced effects favoring anti-TNF agents, and cost-effectiveness, the guideline panel strongly recommends anti-TNF agents for induction and maintenance of remission in adults with UC who have failed or are intolerant to advanced therapies. Specific patient populations, such as those at high risk for infections, with a history of demyelinating disease, chronic infections, and advanced heart failure, would benefit from alternative advanced therapies.

The guideline panel confirms its high acceptability and feasibility, emphasizing the structured monitoring and evaluation of short-term targets (clinical response within 6–12 weeks), intermediate targets (clinical remission, biochemical response/remission, and endoscopic response within 12–24 weeks), and long-term targets (endoscopic remission, and normalization of QoL within 24–48 weeks).[30] We also encourage further research on predictive markers, local/regional real-world evidence, and comparative studies.

This recommendation aligns with the ECCO, ACG, and AGA guidelines in using anti-TNF agents to induce and maintain UC patients.[14,16] However, the ACG guideline rates ADA as inferior efficacy for first-line UC and offers sequencing choices after biologic failure. These contrasts underline the importance of individualized therapy selection. The BSG guideline also endorses anti-TNFs in UC but highlights the importance of patient selection and monitoring. These nuances reinforce the necessity of customizing anti-TNF therapy to the clinical circumstances of each patient.[31,118]

Q23: Should treatment with anti-Integrins (VDZ) vs. no treatment be used for induction and maintenance of remission in patients with moderate to severely active UC?

Recommendation 23: For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend using anti-integrins (VDZ) over no treatment. (Strong recommendation, moderate certainty evidence).

Rationale

This recommendation was based on the GEMINI 1 trial that evaluated the efficacy of VDZ (300 mg) as both induction and maintenance therapy for patients with active UC, compared to a placebo.[119]

The analysis revealed that disease outcomes, including clinical response, mucosal healing, and clinical remission during the induction phase among active UC patients with prior exposure to anti-TNF agents, were superior in the VDZ group compared to the placebo group (RR 1.48, [1.35 to 2.51], moderate certainty, Table S26), (RR 1.65, [1.19 to 2.27], moderate certainty, Table S26), and (RR 3.14, [1.51 to 6.55], moderate certainty, Table S26), respectively.[119]

S Table 26.

Treatment with Anti-Integrins (vedolizumab) compared to no treatment for induction and maintenance of remission in patients with moderately to severely active UC.

Bibliography: Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med [Internet]. 2013 Aug 22 [cited 2025 Apr 13];369(8):699–710. Available from: https://pubmed.ncbi.nlm.nih.gov/23964932/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	treatment with Anti-Integrins (VDZ)	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	treatment with Anti-Integrins (VDZ)	no treatment	Absolute (95% CI)
Clinical response (Induction phase) (follow-up: 6 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	106/225 (47.1%)	38/149 (25.5%)	RR 1.48 (1.35 to 2.51)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	106/225 (47.1%)	38/149 (25.5%)	122 more per 1,000 (from 89 more to 385 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical remission (Induction phase) (follow-up: 6 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	38/225 (16.9%)	8/149 (5.4%)	RR 3.14 (1.51 to 6.55)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	38/225 (16.9%)	8/149 (5.4%)	115 more per 1,000 (from 27 more to 298 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Mucosal healing (Induction phase) (follow-up: 6 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	92/225 (40.9%)	37/149 (24.8%)	RR 1.65 (1.19 to 2.27)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	92/225 (40.9%)	37/149 (24.8%)	161 more per 1,000 (from 47 more to 315 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical remission (Maintenance phase) (follow-up: 52 weeks; assessed with: Administered every 8 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	51/122 (41.8%)	20/126 (15.9%)	RR 2.63 (1.67 to 4.14)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	51/122 (41.8%)	20/126 (15.9%)	259 more per 1,000 (from 106 more to 498 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Durable response (Maintenance phase) (follow-up: 52 weeks; assessed with: Administered every 8 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	69/122 (56.6%)	30/126 (23.8%)	RR 2.37 (1.67 to 3.37)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	69/122 (56.6%)	30/126 (23.8%)	326 more per 1,000 (from 160 more to 564 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Durable remission (Maintenance phase) (follow-up: 52 weeks; assessed with: Administered every 8 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	25/122 (20.5%)	11/126 (8.7%)	RR 2.35 (1.21 to 4.56)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	25/122 (20.5%)	11/126 (8.7%)	118 more per 1,000 (from 18 more to 311 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Corticosteroid-free remission (Maintenance phase) (follow-up: 52 weeks; assessed with: Administered every 8 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	22/70 (31.4%)	10/72 (13.9%)	RR 2.26 (1.15 to 4.43)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	22/70 (31.4%)	10/72 (13.9%)	175 more per 1,000 (from 21 more to 476 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Any adverse events (Induction phase) (follow-up: 6 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	337/746 (45.2%)	69/149 (46.3%)	RR 0.97 (0.81 to 1.18)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	337/746 (45.2%)	69/149 (46.3%)	14 fewer per 1,000 (from 88 fewer to 83 more)	⨁⨁⨁⨁ High	CRITICAL
Any adverse events (Maintenance phase) (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	497/620 (80.2%)	220/275 (80.0%)	RR 1.00 (0.93 to 1.07)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	497/620 (80.2%)	220/275 (80.0%)	0 fewer per 1,000 (from 56 fewer to 56 more)	⨁⨁⨁⨁ High	CRITICAL
Serious adverse events (Induction phase) (follow-up: 6 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	25/746 (3.4%)	10/149 (6.7%)	RR 0.499 (0.240 to 1.020)	⨁⨁⨁⨁ High	IMPORTANT
1	RCT	not serious	not serious	not serious	not serious	none	25/746 (3.4%)	10/149 (6.7%)	34 fewer per 1,000 (from 51 fewer to 1 more)	⨁⨁⨁⨁ High	IMPORTANT
Serious adverse events (Maintenance phase) (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	77/620 (12.4%)	37/275 (13.5%)	RR 0.92 (0.64 to 1.33)	⨁⨁⨁⨁ High	IMPORTANT
1	RCT	not serious	not serious	not serious	not serious	none	77/620 (12.4%)	37/275 (13.5%)	11 fewer per 1,000 (from 48 fewer to 44 more)	⨁⨁⨁⨁ High	IMPORTANT
Mucosal healing (Maintenance phase) (follow-up: 52 weeks; assessed with: Administered every 8 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	63/122 (51.6%)	25/126 (19.8%)	RR 2.60 (1.76 to 3.84)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	63/122 (51.6%)	25/126 (19.8%)	317 more per 1,000 (from 151 more to 563 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Mucosal healing (Maintenance phase) (follow-up: 52 weeks; assessed with: Administered every 4 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	70/125 (56.0%)	25/126 (19.8%)	RR 2.82 (1.92 to 4.14)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	70/125 (56.0%)	25/126 (19.8%)	361 more per 1,000 (from 183 more to 623 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical remission (Maintenance phase) (follow-up: 52 weeks; assessed with: Administered every 4 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	56/125 (44.8%)	20/126 (15.9%)	RR 2.82 (1.80 to 4.41)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	56/125 (44.8%)	20/126 (15.9%)	289 more per 1,000 (from 127 more to 541 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Durable response (Maintenance phase) (follow-up: 52 weeks; assessed with: Administered every 4 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	65/125 (52.0%)	30/126 (23.8%)	RR 2.18 (1.53 to 3.11)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	65/125 (52.0%)	30/126 (23.8%)	281 more per 1,000 (from 126 more to 502 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Durable remission (Maintenance phase) (follow-up: 52 weeks; assessed with: Administered every 4 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	30/125 (24.0%)	11/126 (8.7%)	RR 2.74 (1.44 to 5.24)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	30/125 (24.0%)	11/126 (8.7%)	152 more per 1,000 (from 38 more to 370 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Glucocorticosteroid-free remission (Maintenance phase) (follow-up: 52 weeks; assessed with: Administered every 4 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	33/73 (45.2%)	10/72 (13.9%)	RR 3.25 (1.74 to 6.10)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	33/73 (45.2%)	10/72 (13.9%)	313 more per 1,000 (from 103 more to 708 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.Number of total events is more than 400 and not wide CI

During the maintenance phase, response rates, including clinical remission, durable response, durable remission, corticosteroid-free remission, and mucosal healing, were significantly better among patients in the VDZ group every 8 weeks (RR 2.63, [1.67 to 4.14], moderate certainty, Table S26), (RR 2.37, [1.67 to 3.37], moderate certainty, Table S26), (RR 2.35, [1.21 to 4.56], moderate certainty, Table S26), (RR 2.26, [1.15 to 4.43], moderate certainty, Table S26), and (RR 2.60, [1.76 to 3.84], moderate certainty, Table S26), respectively.[119]

Additionally, the safety profile was comparable between both groups concerning AEs and SAEs during the induction and maintenance phases (RR 0.97, [0.81 to 1.18], high certainty, Table S26), (RR 0.499, [0.24 to 1.02], high certainty, Table S26), (RR 1.00, [0.93 to 1.07], high certainty, Table S26), and (RR 0.92, [0.64 to 1.33], high certainty, Table S26), respectively.[119]

Furthermore, VDZ has shown greater efficacy as induction therapy and was significantly more effective than a placebo as maintenance therapy for Japanese patients with UC.[120] A post hoc analysis of the study revealed response rates of 53% and 39% among anti-TNF-bio-naïve and anti-TNF failure patients, respectively. These findings indicate that both populations show similar clinically meaningful effects.[121]

Based on moderate certainty evidence, the guideline panel strongly recommends using anti-integrin therapies (VDZ) to induce and maintain remission in adults with UC following failure or intolerance to advanced therapies. The ECCO, ACG, and AGA guidelines strongly recommend using VDZ as induction and maintenance therapy for adults with UC,[14,16] while the BSG guideline also supports VDZ but notes that its benefit might be smaller in some analyses and recommends clinicians explicitly discuss this with patients in a shared decision-making framework.[31]

The guideline panel suggests that VDZ be prioritized as a first-line treatment for patient populations at a higher risk for opportunistic infections, such as the elderly, those with comorbidities or occupational exposure, and those with a previous history of treated solid tumors. The panel confirms that VDZ is highly acceptable, feasible, and cost-effective.

Q24. Should treatment with anti-IL-12/23 vs. no treatment be used for induction and maintenance of remission in patients with moderate-to-severe UC?

Recommendation 24: For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend using anti-IL12/23 over no treatment (Strong recommendation, moderate certainty evidence).

Rationale

This recommendation was based on a phase 3 RCT (UNIFI) involving 961 UC patients who were evaluated with IV 130 mg or approximately 6 mg/kg of ustekinumab, compared to a placebo during an 8-week induction phase, followed by SC 90 mg of ustekinumab every 8 to 12 weeks for a 44-week maintenance phase. The study demonstrated the superiority of ustekinumab across all efficacy outcomes, while showing comparable safety outcomes to the placebo.[122]

For induction therapy at 8 weeks, ustekinumab demonstrated significantly higher clinical remission rates (RR 2.93, [1.72 to 4.97], moderate certainty, Table S27), endoscopic improvement (RR 1.9, [1.4 to 2.6], moderate certainty, Table S27), clinical response (RR 1.64, [1.35 to 1.99], moderate certainty, Table S27), and histo-endoscopic mucosal healing (RR 2.3, [1.5 to 3.5], moderate certainty, Table S27). Furthermore, for the maintenance phase at 44 weeks, ustekinumab maintained superiority in clinical remission (RR 1.59, [1.15 to 2.21], moderate certainty, Table S27), endoscopic improvement (RR 1.50, [1.14 to 2.03], moderate certainty, Table S27), clinical response (RR 1.5, [1.3 to 1.8], moderate certainty, Table S27), and corticosteroid-free remission (RR 1.61, [1.16 to 2.24], moderate certainty, Table S27). SAEs at 44 weeks were lower in the ustekinumab group (3.7% vs. 6.9%). Infections were comparable at 8 weeks (15.5% vs. 15.4%) but decreased at 44 weeks (13.7% vs. 46.3%).

S Table 27.

Treatment with Anti-IL-12/23 compared to no treatment for induction and maintenance of remission in patients with moderate-to-severe UC.

Bibliography: Sands BE, Sandborn WJ, Panaccione R, O’Brien CD, Zhang H, Johanns J, et al. Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med [Internet]. 2019 Sep 26 [cited 2025 Apr 13];381(13):1201–14. Available from: https://pubmed.ncbi.nlm.nih.gov/31553833/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	treatment with Anti-IL-12/23	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	treatment with Anti-IL-12/23	no treatment	Absolute (95% CI)
8 weeks clinical remission (Induction therapy)
1	RCT	not serious	not serious	not serious	serious^a	none	50/320 (15.6%)	17/319 (5.3%)	RR 2.93 (1.72 to 4.97)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	50/320 (15.6%)	17/319 (5.3%)	103 more per 1,000 (from 38 more to 212 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
8 weeks endoscopic improvement
1	RCT	not serious	not serious	not serious	serious^a	none	84/320 (26.3%)	44/319 (13.8%)	RR 1.9 (1.4 to 2.6)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	84/320 (26.3%)	44/319 (13.8%)	124 more per 1,000 (from 55 more to 221 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical Response T 8 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	164/320 (51.2%)	100/320 (31.3%)	RR 1.64 (1.35 to 1.99)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	164/320 (51.2%)	100/320 (31.3%)	200 more per 1,000 (from 109 more to 309 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Histo-Endoscopic Mucosal Healing at 8 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	65/320 (20.3%)	28/319 (8.8%)	RR 2.3 (1.5 to 3.5)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	65/320 (20.3%)	28/319 (8.8%)	114 more per 1,000 (from 44 more to 219 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical remission at 44 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	66/172 (38.4%)	42/175 (24.0%)	RR 1.59 (1.15 to 2.21)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	66/172 (38.4%)	42/175 (24.0%)	142 more per 1,000 (from 36 more to 290 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Maintenance of Clinical Response through Wk 44
1	RCT	not serious	not serious	not serious	serious^a	none	117/172 (68.0%)	78/175 (44.6%)	RR 1.5 (1.3 to 1.8)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	117/172 (68.0%)	78/175 (44.6%)	223 more per 1,000 (from 134 more to 357 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Endoscopic Improvement at 44 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	75/172 (43.6%)	50/175 (28.6%)	RR 1.50 (1.14 to 2.03)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	75/172 (43.6%)	50/175 (28.6%)	143 more per 1,000 (from 40 more to 294 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Corticosteroid-free Remission at 44 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	65/172 (37.8%)	41/175 (23.4%)	RR 1.61 (1.16 to 2.24)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	65/172 (37.8%)	41/175 (23.4%)	143 more per 1,000 (from 37 more to 291 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Any adverse event at 8 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	133/321 (41.4%)	153/319 (48.0%)	RR 0.86 (0.72 to 1.03)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	133/321 (41.4%)	153/319 (48.0%)	67 fewer per 1,000 (from 134 fewer to 14 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Any adverse event at 44 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	119/172 (69.2%)	138/175 (78.9%)	RR 0.87 (0.77 to 0.99)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	119/172 (69.2%)	138/175 (78.9%)	103 fewer per 1,000 (from 181 fewer to 8 fewer)	⨁⨁⨁◯ Moderate^a	CRITICAL
Serious adverse events at 8 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	12/321 (3.7%)	22/319 (6.9%)	RR 0.540 (0.270 to 1.076)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	12/321 (3.7%)	22/319 (6.9%)	32 fewer per 1,000 (from 50 fewer to 5 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Any infection at 8 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	51/321 (15.9%)	49/319 (15.4%)	RR 1.03 (0.72 to 1.48)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	51/321 (15.9%)	49/319 (15.4%)	5 more per 1,000 (from 43 fewer to 74 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Any infection at 44 weeka
1	RCT	not serious	not serious	not serious	serious^a	none	58/172 (33.7%)	81/175 (46.3%)	RR 0.73 (0.56 to 0.95)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	58/172 (33.7%)	81/175 (46.3%)	125 fewer per 1,000 (from 204 fewer to 23 fewer)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Serious adverse events at 44 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	13/172 (7.6%)	17/175 (9.7%)	RR 0.79 (0.39 to 1.55)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	13/172 (7.6%)	17/175 (9.7%)	20 fewer per 1,000 (from 59 fewer to 53 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.the total events below 400.

An NMA found that, in patients with prior exposure to anti-TNF agents, ustekinumab was ranked as one of the drugs with the highest efficacy for the induction of clinical remission.[123]

Real-world studies have supported these findings; ustekinumab demonstrated both short- and long-term effectiveness in patients with UC, with overall remission rates of 66.0% at 8 weeks and 70.2% at 56 weeks. Remission was achieved among biologic-bio-naïve (73.7% at 8 and 56 weeks) and biologic-failure patients (60.7% at 8 weeks and 67.9% at 56 weeks).[124] Another meta-analysis confirmed the efficacy and safety of ustekinumab in RCTs and its effectiveness in real-world clinical practice.[125]

Based on moderate certainty evidence demonstrating extensive clinical benefits, minor undesirable effects, revealing effect balance, and moderate cost favoring the anti-IL-12/23 therapy, the guideline panel strongly recommends anti-IL-12/23 in patients with UC who have failed conventional or advanced therapy. We also emphasize that anti-IL-12/23 could be considered in patients with UC who have failed IFX. The strong recommendation reflects the feasibility and acceptability of the drug. This recommendation aligns with the ECCO guideline, which strongly recommends ustekinumab among UC patients with conventional therapy intolerance or inadequate response.[16] The ACG guideline also suggests ustekinumab as an effective treatment option, particularly after anti-TNF failure, emphasizing therapy sequencing and evaluation.[118] The BSG guideline also accepts ustekinumab as an option but makes a conditional recommendation, emphasizing the importance of shared decision-making.[31] The AGA guideline aligns with the current recommendation favoring ustekinumab among primary nonresponders to IFX.[14]

Q25. Should Anti-IL-23 (RZB, Mirikizumab, Guselkumab) vs. no treatment be used for induction and maintenance of remission in patients with moderate-to-severely active UC?

Recommendation 25: For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend using anti-IL-23 (RZB, Mirikizumab, Guselkumab) over no treatment (Strong recommendation, moderate certainty evidence).

Rationale

This recommendation arises from phase III clinical trials for all three IL-23 inhibitors. A phase 3 RCT (LUCENT-1 and LUCENT-2) assesses the effectiveness of mirikizumab, a p19-targeted IL-23 inhibitor, for achieving remission at 12 weeks compared to placebo. It involved an IV administration of mirikizumab 300 mg every 4 weeks during the induction phase and a maintenance phase of SC mirikizumab 200 mg every 4 weeks for 40 weeks in patients with UC.[126]

The mirikizumab demonstrated superior efficacy by achieving higher clinical remission rates (RR 1.82, [1.33 to 2.50], high certainty, Table S28), increased endoscopic remission (RR 1.7, [1.4 to 2.2], moderate certainty, Table S28), significant improvement in histologic–endoscopic mucosal healing (RR 1.94, [1.43 to 2.63], moderate certainty, Table S28), and enhanced symptomatic remission (RR 1.63, [1.33 to 1.98], high certainty, Table S28) at the induction trial.

S Table 28.

Anti-IL-23 (Risankizumab, Mirikizumab, Guselkumab) compared to no treatment for induction and maintenance of remission in patients with moderately-to-severely active UC.

Bibliography: D’Haens G, Dubinsky M, Kobayashi T, Irving PM, Howaldt S, Pokrotnieks J, et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2023 Jun;388(26):2444–55.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Anti-IL-23 (RZB, Mirikizumab, Guselkumab)	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Anti-IL-23 (RZB, Mirikizumab, Guselkumab)	no treatment	Absolute (95% CI)
Clinical remission of the induction at 12 weeks
1	RCT	not serious	not serious	not serious	not serious^a	none	210/868 (24.2%)	39/294 (13.3%)	RR 1.82 (1.33 to 2.50)	⨁⨁⨁⨁ High^a	CRITICAL
1	RCT	not serious	not serious	not serious	not serious^a	none	210/868 (24.2%)	39/294 (13.3%)	109 more per 1,000 (from 44 more to 199 more)	⨁⨁⨁⨁ High^a	CRITICAL
Clinical response at 12 weeks
1	RCT	not serious	not serious	not serious	not serious	none	551/868 (63.5%)	124/294 (42.2%)	RR 1.5 (1.3 to 1.7)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	551/868 (63.5%)	124/294 (42.2%)	211 more per 1,000 (from 127 more to 295 more)	⨁⨁⨁⨁ High	CRITICAL
Endoscopic Remission at 12 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	315/868 (36.3%)	62/294 (21.1%)	RR 1.7 (1.4 to 2.2)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	315/868 (36.3%)	62/294 (21.1%)	148 more per 1,000 (from 84 more to 253 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Histologic–Endoscopic Mucosal Improvement at 12 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	235/868 (27.1%)	41/294 (13.9%)	RR 1.94 (1.43 to 2.63)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	235/868 (27.1%)	41/294 (13.9%)	131 more per 1,000 (from 60 more to 227 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Remission of Symptoms at 12 weeka
1	RCT	not serious	not serious	not serious	not serious	none	395/868 (45.5%)	82/294 (27.9%)	RR 1.63 (1.33 to 1.98)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	395/868 (45.5%)	82/294 (27.9%)	176 more per 1,000 (from 92 more to 273 more)	⨁⨁⨁⨁ High	CRITICAL
Clinical Remission at 52 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	182/365 (49.9%)	45/179 (25.1%)	RR 1.98 (1.50 to 2.60)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	182/365 (49.9%)	45/179 (25.1%)	246 more per 1,000 (from 126 more to 402 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Glucocorticoid-free Clinical Remission at 52 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	164/365 (44.9%)	39/178 (21.9%)	RR 2.05 (1.50 to 2.76)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	164/365 (44.9%)	39/178 (21.9%)	230 more per 1,000 (from 110 more to 386 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Maintenance of Clinical Remission at 52 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	91/143 (63.6%)	24/65 (36.9%)	RR 1.72 (1.22 to 2.42)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	91/143 (63.6%)	24/65 (36.9%)	266 more per 1,000 (from 81 more to 524 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Endoscopic Remission at 52 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	214/365 (58.6%)	52/179 (29.1%)	RR 2.01 (1.58 to 2.57)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	214/365 (58.6%)	52/179 (29.1%)	293 more per 1,000 (from 168 more to 456 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Histologic– Endoscopic Mucosal Remission at 52 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	158/365 (43.3%)	39/179 (21.8%)	RR 1.98 (1.46 to 2.68)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	158/365 (43.3%)	39/179 (21.8%)	214 more per 1,000 (from 100 more to 366 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Bowel-Urgency Remission at 52 weeks
1	RCT	not serious	not serious	not serious	serious^a	none	144/336 (42.9%)	43/172 (25.0%)	RR 1.71 (1.28 to 2.28)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	144/336 (42.9%)	43/172 (25.0%)	178 more per 1,000 (from 70 more to 320 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Any adverse events (Induction trial)
1	RCT	not serious	not serious	not serious	not serious	none	426/958 (44.5%)	148/321 (46.1%)	RR 0.69 (0.84 to 1.11)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	426/958 (44.5%)	148/321 (46.1%)	143 fewer per 1,000 (from 74 fewer to 51 more)	⨁⨁⨁⨁ High	CRITICAL
Serious adverse events (Induction trial)
1	RCT	not serious	not serious	not serious	not serious	none	27/958 (2.8%)	17/321 (5.3%)	RR 0.53 (0.29 to 0.96)	⨁⨁⨁⨁ High	IMPORTANT
1	RCT	not serious	not serious	not serious	not serious	none	27/958 (2.8%)	17/321 (5.3%)	25 fewer per 1,000 (from 38 fewer to 2 fewer)	⨁⨁⨁⨁ High	IMPORTANT
Any adverse events (Maintenance trial)
1	RCT	not serious	not serious	not serious	not serious	none	251/389 (64.5%)	132/192 (68.8%)	RR 0.94 (0.83 to 1.06)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	251/389 (64.5%)	132/192 (68.8%)	41 fewer per 1,000 (from 117 fewer to 41 more)	⨁⨁⨁⨁ High	CRITICAL
Serious adverse events (Maintenance trial)
1	RCT	not serious	not serious	not serious	not serious	none	13/389 (3.3%)	15/192 (7.8%)	RR 0.43 (0.21 to 0.88)	⨁⨁⨁⨁ High	IMPORTANT
1	RCT	not serious	not serious	not serious	not serious	none	13/389 (3.3%)	15/192 (7.8%)	45 fewer per 1,000 (from 62 fewer to 9 fewer)	⨁⨁⨁⨁ High	IMPORTANT

Open in a new tab

CI: confidence interval; RR: risk ratio

Explanations

^a.Number of events below 400.

For maintenance at 52 weeks, mirikizumab sustained higher clinical remission rates (RR 1.98, [1.50 to 2.60], moderate certainty, Table S28) and greater glucocorticoid-free clinical remission (RR 2.05, [1.50 to 2.76], moderate certainty, Table S28). Additionally, the rate of patients who maintained remission from the induction trial was higher with mirikizumab (RR 1.72, [1.22 to 2.42], moderate certainty, Table S28). Furthermore, endoscopic remission (RR 2.01, [1.58 to 2.57], moderate certainty, Table S28) and bowel urgency remission (RR 1.71, [1.28 to 2.28], moderate certainty, Table S28) were greater with mirikizumab.[126]

Additionally, the safety profile was comparable between both groups concerning AEs and SAEs during the induction and maintenance phases (RR 0.69, [0.84 to 1.11], high certainty, Table S28), (RR 0.53, [0.29 to 0.96], high certainty, Table S28), (RR 0.94, 95% CI 0.83 to 1.06], high certainty, Table S28), and (RR 0.43, [0.21 to 0.88], high certainty, Table S28]

The INSPIRE phase 3 RCT demonstrated that IV RZB significantly improved clinical remission rates compared to placebo at week 12 and maintained higher rates in maintenance patients. The therapy showed robust efficacy across secondary endpoints, including endoscopic improvement and symptom relief, with a favorable safety profile.[127]

Post hoc analysis of the INSPIRE and COMMAND Phase 3 studies demonstrated that RZB was effective and well tolerated for remission induction and maintenance in patients with UC, regardless of their prior experience with advanced therapies. However, higher efficacy outcomes were observed in biologic-naive patients compared to those refractory to prior advanced therapy.[128]

In the QUASAR phase 3 trial, guselkumab demonstrated a favorable safety profile over placebo in the induction and maintenance phases, with comparable AE rates in both groups (49%). However, SAEs were less frequent with guselkumab (3% vs. 7% for placebo), and lower discontinuations in the guselkumab group.[129]

The guideline panel strongly recommends anti-IL-23 in moderate-to-severe UC patients who have failed conventional or advanced therapy, supported by moderate certainty evidence. The balance of effects favors anti-IL-23, demonstrating substantial benefits and minor undesirable effects, with a moderate cost of the drug as also favorable.

This recommendation is in line with the most recent ACG guideline, which highly supports mirikizumab, RZB, and guselkumab for the induction and maintenance of remission in moderate-to-severe UC.[118] The BSG guideline, although noting the increasing efficacy of IL-23 inhibitors, makes a conditional recommendation based on limited long-term and comparative data, and highlights the importance of shared decision-making.[31]

Q26. Should treatment with JAKIs (tofacitinib, upadacitinib, filgotinib) vs. no treatment be used for induction and maintenance of remission in patients with moderate-to-severe UC?

Recommendation 26: For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend the treatment with JAK inhibitors (tofacitinib, upadacitinib, and filgotinib) over no treatment (Strong recommendation, Moderate certainty evidence).

Rationale

This recommendation was based on RCTs demonstrating the efficacy of JAKIs in managing patients with moderate-to-severe UC.

In the U-ACHIEVE induction and maintenance phase 3 trials, upadacitinib was evaluated in patients with UC. In the induction studies, clinical remission at week 8 was superior among patients receiving upadacitinib 45 mg once daily, compared to the placebo (P < 0.001) (RR 6.99, [4.13 to 11.83, moderate certainty, Table S29).[130]

S Table 29.

Treatment with JAK Inhibitors (JAKIs) (Tofacitinib, Upadacitinib, Filgotinib) compared to no treatment for induction and maintenance of remission in patients with moderate-to-severe UC.

Bibliography: Danese S, Vermeire S, Zhou W, Pangan AL, Siffledeen J, Greenbloom S, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, RCT. Lancet. 2022 Jun;399(10341):2113–28.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	treatment with (JAKIs) (Tofacitinib, Upadacitinib, Filgotinib)	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations		no treatment	Absolute (95% CI)
Clinical remission at 10 weeks (filgotinib)
1	RCT	not serious	not serious	not serious	serious^a	none	30/262 (11.5%)	6/142 (4.2%)	RR 2.70 (1.15 to 6.35)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	30/262 (11.5%)	6/142 (4.2%)	72 more per 1,000 (from 6 more to 226 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Mayo Clinic Score remission at 10 weeks (filgotinib)
1	RCT	not serious	not serious	not serious	serious^a	none	25/262 (9.5%)	6/142 (4.2%)	RR 2.25 (0.94 to 5.37)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	25/262 (9.5%)	6/142 (4.2%)	53 more per 1,000 (from 3 fewer to 185 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Endoscopic remission at 10 weeks (filgotinib)
1	RCT	not serious	not serious	not serious	serious^a	none	9/262 (3.4%)	3/142 (2.1%)	RR 1.62 (0.44 to 5.90)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	9/262 (3.4%)	3/142 (2.1%)	13 more per 1,000 (from 12 fewer to 104 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Histological remission at 10 weeks (filgotinib)
1	RCT	not serious	not serious	not serious	serious^a	none	52/262 (19.8%)	12/142 (8.5%)	RR 2.34 (1.29 to 4.25)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	52/262 (19.8%)	12/142 (8.5%)	113 more per 1,000 (from 25 more to 275 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical remission at week 58 (filgotinib)
1	RCT	not serious	not serious	not serious	serious^a	none	74/199 (37.2%)	11/98 (11.2%)	RR 3.31 (1.84 to 5.94)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	74/199 (37.2%)	11/98 (11.2%)	259 more per 1,000 (from 94 more to 554 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
6-month corticosteroid-free remission (filgotinib)
1	RCT	not serious	not serious	not serious	serious^a	none	25/92 (27.2%)	3/47 (6.4%)	RR 4.25 (1.35 to 13.37)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	25/92 (27.2%)	3/47 (6.4%)	207 more per 1,000 (from 22 more to 790 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Endoscopic remission at week 58 (filgotinib)
1	RCT	not serious	not serious	not serious	serious^a	none	31/199 (15.6%)	6/98 (6.1%)	RR 2.54 (1.09 to 5.80)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	31/199 (15.6%)	6/98 (6.1%)	94 more per 1,000 (from 6 more to 294 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Mayo Clinic Score remission at week 58 (filgotinib)
1	RCT	not serious	not serious	not serious	serious^a	none	69/199 (34.7%)	9/98 (9.2%)	RR 3.70 (1.96 to 7.20)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	69/199 (34.7%)	9/98 (9.2%)	248 more per 1,000 (from 88 more to 569 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Histologic remission at week 58 (filgotinib)
1	RCT	not serious	not serious	not serious	serious^a	none	76/199 (38.2%)	13/98 (13.3%)	RR 2.87 (1.68 to 4.90)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	76/199 (38.2%)	13/98 (13.3%)	248 more per 1,000 (from 90 more to 517 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical remission (Induction trials) (upadacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	serious^b	none	197/660 (29.8%)	14/328 (4.3%)	RR 6.99 (4.13 to 11.83)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	197/660 (29.8%)	14/328 (4.3%)	256 more per 1,000 (from 134 more to 462 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Clinical remission (Maintenance trial) ( 15 mg upadacitinib) (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	63/148 (42.6%)	18/149 (12.1%)	RR 3.52 (2.20 to 5.64)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	63/148 (42.6%)	18/149 (12.1%)	304 more per 1,000 (from 145 more to 561 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical remission (Maintenance trial) ( 30 mg upadacitinib) (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	80/154 (51.9%)	18/149 (12.1%)	RR 4.3 (2.7 to 6.8)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	80/154 (51.9%)	18/149 (12.1%)	399 more per 1,000 (from 205 more to 701 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Serious adverse events (Induction trials) (upadacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	19/663 (2.9%)	17/332 (5.1%)	RR 0.56 (0.29 to 1.06)	⨁⨁⨁⨁ High	IMPORTANT
1	RCT	not serious	not serious	not serious	not serious	none	19/663 (2.9%)	17/332 (5.1%)	23 fewer per 1,000 (from 36 fewer to 3 more)	⨁⨁⨁⨁ High	IMPORTANT
Serious adverse events (Maintenance trial) (15 mg upadacitinib) (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	10/148 (6.8%)	19/149 (12.8%)	RR 0.53 (0.25 to 1.10)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	10/148 (6.8%)	19/149 (12.8%)	60 fewer per 1,000 (from 96 fewer to 13 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Serious adverse events (Maintenance trial) (30 mg upadacitinib) (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	9/154 (5.8%)	19/149 (12.8%)	RR 0.45 (0.21 to 0.98)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	9/154 (5.8%)	19/149 (12.8%)	70 fewer per 1,000 (from 101 fewer to 3 fewer)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Remission (OCTAVE 1-tofacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	serious^b	none	88/476 (18.5%)	10/122 (8.2%)	RR 2.25 (1.21 to 4.20)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	88/476 (18.5%)	10/122 (8.2%)	102 more per 1,000 (from 17 more to 262 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Remission (OCTAVE 2-tofacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	71/429 (16.6%)	4/112 (3.6%)	RR 4.63 (1.73 to 12.40)	⨁⨁◯◯ Low^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a,b	none	71/429 (16.6%)	4/112 (3.6%)	130 more per 1,000 (from 26 more to 407 more)	⨁⨁◯◯ Low^a,b	CRITICAL
Remission (OCTAVE Sustain-tofacitinib) (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	80/197 (40.6%)	22/198 (11.1%)	RR 3.65 (2.38 to 5.60)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	80/197 (40.6%)	22/198 (11.1%)	294 more per 1,000 (from 153 more to 511 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Mucosal healing (OCTAVE 1-tofacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	serious^b	none	149/476 (31.3%)	19/122 (15.6%)	RR 2.01 (1.30 to 3.10)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	149/476 (31.3%)	19/122 (15.6%)	157 more per 1,000 (from 47 more to 327 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Mucosal healing (OCTAVE 2-tofacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	122/429 (28.4%)	13/112 (11.6%)	RR 2.45 (1.44 to 4.17)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a,b	none	122/429 (28.4%)	13/112 (11.6%)	168 more per 1,000 (from 51 more to 368 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
Mucosal healing (OCTAVE sustain-tofacitinib) (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	90/197 (45.7%)	26/198 (13.1%)	RR 3.47 (2.35 to 5.13)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a,b	none	90/197 (45.7%)	26/198 (13.1%)	324 more per 1,000 (from 177 more to 542 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
Endoscopic remission (OCTAVE 1-tofacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	serious^b	none	32/476 (6.7%)	2/122 (1.6%)	RR 4.10 (0.99 to 16.87)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	32/476 (6.7%)	2/122 (1.6%)	51 more per 1,000 (from 0 fewer to 260 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Endoscopic remission (OCTAVE 2-tofacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	30/429 (7.0%)	2/112 (1.8%)	RR 3.19 (0.95 to 16.14)	⨁⨁◯◯ Low^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a,b	none	30/429 (7.0%)	2/112 (1.8%)	39 more per 1,000 (from 1 fewer to 270 more)	⨁⨁◯◯ Low^a,b	CRITICAL
Clinical response (OCTAVE sustain-tofacitinib) (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a,b	none	122/197 (61.9%)	40/198 (20.2%)	RR 3.10 (2.27 to 4.12)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a,b	none	122/197 (61.9%)	40/198 (20.2%)	424 more per 1,000 (from 257 more to 630 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
Adverse events (OCTAVE 1- tofacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	269/476 (56.5%)	73/122 (59.8%)	RR 0.94 (0.80 to 1.11)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	269/476 (56.5%)	73/122 (59.8%)	36 fewer per 1,000 (from 120 fewer to 66 more)	⨁⨁⨁⨁ High	CRITICAL
Adverse events (OCTAVE 2- tofacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	232/429 (54.1%)	59/112 (52.7%)	RR 1.02 (0.84 to 1.25)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	232/429 (54.1%)	59/112 (52.7%)	11 more per 1,000 (from 84 fewer to 132 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Adverse events (OCTAVE sustain- tofacitinib) (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	156/196 (79.6%)	149/198 (75.3%)	RR 1.06 (0.95 to 1.17)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	156/196 (79.6%)	149/198 (75.3%)	45 more per 1,000 (from 38 fewer to 128 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Serious adverse events (OCTAVE 1- tofacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	16/476 (3.4%)	5/122 (4.1%)	RR 0.82 (0.30 to 2.19)	⨁⨁⨁⨁ High	IMPORTANT
1	RCT	not serious	not serious	not serious	not serious	none	16/476 (3.4%)	5/122 (4.1%)	7 fewer per 1,000 (from 29 fewer to 49 more)	⨁⨁⨁⨁ High	IMPORTANT
Serious adverse events (OCTAVE 2- tofacitinib) (follow-up: 8 weeks)
1	RCT	not serious	not serious	not serious	not serious	none	18/429 (4.2%)	9/112 (8.0%)	RR 0.52 (0.24 to 1.13)	⨁⨁⨁⨁ High	IMPORTANT
1	RCT	not serious	not serious	not serious	not serious	none	18/429 (4.2%)	9/112 (8.0%)	39 fewer per 1,000 (from 61 fewer to 10 more)	⨁⨁⨁⨁ High	IMPORTANT
Serious adverse events (OCTAVE sustain- tofacitinib) (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	11/196 (5.6%)	13/198 (6.6%)	RR 0.85 (0.39 to 1.86)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	11/196 (5.6%)	13/198 (6.6%)	10 fewer per 1,000 (from 40 fewer to 56 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.Total events below 400

^b.Wide CI.

In the maintenance study, patients who achieved clinical response during induction were rerandomized to receive upadacitinib 15 mg or 30 mg once daily, or placebo. At week 52, the clinical remission rates were 42% (15 mg), 52% (30 mg), and 12% (placebo) (RR 3.52, [2.20 to 5.64], moderate certainty, Table S29) and (RR 4.3, [2.7 to 6.8], moderate certainty, Table S29), for upadacitinib 15 mg or 30 mg, respectively (P < 0.001).[130]

Additionally, SAEs were less frequent in upadacitinib groups at the induction and maintenance trial (either 15 mg or 30 mg) (RR 5.56, [0.29 to 1.06], high certainty, Table S29), (RR 0.53, [0.25 to 1.10], moderate certainty, Table S29), and (RR 0.45, [0.21 to 0.98], moderate certainty, Table S29).[130]

Tofacitinib was investigated in a phase 3 OCTAVE induction 1 and 2 trial and found to be effective induction and maintenance therapy among patients with UC despite previous conventional or anti-TNF therapy.[131]

In OCTAVE Induction 1, remission at 8 weeks was achieved in 18.5% of patients receiving tofacitinib compared to 8.2% with placebo (P = 0.007). In OCTAVE Induction 2, the remission rates were 16.6% for tofacitinib vs. 3.6% for placebo (RR 2.25, [1.21 to 4.20], moderate certainty, Table S29) and (RR 4.63, [1.73 to 12.40], low certainty, Table S29), respectively (P < 0.001). Additionally, mucosal healing and endoscopic remission were significantly higher in the tofacitinib group in OCTAVE 1 (RR 2.01, [1.30 to 3.10], moderate certainty, Table S29) and (RR 4.10, [0.99 to 16.87], moderate certainty, Table S29), as well as in OCTAVE 2 (RR 2.45, [1.44 to 4.17], moderate certainty, Table S29) and (RR 3.19, [0.95 to 16.14], low certainty, Table S29), respectively.[131]

Patients who responded to induction therapy were rerandomized to receive tofacitinib (5 mg or 10 mg twice daily) or placebo for 52 weeks in the OCTAVE Sustain Trial. Remission at 52 weeks occurred in 34.3% (5 mg), 40.6% (10 mg), and 11.1% (placebo) of patients (P < 0.001 for both tofacitinib doses vs. placebo) (RR 3.65, [2.38 to 5.60], moderate certainty, Table S29). The safety profile was comparable between all groups in the induction and maintenance trials.[131]

The SELECTION trial, a phase 2b/3 double-blind RCT that evaluated the efficacy of filgotinib as induction therapy in two studies (biologic-naive patients; biologic-experienced patients) and one maintenance study for adults with moderately to severely UC, revealed that JAKIs are more effective and better tolerated than placebo for the induction and maintenance of remission among both biologic-naive and biologic-experienced patients.[132]

For induction therapy at 10 weeks, filgotinib demonstrated higher clinical remission rates compared to placebo (RR 2.70, [1.15 to 6.35], moderate certainty, Table S29) and a higher Mayo Clinic Score (MCS) remission (RR 2.25, [0.94 to 5.37], moderate certainty, Table S29). Additionally, endoscopic and histological remission showed potential benefits with filgotinib (RR 1.62, [0.44 to 5.90], moderate certainty, Table S29) and (RR 2.34, [1.29 to 4.25], moderate certainty, Table S29), respectively.

For maintenance at 58 weeks, filgotinib exhibited superior efficacy compared to placebo, indicating higher clinical remission (RR 3.31, [1.84 to 5.94], moderate certainty, Table S29), greater MCS remission (RR 3.70, [1.96 to 7.20], moderate certainty, Table S29), and 6-month corticosteroid-free remission (RR 4.25, [1.35 to 13.37], moderate certainty, Table S29). Additionally, endoscopic and histological remissions were also higher with filgotinib (RR 2.54, [1.09 to 5.80], moderate certainty, Table S29) and (RR 2.87, [1.68 to 4.90], moderate certainty, Table S29), respectively.

Based on the moderate certainty evidence demonstrating the effect balance, including substantial desirable and minor undesirable effects, moderate cost, acceptability, and feasibility, the guideline panel strongly recommends JAKIs over placebo in remission induction and maintenance in UC patients who have failed previous conventional or advanced therapy.

However, the panel highlights the importance of cautious use of this class of medication in patients with elevated liver enzymes or mild renal impairment. It should be avoided in patients with a history of cardiovascular risk factors, venous thromboembolism, solid tumors, severe acne, high risk of acquiring infection, or severe renal impairment. Furthermore, it is contraindicated in pregnancy. Therefore, females of childbearing age should use contraception.

This recommendation is in line with the ACG guideline, which recommends JAKIs as effective options for induction and maintenance in moderate-to-severe UC, particularly in patients who fail or cannot tolerate biologics.[118] The BSG guideline also notes the efficacy of JAKIs but makes a conditional recommendation, highlighting safety concerns such as thromboembolism and cardiovascular risk, and stresses the significance of shared decision-making when choosing this class.[31]

Q27. Should S1P-R modulator (Ozanimod, Etrasimod) vs. no treatment be used for induction and maintenance of remission in patients with moderate-to-severe UC?

Recommendation 27: For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend using S1P-R modulators (Ozanimod and Etrasimod) over no treatment (Strong recommendation, moderate certainty evidence).

Rationale

This recommendation was generated based on an SR and MA that evaluated the efficacy and safety of etrasimod (a sphingosine-1-phosphate receptor modulator (S1P-R modulator)) in adults with UC during the induction phase in three RCTs. The study demonstrated the superior efficacy of etrasimod in treating UC patients, with a favorable benefit-to-risk profile at week 12.[133]

Etrasimod demonstrated efficacy over placebo in inducing higher clinical remission rates (OR 3.09, [2.04 to 4.69], moderate certainty, Table S30) and higher clinical response (OR 2.56, [1.91 to 3.43], high certainty, Table S30). Additionally, endoscopic improvement (OR 2.15, [1.51 to 3.05], moderate certainty, Table S30) and histologic remission (OR 3.39, [2.03 to 5.68], high certainty, Table S30) further supported the efficacy of etrasimod.

S Table 30.

S1P-R modulators (Ozanimod, Etrasimod) compared to no treatment for induction and maintenance of remission in patients with moderate-to-severe UC.

Bibliography: Qiu J, Liu J, Cai K, Xu T, Liu W, Lin F, et al. Efficacy and safety of the S1PR modulator etrasimod in the treatment of moderately to severely active ulcerative colitis during the induction phase: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2024 Sep 9;15:1420455.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	S1P-R modulators (Ozanimod, Etrasimod)	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	S1P-R modulators (Ozanimod, Etrasimod)	no treatment	Absolute (95% CI)
clinical remission at week 12
3	RCT	not serious	serious^a	not serious	not serious^b	none	146/550 (26.5%)	31/297 (10.4%)	OR 3.09 (2.04 to 4.69)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
3	RCT	not serious	serious^a	not serious	not serious^b	none	146/550 (26.5%)	31/297 (10.4%)	160 more per 1,000 (from 88 more to 249 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
Clinical response at week 12
3	RCT	not serious	not serious	not serious	not serious	none	334/550 (60.7%)	110/297 (37.0%)	OR 2.56 (1.91 to 3.43)	⨁⨁⨁⨁ High	CRITICAL
3	RCT	not serious	not serious	not serious	not serious	none	334/550 (60.7%)	110/297 (37.0%)	231 more per 1,000 (from 159 more to 298 more)	⨁⨁⨁⨁ High	CRITICAL
Endoscopic improvement at week 12
3	RCT	not serious	serious^a	not serious	not serious^b	none	174/550 (31.6%)	52/297 (17.5%)	OR 2.15 (1.51 to 3.05)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
3	RCT	not serious	serious^a	not serious	not serious^b	none	174/550 (31.6%)	52/297 (17.5%)	138 more per 1,000 (from 68 more to 218 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
Histologic remission at week 12
3	RCT	not serious	not serious	not serious	not serious^b	none	102/537 (19.0%)	19/296 (6.4%)	OR 3.39 (2.03 to 5.68)	⨁⨁⨁⨁ High^b	CRITICAL
3	RCT	not serious	not serious	not serious	not serious^b	none	102/537 (19.0%)	19/296 (6.4%)	124 more per 1,000 (from 58 more to 216 more)	⨁⨁⨁⨁ High^b	CRITICAL
Treatment-Emergent Adverse Events
3	RCT	not serious	not serious	not serious	not serious	none	346/581 (59.6%)	162/310 (52.3%)	OR 1.34 (1.01 to 1.78)	⨁⨁⨁⨁ High	CRITICAL
3	RCT	not serious	not serious	not serious	not serious	none	346/581 (59.6%)	162/310 (52.3%)	72 more per 1,000 (from 2 more to 138 more)	⨁⨁⨁⨁ High	CRITICAL
Serious Adverse Events
3	RCT	not serious	not serious	not serious	not serious	none	26/581 (4.5%)	18/310 (5.8%)	OR 0.77 (0.41 to 1.43)	⨁⨁⨁⨁ High	IMPORTANT
3	RCT	not serious	not serious	not serious	not serious	none	26/581 (4.5%)	18/310 (5.8%)	13 fewer per 1,000 (from 33 fewer to 23 more)	⨁⨁⨁⨁ High	IMPORTANT
Worsening of UC
3	RCT	not serious	not serious	not serious	not serious	none	36/581 (6.2%)	18/310 (5.8%)	OR 1.07 (0.59 to 1.94)	⨁⨁⨁⨁ High	IMPORTANT
3	RCT	not serious	not serious	not serious	not serious	none	36/581 (6.2%)	18/310 (5.8%)	4 more per 1,000 (from 23 fewer to 49 more)	⨁⨁⨁⨁ High	IMPORTANT

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CI: confidence interval; OR: odds ratio

Explanations

^a.Significant heterogeneity

^b.Total number of events below 400.

The TRUE NORTH phase 3 study on the efficacy of ozanimod in moderately to severely active UC has shown that during induction treatment (at Week 10), 18.4% of patients taking ozanimod achieved clinical remission, compared to 6.0% with a placebo (P < 0.001). During maintenance treatment (at Week 52), 37.0% of ozanimod-treated patients maintained clinical remission, compared to 18.5% in the placebo group (P < 0.001). These findings demonstrate ozanimod’s ability to induce and sustain remission in UC.[134]

The ELEVATE, a two-phase 3 RCTs, demonstrated that in ELEVATE UC 52 at week 12, a significant clinical remission was achieved in 27% (74/274) of etrasimod-treated patients compared with placebo, which had 7% (10/135) (P < 0.0001); this benefit persisted at week 52 (32% (88/274) vs. 7% (9/135)). In ELEVATE UC 12, at week 12, 25% (55/222) of etrasimod-treated patients achieved a significant remission compared with placebo, which had 15% (17/112) (P = 0.026).[135]

The safety profile was evaluated in a meta-analysis of 2471 patients, where the incidence of SAEs was lower with S1P-R modulators than with placebo, and it was associated with AEs such as macular edema, bradycardia, abdominal pain, and pyrexia at the induction phase. The study also demonstrated significant efficacy outcomes favoring S1P-R modulators, suggesting that S1P-R modulators have promising potential for achieving histologic remission, endoscopic improvement, clinical remission, and corticosteroid-free clinical remission, making it a reliable therapeutic choice for UC patients.[136]

The guideline panel strongly recommends using S1P-R modulators for remission induction and maintenance in UC patients refractory to advanced therapy, supported by moderate certainty evidence, which demonstrates that the benefits of S1P-R modulators are probably desirable and outweigh the small undesirable effects. Additionally, the strong recommendation reflects the drugs’ moderate cost, feasibility, and probability.

This recommendation is consistent with the ACG guideline, which recommends S1P modulators as appropriate treatment alternatives for UC, especially following conventional or biologic therapy failure.[118] The BSG guideline also recognizes their efficacy but gives a conditional recommendation based on insufficient long-term safety data, emphasizing careful patient selection.[31]

Q28. Should VDZ vs. ADA be used for induction and maintenance of remission in moderate-to-severe ambulatory UC patients bio-naïve to advanced therapies?

Recommendation 28: For induction and maintenance of remission in naive adults with moderate-to-severe UC, we suggest using VDZ over ADA (Conditional recommendation, Moderate certainty evidence).

Rationale

This recommendation was generated based on the head-to-head VARSITY trial.[137,138] The recommendation also supported pooled patient-level data from the GEMINI-1 (VDZ)[119] and ULTRA-1 (ADA) clinical trials.[139] Both indirect comparisons and the head-to-head VARSITY trial revealed an advantage for VDZ over ADA in UC patients.[138]

At week 6, VDZ demonstrated a higher clinical remission rate (OR 1.27, [0.92 to 1.76], moderate certainty, Table S31) and a higher clinical response rate (OR 1.32, [0.95 to 1.84], moderate certainty, Table S31). Mucosal healing was more prevalent in the VDZ group compared to ADA (39.7% and 27.7%, respectively, P = 0.0005), while there was no significant difference in corticosteroid-free remission between the two groups.[138]

S Table 31.

Vedolizumab compared to Adalimumab for induction and maintenance of remission in moderate-to-severe ambulatory UC patients bio-naïve to advanced therapies.

Bibliography: Narula N, Wong ECL, Dulai PS, Marshall JK, Jairath V, Reinisch W. Vedolizumab and Adalimumab in Biologic-Naïve Ulcerative Colitis: Comparison of Patient-Level Clinical Trial Data and VARSITY for Week 6 Clinical Remission. Dig Dis Sci [Internet]. 2023 Jun 1 [cited 2025 Apr 13];68(6):2658–66. Available from: https://pubmed.ncbi.nlm.nih.gov/36645636/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	VDZ	ADA	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	VDZ	ADA	Absolute (95% CI)
Week 6 clinical remission
1	RCT	not serious	not serious	not serious	serious^a	none	131/305 (43.0%)	114/307 (37.1%)	OR 1.27 (0.92 to 1.76)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	131/305 (43.0%)	114/307 (37.1%)	57 more per 1,000 (from 19 fewer to 138 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Week 6 clinical response
1	RCT	not serious	not serious	not serious	serious^b	none	208/305 (68.2%)	190/307 (61.9%)	OR 1.32 (0.95 to 1.84)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	208/305 (68.2%)	190/307 (61.9%)	63 more per 1,000 (from 12 fewer to 130 more)	⨁⨁⨁◯ Moderate^b	CRITICAL

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CI: confidence interval; OR: odds ratio

Explanations

^a.number of events below 400

^b.downgrade one level for crossing line of no effect.

The panel conditionally recommends VDZ over ADA based on moderate certainty evidence, emphasizing the importance of tailoring decisions to patient values and available resources. This recommendation aligns with the AGA guideline that conditionally recommends IFX or VDZ rather than ADA in UC patients who are bio-naïve to biologic agents.[14] Similarly, the ECCO guideline recommends VDZ over ADA and mentions that it could be considered as a first-line therapy in UC patients who failed on conventional therapy.[16]

This recommendation aligns with the ACG guideline, which supports VDZ over ADA for induction and maintenance in bio-naïve UC, supported by the VARSITY trial.[118] The BSG guideline also supports VDZ in this case, but makes a conditional recommendation that emphasizes collaborative decision-making due to the effect size and patient-specific considerations.[31]

Q29. Should treatment with biosimilars of anti-TNF agents or anti-IL-12/23 vs. no treatment be used for induction and maintenance of remission in patients with moderate-to-severe UC?

Recommendation 29: For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend using anti-TNF or IL-12/23 biosimilars over no treatment (Strong recommendation, high certainty evidence).

Rationale

In a phase 3 RCT (LIBERTY-UC), SC CT-P13 was evaluated for efficacy and safety at 10 weeks for the induction phase (5 mg/kg IV) and 54 weeks for the maintenance phase (120 mg SC every 2 weeks).[54]

At week 54, SC CT-P13 exhibited better efficacy outcomes, including increased clinical remission rates (RR 2.07, [1.47 to 2.92], high certainty, Table S32), endoscopic-histologic mucosal improvement (RR 2.14, [1.44 to 3.18], moderate certainty, Table S32), and corticosteroid-free remission (RR 2.03, [1.13 to 3.64], moderate certainty, Table S32). AEs were reported less frequently with CT-P13 (RR 1.14, [0.97 to 1.33], high certainty, Table S32), and the rate of TEAE resulting in discontinuation was also lower with CT-P13 (RR 2.24, [0.77 to 6.50], moderate certainty, Table S32).[54]

S Table 32.

Treatment with biosimilars of anti-tumor necrosis factor [TNF] agents or Anti-IL-12/23 compared to no treatment for induction and maintenance of remission in patients with moderate-to-severe UC.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	treatment with biosimilars of aTNF agents or Anti-IL-12/23	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	treatment with biosimilars of aTNF agents or Anti-IL-12/23	no treatment	Absolute (95% CI)
Clinical remission (follow-up: mean 54 weeks; assessed with: CDAI score)
1	RCT	not serious	not serious	not serious	not serious	none	127/294 (43.2%)	30/144 (20.8%)	RR 2.07 (1.47 to 2.92)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	127/294 (43.2%)	30/144 (20.8%)	223 more per 1,000 (from 98 more to 400 more)	⨁⨁⨁⨁ High	CRITICAL
Endoscopic–histologic mucosal improvement (follow-up: mean 54 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	105/294 (35.7%)	24/144 (16.7%)	RR 2.14 (1.44 to 3.18)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	105/294 (35.7%)	24/144 (16.7%)	190 more per 1,000 (from 73 more to 363 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Corticosteroid-free remission (follow-up: mean 54 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	44/120 (36.7%)	11/61 (18.0%)	RR 2.03 (1.13 to 3.64)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	44/120 (36.7%)	11/61 (18.0%)	186 more per 1,000 (from 23 more to 476 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Safety (follow-up: mean 54 weeks; assessed with: Patients with ≥ 1 TEAE)
1	RCT	not serious	not serious	not serious	not serious	none	200/296 (67.6%)	83/140 (59.3%)	RR 1.14 (0.97 to 1.33)	⨁⨁⨁⨁ High	CRITICAL
1	RCT	not serious	not serious	not serious	not serious	none	200/296 (67.6%)	83/140 (59.3%)	83 more per 1,000 (from 18 fewer to 196 more)	⨁⨁⨁⨁ High	CRITICAL
Safety (follow-up: mean 54 weeks; assessed with: Patients with ≥ 1 TEAE leading to drug discontinuation)
1	RCT	not serious	not serious	not serious	serious^a	none	19/296 (6.4%)	4/140 (2.9%)	RR 2.24 (0.77 to 6.50)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	19/296 (6.4%)	4/140 (2.9%)	35 more per 1,000 (from 7 fewer to 157 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.Wide CI.

Several biosimilars of ustekinumab have been developed and are becoming available for patients. These biosimilars have demonstrated comparable efficacy, pharmacokinetics, safety, and immunogenicity to the originator. They were approved for moderate to severe UC and CD based on extrapolation from an RCT that reported similar safety and efficacy between both formulations in patients with plaque psoriasis. However, there are currently no real-world data available for this indication.[57,140]

The guideline panel strongly recommends biosimilars of anti-TNF agents for inducing remission and maintaining remission in UC patients. The panel is supported by high-certainty evidence demonstrating moderate desirable and low undesirable effects, as well as moderate savings.

The panel highlights the favorable risk-balance effects, feasibility, and acceptability. The strong recommendation underscores a favorable risk–benefit balance, driven by robust efficacy, cost advantages, and comparable safety to originators.

This recommendation aligns with ACG and BSG guidelines. BSG also emphasizes that shared decision-making and patient education are important when initiating or switching to biosimilars.[31,118]

Q30: Should combining IFX with AZA vs. IFX monotherapy be used to induce and maintain remission in patients with moderate-to-severe UC?

Recommendation 30: For induction and maintenance of remission in adults with moderate-to-severe UC, we suggest combining IFX with AZA over IFX monotherapy (Conditional recommendation, very low certainty evidence).

Rationale

An SR and MA that compared the clinical efficacy of a combination of IFX and immunosuppressant therapy to IFX monotherapy in patients with moderate-to-severe UC found that clinical remission at 4–6 months was significantly higher in the combination group (RR 1.61, [1.20 to 2.15], moderate certainty, Table S33). However, at 12 months, there was no significant difference in clinical remission between the combination and monotherapy groups (RR 1.26, [CI 0.91 to 1.75], very low certainty, Table S33).[141]

S Table 33.

Combining infliximab with thiopurine compared to infliximab monotherapy for induction and maintenance of remission in patients with moderate-to-severe UC.

Bibliography: Christophorou D, Funakoshi N, Duny Y, Valats JC, Bismuth M, Pineton De Chambrun G, et al. Systematic review with meta-analysis: infliximab and immunosuppressant therapy vs. infliximab alone for active ulcerative colitis. Aliment Pharmacol Ther. 2015 Apr;41(7):603–12.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	combining IFX with thiopurine	IFX alone	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	combining IFX with thiopurine	IFX alone	Absolute (95% CI)
Clinical remission rate at 4–6 months
3	RCT	serious^a,b,c,d	not serious	not serious	not serious	none	113/251 (45.0%)	76/271 (28.0%)	RR 1.60 (1.20 to 2.15)	⨁⨁⨁◯ Moderate^a,b,c,d	CRITICAL
3	RCT	serious^a,b,c,d	not serious	not serious	not serious	none	113/251 (45.0%)	76/271 (28.0%)	168 more per 1,000 (from 56 more to 323 more)	⨁⨁⨁◯ Moderate^a,b,c,d	CRITICAL
Clinical remission rate at 12 months
2	RCT	serious^a,b,c,d	very serious^e	not serious	not serious	none	84/196 (42.9%)	59/173 (34.1%)	RR 1.26 (0.91 to 1.75)	⨁◯◯◯ Very low^a,b,c,d,e	CRITICAL
2	RCT	serious^a,b,c,d	very serious^e	not serious	not serious	none	84/196 (42.9%)	59/173 (34.1%)	89 more per 1,000 (from 31 fewer to 256 more)	⨁◯◯◯ Very low^a,b,c,d,e	CRITICAL

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CI: confidence interval; RR: risk ratio

Explanations

^a.No generation of allocation sequence

^b.No concealment of allocation sequence

^c.No successful randomisation

^d.No blinding

^e.Test for heterogeneity: (P = 0.01) I2 = 86.4%.

Similarly, an RCT involving 239 patients with UC found that 39.7% of those receiving IFX plus azathioprine achieved corticosteroid-free remission at week 16, compared to 22.1% and 23.7% of patients receiving IFX alone and azathioprine alone, respectively. Mucosal healing was also more common in patients receiving IFX plus azathioprine, at 62.8%, vs. IFX monotherapy, at 54.6%. The study revealed that both the combination and monotherapies were well tolerated.[142]

Therefore, the panel conditionally recommends the IFX-thiopurine combination therapy for the induction and maintenance of remission in moderate-to-severe UC patients. The panel recommends using combination therapy, rather than monotherapy, during the initial months of treatment with IFX, as it significantly reduces the risk of immunogenicity and secondary loss of response; thus, it is regarded as the standard of care. This recommendation aligns with AGA guidelines that conditionally recommend the combination over monotherapy of thiopurines.[14]

Nonetheless, the panel highlights that prolonged use of combination therapy could increase the risk of opportunistic infections or lymphoma, especially in young males. Additionally, the available evidence primarily focuses on combining thiopurines with IFX and no other anti-TNF agents; therefore, the generalizability of these findings across all anti-TNF agents should be interpreted cautiously.

Patients with increased infection risk, such as age (frailty), or comorbidities, should receive counseling and be involved in treatment decisions. The panel emphasizes the importance of structured monitoring for short-term, intermediate, and long-term targets, and calls for further research on predictive markers and comparative studies. In addition, considerations should be made to de-escalate treatment to IFX monotherapy after achieving remission and ensuring adequate IFX drug exposure by therapeutic drug monitoring (typically 6–12 months after initiation of combination therapy).

The panel confirms its high acceptability and feasibility, emphasizing the structured monitoring and evaluation of short-term targets (clinical response within 6–12 weeks), intermediate targets (clinical remission, biochemical response/remission, and endoscopic response within 12–24 weeks), and long-term targets (endoscopic remission, radiological transmural remission, and normalization of QoL within 24–48 weeks).[30] Further research on predictive markers, local/regional real-world evidence, and comparative studies is needed.

This recommendation is in line with the ACG guideline, which supports the IFX-thiopurine combination over monotherapy for improved early remission and decreased immunogenicity. The BSG guideline supports its effectiveness but cautions against long-term risks, emphasizing the significance of collaborative decision-making and potential de-escalation once remission is established.[31,118]

Treatment Optimization Strategies for Adults with UC and Secondary Loss of Response to Advanced Therapy

Q31. Should adjusting the dose based on measured anti-TNF trough levels vs. empirically optimizing the dose without measuring anti-TNF trough levels be used for UC patients with secondary loss of response to anti-TNF therapy?

Recommendation 31: For adults with UC and secondary loss of response to anti-TNF therapy, we suggest measurement of anti-TNF trough levels and dose optimization based on these levels over maintaining the standard anti-TNF dose without trough level monitoring (Conditional recommendation, moderate certainty evidence).

Rationale

There are limited number of studies that examined the efficacy of reactive TDM among IBD patients, specifically UC patients. This recommendation was based on an SR and MA of 1 RCT and 2 observational studies, evaluating the efficacy of reactive therapeutic TDM compared to empiric dose optimization management in IBD patients treated with anti-TNF agents.[143]

The clinical response rate did not differ between the two groups (OR 1.31, [0.72 to 2.36], low certainty, Table S34). However, reactive TDM was associated with a significant cost reduction.[143]

S Table 34.

Adjusting the dose based on measured anti-TNF trough levels compared to empirically optimizing the dose without measuring anti-TNF trough levels for UC patients with secondary loss of response to anti-TNF therapy.

Bibliography: Cogan RC, El-Matary BW, El-Matary WM. Therapeutic drug monitoring for biological medications in inflammatory bowel disease. Saudi J Gastroenterol. 2022 Sep;28(5):322–31.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	adjusting the dose based on measured anti-TNF trough levels	empirically optimizing the dose without measuring anti-TNF trough levels	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	adjusting the dose based on measured anti-TNF trough levels		Absolute (95% CI)
Clinical response
2	RCT	not serious^a	serious^b	not serious	not serious^c	none	151/242 (62.4%)	121/215 (56.3%)	RR 1.31 (0.72 to 2.36)	⨁⨁⨁◯ Moderate^a,b,c	CRITICAL
2	RCT	not serious^a	serious^b	not serious	not serious^c	none	151/242 (62.4%)	121/215 (56.3%)	174 more per 1,000 (from 158 fewer to 765 more)	⨁⨁⨁◯ Moderate^a,b,c	CRITICAL

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CI: confidence interval; RR: risk ratio

Explanations

^a.Moderate risk of bias

^b.I2=53%

^c.Small size.

Kelly et al.[86] have previously demonstrated a clinical response and endoscopic remission benefit with reactive TDM over 6 months of follow-up (OR 1.69, [1.06 to 2.69]) and (OR 2.21, [1.40 to 3.50]), respectively.

A large local cross-sectional observational study involving 129 patients assessed TDM of IFX and concluded that therapeutic IFX levels were significantly associated with higher rates of endoscopic and clinical remission, as well as lower incidence of anti-IFX antibody formation, compared to patients with subtherapeutic levels.[89]

To achieve favorable therapeutic outcomes, it is recommended that reactive TDM be conducted early during induction. Higher serum concentrations of anti-TNF during this period are linked to reduced immunogenicity, increased drug exposure, and a lower risk of treatment failure.[144]

The guideline panel emphasizes the limited availability and acceptability, moderate certainty evidence, and moderate cost. Therefore, the panel conditionally recommends adjusting anti-TNF doses through reactive TDM for UC patients. The panel emphasizes the structured monitoring and evaluation of short, intermediate, and long-term TDM to optimize patient outcomes.

This recommendation is consistent with the ACG and BSG guidelines, which both support reactive TDM for adjusting anti-TNF doses in patients with subsequent loss of response, leading to better results and lower immunogenicity compared to empiric dose escalation.[31,118]

Q32. Should dose escalation (by shortening dosing intervals) be used for advanced therapies (VDZ and ustekinumab) vs. standard dose be used for maintaining the remission of patients with moderate-to-severe UC who demonstrated a partial response to standard 8-weekly dosing?

Recommendation 32: For adults with moderate-to-severe UC who have achieved partial remission on a standard dose of advanced therapies (VDZ and Ustekinumab), we suggest dose escalation over standard dosing (Conditional recommendation, very low certainty evidence).

Rationale

This recommendation is supported by an observational study that evaluated the efficacy of ustekinumab dose escalation among patients with UC.[145] The findings suggested that dose escalation (either by intensification to once every 4 or 6 weeks) was an effective strategy. A clinical response was observed in 55% of patients ([35% to 83%, very low certainty, Table S35), while steroid-free remission occurred in 68% (95% CI: 45% to 98%, very low certainty, Table S35). Endoscopic response and colectomy were reported in 56% ([25% to 100%], moderate certainty, Table S35) and 30% ([15% to 52%], very low certainty, Table S35), respectively.

S Table 35.

Dose escalation (by shortening dosing intervals) used for advanced therapies (Vedolizumab and Ustekinumab) compared to the standard dose for maintaining the remission of patients with moderate-to-severe UC who demonstrated a partial response to standard 8-weekly dosing.

Bibliography: Dalal RS, Esckilsen S, Barnes EL, Pruce JC, Marcus J, Allegretti JR. Predictors and outcomes of ustekinumab dose intensification in ulcerative colitis: a multicenter cohort study. Clin Gastroenterol Hepatol. 2021 Oct;20(10):2399.

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Dose escalation (by shortening dosing intervals) used for advanced therapies (VDZ and Ustekinumab)	standard dose	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations		standard dose	Absolute (95% CI)
clinical response (follow-up: range 12 weeks to 16 weeks; assessed with: q4w or 6qw)
1	non-RCT	not serious	not serious	serious^a	serious^b	none	22/40	0/0	Rate ratio 55 (35 to 83)	⨁◯◯◯ Very low^a,b	CRITICAL
1	non-RCT	not serious	not serious	serious^a	serious^b	none	22/40	0/0	-- per 1000 patient(s) per years (from -- to --)	⨁◯◯◯ Very low^a,b	CRITICAL
steroid free remission (follow-up: range 12 weeks to 16 weeks; assessed with: q4w or 6qw)
1	non-RCT	not serious	not serious	not serious	serious^b	none	27/40	0/0	Rate ratio 68 (45 to 98)	⨁◯◯◯ Very low^b	IMPORTANT
1	non-RCT	not serious	not serious	not serious	serious^b	none	27/40	0/0	-- per 1000 patient(s) per years (from -- to --)	⨁◯◯◯ Very low^b	IMPORTANT
endoscopic response (assessed with: q4w or 6qw)
1	non-RCT	not serious	not serious	serious^a	serious^a	none	9/16	0/0	-- per 1000 patient(s) per years (from -- to --)	⨁◯◯◯ Very low^a	CRITICAL
1	non-RCT	not serious	not serious	serious^a	serious^a	none	9/16	0/0	-- per 1000 patient(s) per years (from -- to --)	⨁◯◯◯ Very low^a	CRITICAL
Colectomy (follow-up: 16 weeks; assessed with: 4qw or 6qw)
1	non-RCT	not serious	not serious	serious^a	not serious	none	12/40	0/0	Rate ratio 30 (15 to 52)	⨁◯◯◯ Very low^a	IMPORTANT
1	non-RCT	not serious	not serious	serious^a	not serious	none	12/40	0/0	-- per 1000 patient(s) per years (from -- to --)	⨁◯◯◯ Very low^a	IMPORTANT

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CI: confidence interval

Explanations

^a.No comparator

^b.small sample size.

A retrospective study demonstrated that dose escalation benefited patients with UC who experienced a partial response to standard dosing. It also recommended early VDZ dose escalation, particularly for patients with severe disease and those previously treated with anti-TNF agents.[146]

A post hoc analysis of the VISIBLE trial revealed that escalating the dose of SC VDZ from every 2 weeks to weekly administration can effectively maintain remission and recapture lost response in patients with UC.[147]

The very low certainty evidence, alongside moderate desirable and small undesirable effects, and a moderate cost, has led to the conditional recommendation of dose escalation for advanced therapy.

This recommendation aligns with ACG and BSG guidelines. Both guidelines recommend individualized decisions, with close monitoring and shared decision-making.[31,118]

Q33. Should switching to a different class, such as anti-IL-12/23, anti-IL-23, anti-integrins, JAKIs, or S1P-R modulators, vs. no treatment be used for optimizing the management of the disease in UC patients with secondary loss of response to anti-TNF therapy based on TDM?

Recommendation 33: In UC patients with loss of response to anti-TNF therapy despite adequate serum drug levels and negative ADAs, we suggest switching to a different class, such as anti-IL-12/23, anti-IL-23, anti-Integrins, JAKi, or S1P-R modulators, for optimizing the management of the disease over switching to another anti-TNF (Conditional recommendation, low certainty evidence).

Rationale

This recommendation is based on a post hoc analysis that assessed VDZ’s 831 UC patients. VDZ demonstrated a superior clinical response at week 6 and clinical remission by week 52 compared to placebo in UC patients with anti-TNF failure.[121]

Switching to VDZ 300 mg every 8 weeks after secondary anti-TNF failure demonstrated higher clinical remission (RR 6.3, [1.5 to 27.0], low certainty, Table S36) and a higher durable clinical response (RR 2.7, [1.2 to 5.9], low certainty, Table S36), and mucosal healing also favoring VDZ (RR 4.8, [1.5 to 15.2], low certainty, Table S36). Similarly, efficacy outcomes were higher compared to placebo with VDZ 300 mg every 4 weeks, including higher clinical remission rates (RR 6.9, [1.7 to 27.7], low certainty, Table S36), a higher durable clinical response (RR 2.5, [1.1 to 5.7], low certainty, Table S36), and enhanced mucosal healing (RR 5.8, [1.9 to 17.9], low certainty, Table S36). VDZ was associated with less frequent AEs (RR 0.82, [0.63 to 1.06], moderate certainty, Table S36) and SAEs (RR 0.81, [0.26 to 2.49], low certainty, Table S36).[121]

S Table 36.

Switching to a different class, such as Anti-IL-12/23, Anti-IL-23, Anti-Integrins, JAKi, or S1P-R modulators, compared to no treatment, for optimizing the management of the disease in UC patients with secondary loss of response to anti-TNF therapy based on therapeutic drug monitoring (TDM).

Bibliography: Feagan BG, Rubin DT, Danese S, Vermeire S, Abhyankar B, Sankoh S, et al. Efficacy of Vedolizumab Induction and Maintenance Therapy in Patients With Ulcerative Colitis, Regardless of Prior Exposure to Tumor Necrosis Factor Antagonists. Clin Gastroenterol Hepatol [Internet]. 2017 Feb 1 [cited 2025 Apr 16];15(2):229-239.e5. Available from: https://pubmed.ncbi.nlm.nih.gov/27639327/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	switching to a different class, such as Anti-IL-12/23, Anti-IL-23, Anti-Integrins, JAKi or S1P-R modulators	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations		no treatment	Absolute (95% CI)
Clinical remission (follow-up: mean 52 weeks; assessed with: Q8W Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	16/43 (37.2%)	2/38 (5.3%)	RR 6.3 (1.5 to 27.0)	⨁⨁◯◯ Low^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a,b	none	16/43 (37.2%)	2/38 (5.3%)	279 more per 1,000 (from 26 more to 1,000 more)	⨁⨁◯◯ Low^a,b	CRITICAL
Durable clinical response (follow-up: mean 52 weeks; assessed with: Q8W Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,c	none	20/43 (46.5%)	6/38 (15.8%)	RR 2.7 (1.2 to 5.9)	⨁⨁◯◯ Low^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a,c	none	20/43 (46.5%)	6/38 (15.8%)	268 more per 1,000 (from 32 more to 774 more)	⨁⨁◯◯ Low^a,b	CRITICAL
Mucosal healing (follow-up: mean 52 weeks; assessed with: Q8W Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	18/43 (41.9%)	3/38 (7.9%)	RR 4.8 (1.5 to 15.2)	⨁⨁◯◯ Low^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a,b	none	18/43 (41.9%)	3/38 (7.9%)	300 more per 1,000 (from 39 more to 1,000 more)	⨁⨁◯◯ Low^a,b	CRITICAL
Clinical remission (follow-up: mean 52 weeks; assessed with: Q4W Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	14/40 (35.0%)	2/38 (5.3%)	RR 6.9 (1.7 to 27.7)	⨁⨁◯◯ Low^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a,b	none	14/40 (35.0%)	2/38 (5.3%)	311 more per 1,000 (from 37 more to 1,000 more)	⨁⨁◯◯ Low^a,b	CRITICAL
Durable clinical response (follow-up: mean 52 weeks; assessed with: Q4W Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,c	none	17/40 (42.5%)	6/38 (15.8%)	RR 2.5 (1.1 to 5.7)	⨁⨁◯◯ Low^a,c	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a,c	none	17/40 (42.5%)	6/38 (15.8%)	237 more per 1,000 (from 16 more to 742 more)	⨁⨁◯◯ Low^a,c	CRITICAL
Mucosal healing (follow-up: mean 52 weeks; assessed with: Q4W Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	19/40 (47.5%)	3/38 (7.9%)	RR 5.8 (1.9 to 17.9)	⨁⨁◯◯ Low^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a,b	none	19/40 (47.5%)	3/38 (7.9%)	379 more per 1,000 (from 71 more to 1,000 more)	⨁⨁◯◯ Low^a,b	CRITICAL
Any adverse event (follow-up: mean 52 weeks; assessed with: Vedolizumab )
1	RCT	not serious	not serious	not serious	serious^a,d	none	154/304 (50.7%)	39/63 (61.9%)	RR 0.82 (0.63 to 1.06)	⨁⨁⨁◯ Moderate^a,d	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a,d	none	154/304 (50.7%)	39/63 (61.9%)	111 fewer per 1,000 (from 229 fewer to 37 more)	⨁⨁⨁◯ Moderate^a,d	CRITICAL
Any serious adverse event (follow-up: mean 52 weeks; assessed with: Vedolizumab )
1	RCT	not serious	not serious	not serious	very serious^a,c	none	12/304 (3.9%)	3/63 (4.8%)	RR 0.81 (0.26 to 2.49)	⨁⨁◯◯ Low^a,c	IMPORTANT
1	RCT	not serious	not serious	not serious	very serious^a,c	none	12/304 (3.9%)	3/63 (4.8%)	9 fewer per 1,000 (from 35 fewer to 71 more)	⨁⨁◯◯ Low^a,c	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.Wide CI

^b.small sample size

^c.downgrade by two levels for a small number of events

^d.downgrade one level for crossing the line of no effect

An RCT has evaluated the efficacy of etrasimod, an S1P-R modulator, and found that etrasimod is effective in inducing and maintaining remission in biologically experienced patients.[148] In the LUCENT trials, mirikizumab, an anti-IL-23p19, demonstrated efficacy in inducing and maintaining remission in patients with one prior anti-TNF failure.[149] Ustekinumab and tofacitinib have similar effectiveness to second-line biological therapies for UC after treatment failure of anti-TNF.[150]

A recent local retrospective study has evaluated the efficacy of VDZ among advanced therapy-experienced UC patients. Clinical remission was achieved in 61.9% of patients receiving VDZ every 8 weeks and in 89.3% of those receiving it every 4 weeks. Furthermore, corticosteroids were discontinued among most UC patients. The authors observed that the probability of achieving clinical remission was positively associated with female gender, extensive disease, and a 4-week dosing schedule. However, prior exposure to a large number of biologics was linked to a decreased likelihood of achieving clinical remission.[151]

The panel issues a conditional recommendation to switch to a different therapeutic class in patients with UC experiencing secondary loss of response to anti-TNF therapy, based on low-certainty evidence and a judgment that the moderate desirable effects outweigh the small undesirable effects. Optimization strategies may still be beneficial for selected patients and should be considered before transitioning between advanced therapies. Subgroup considerations such as pregnancy, fertility concerns, and the presence of EIMs should guide individualized treatment decisions. The panel also highlights the importance of generating further local and regional real-world evidence to support and refine this recommendation.

This approach is supported by ACG and BSG guidelines.[31,118] The AGA guidelines issued a conditional recommendation supporting the use of ustekinumab or tofacitinib, rather than VDZ or ADA, for the induction of remission in adult outpatients with UC with a prior experience with IFX, particularly those with primary nonresponse.[14]

Management of Adults with Acute Severe UC

Q34. Should IFX or cyclosporine vs. no treatment be used for decreasing the risk of short-term colectomy in hospitalized adult patients with acute severe UC (ASUC) refractory to IV corticosteroids?

Recommendation 34: In hospitalized adults with ASUC refractory to IV corticosteroids, we recommend using rescue therapy with IFX or cyclosporine over no treatment to reduce the short-term risk of colectomy (Strong recommendation, Moderate certainty evidence).

Remarks: We suggest using IFX or cyclosporine as rescue therapy in patients admitted with ASUC and who have failed adequate doses and duration of IV steroids.

Rationale

This recommendation was based on an NMA that evaluated the efficacy and safety of IFX and ciclosporin in 7 RCTs involving 534 ASUC patients.[152] The colectomy rates at ≤1 month after starting therapy were significantly less frequent in IFX (RR 0.37, [0.21 to 0.65], moderate certainty, Table S37) and cyclosporine (RR 0.40, [0.21 to 0.77], moderate certainty, Table S37) groups.

S Table 37.

Infliximab or cyclosporine compared to no treatment for decreasing the risk of short-term colectomy in hospitalized adult patients with acute severe ulcerative colitis (ASUC) refractory to intravenous corticosteroids.

Bibliography: Barberio B, Black CJ, Savarino E V., Ford AC. Ciclosporin or Infliximab as Rescue Therapy in Acute Glucorticosteroid-Refractory Ulcerative Colitis: Systematic Review and Network Meta-Analysis. J Crohns Colitis [Internet]. 2021 May 4 [cited 2025 Apr 16];15(5):733–41. Available from: pubmed.ncbi.nlm.nih.gov/33175102/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IFX or cyclosporine	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IFX or cyclosporine	no treatment	Absolute (95% CI)
colectomy rates ≤ 1 month after starting therapy (infliximab vs. placebo)
3	RCT	not serious	not serious	not serious^a	serious^b	none	7/24 (29.2%)	14/21 (66.7%)	RR 0.37 (0.21 to 0.65)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
3	RCT	not serious	not serious	not serious^a	serious^b	none	7/24 (29.2%)	14/21 (66.7%)	420 fewer per 1,000 (from 527 fewer to 233 fewer)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
colectomy rates ≤ 1 month after starting therapy (cyclosporine vs. placebo)
1	RCT	not serious	not serious	not serious^a	serious^b	none	2/11 (18.2%)	4/9 (44.4%)	RR 0.40 (0.21 to 0.77)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious^a	serious^b	none	2/11 (18.2%)	4/9 (44.4%)	267 fewer per 1,000 (from 351 fewer to 102 fewer)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
colectomy rates ≤ 1 month after starting therapy (infliximab vs. cyclosporine)
7	RCT	serious^c	not serious	not serious^d	serious^b	none	55/135 (40.7%)	65/135 (48.1%)	39 fewer per 1,000 (from 183 fewer to 183 more)	⨁⨁◯◯ Low^b,c,d	CRITICAL
7	RCT	serious^c	not serious	not serious^d	serious^b	none	55/135 (40.7%)	65/135 (48.1%)	39 fewer per 1,000 (from 183 fewer to 183 more)	⨁⨁◯◯ Low^b,c,d	CRITICAL
Adverse events (infliximab vs. placebo)
3	RCT	not serious	not serious	not serious^a	serious^b	none	9/24 (37.5%)	8/21 (38.1%)	RR 0.63 (0.20 to 1.98)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
3	RCT	not serious	not serious	not serious^a	serious^b	none	9/24 (37.5%)	8/21 (38.1%)	141 fewer per 1,000 (from 305 fewer to 373 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
Adverse events (cyclosporine vs. placebo)
1	RCT	not serious	not serious	not serious^a	serious^b	none	11/11 (100.0%)	4/9 (44.4%)	RR 0.54 (0.16 to 1.85)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious^a	serious^b	none	11/11 (100.0%)	4/9 (44.4%)	204 fewer per 1,000 (from 373 fewer to 378 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
Adverse events (infliximab vs. cyclosporine)
7	RCT	serious^c	not serious	not serious^d	serious^b	none	16/135 (11.9%)	10/135 (7.4%)	RR 0.85 b	⨁⨁◯◯ Low^b,c,d	CRITICAL
7	RCT	serious^c	not serious	not serious^d	serious^b	none	16/135 (11.9%)	10/135 (7.4%)	11 fewer per 1,000 (from 38 fewer to 36 more)	⨁⨁◯◯ Low^b,c,d	CRITICAL

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CI: confidence interval; RR: risk ratio

Explanations

^a.Each drug compared with placebo, but not both drugs vs. placebo

^b.Very low sample size

^c.high risk of bias in blinding

^d.infliximab versus cyclosporine

Indirect analysis showed no difference in colectomy rates between IFX and cyclosporine (RR 0.92, [0.62 to 1.38], low certainty, Table S37). AEs were comparable in both groups (RR 0.63, [0.20 to 1.98], moderate certainty, Table S37). At the same time, cyclosporine demonstrated marginally higher AEs compared to placebo without a significant difference (RR 0.54, [0.16 to 1.85], moderate certainty, Table S37).

The CONSTRUCT trial, a pragmatic randomized study involving 270 patients, found no significant difference in colectomy rates between IFX and cyclosporine. However, IFX was associated with improved patient-reported QoL and required less monitoring, making it more practical in clinical settings.[153]

An RCT evaluated IFX in ASUC patients and found that it is an effective and safe rescue therapy for ASUC patients who are not responding to corticosteroids, thereby reducing the risk of colectomy.[154]

Notably, there are some concerns about the safety of cyclosporine. Sternthal et al.[155] have previously reported that cyclosporine use was associated with several side effects, including seizures, paresthesia, hypertension, hyperkalemia, and gingival swelling. Therefore, strict and close drug monitoring is warranted.

The moderate certainty of the evidence, supported by the feasibility and acceptability of both interventions, indicates a balance of moderately desirable and undesirable effects, leading the guideline panel to strongly recommend IFX or cyclosporin for a short-term decrease in colectomy in ASUC hospitalized patients. The ACG, BSG, and AGA guideline aligns with this recommendation for using IFX or cyclosporine in UC patients who are refractory to corticosteroids.[14] While efficacy is considered similar, the BSG and ACG emphasize practical differences: IFX is favored because of easier administration, less intensive monitoring, and better patient-reported outcomes, whereas cyclosporine use necessitates strict monitoring due to its toxicity profile.[31,118]

Q35. Should JAKIs vs. no treatment be used for remission induction in adults with ASUC who had an inadequate response or intolerance to at least one therapy, including IV corticosteroids, cyclosporine, or IFX?

Recommendation 35: In adults with ASUC who had an inadequate response or intolerance to at least one therapy, including IV corticosteroids, cyclosporine, or IFX, we suggest using JAK inhibitors over no treatment to induce remission (Conditional recommendation, Moderate certainty evidence).

Remark: A cautious risk and benefit approach should be considered to not delay colectomy in patients who are unlikely to benefit from further sequential medical rescue therapy.

Rationale

This recommendation was generated based on the TACOS study, an RCT that evaluated the efficacy of tofacitinib vs. placebo in ASUC patients refractory to corticosteroids.[156]

Tofacitinib reduced the need for rescue therapy at 7 days (OR 0.27, [0.09 to 0.78], moderate certainty, Table S38) and the need for colectomy at 90 days (OR 0.21, [0.04 to 1.04], moderate certainty, Table S38). Tofacitinib revealed a higher treatment response rate (defined by a ≥3-point reduction in the Lichtiger index and score <10) by day 7 (OR 3.42, [1.37 to 8.48, moderate certainty, Table S38). There was no significant difference in the AEs between tofacitinib and placebo (RR 1.78, [0.77 to 4.12, moderate certainty, Table S38).

S Table 38.

JAK Inhibitors (JAKIs) compared to no treatment for remission induction in adults with acute severe ulcerative colitis (ASUC) who had an inadequate response or intolerance to at least one therapy, including IV corticosteroids, cyclosporine, or infliximab.

Bibliography: Singh A, Goyal MK, Midha V, Mahajan R, Kaur K, Gupta YK, et al. Tofacitinib in Acute Severe Ulcerative Colitis (TACOS): A Randomized Controlled Trial. Am J Gastroenterol [Internet]. 2024 Jul 1 [cited 2025 Apr 16];119(7):1365–72. Available from: https://pubmed.ncbi.nlm.nih.gov/38131615/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	JAKIs	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	JAKIs	no treatment	Absolute (95% CI)
Rate of response to treatment (follow-up: 7 days)
1	RCT	not serious	not serious	not serious	serious^a,b	none	44/53 (83.0%)	30/51 (58.8%)	OR 3.42 (1.37 to 8.48)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a,b	none	44/53 (83.0%)	30/51 (58.8%)	242 more per 1,000 (from 74 more to 336 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
The need for rescue therapy (follow-up: 7 days)
1	RCT	not serious	not serious	not serious	serious^a	none	6/53 (11.3%)	16/51 (31.4%)	OR 0.27 (0.09 to 0.78)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	6/53 (11.3%)	16/51 (31.4%)	204 fewer per 1,000 (from 274 fewer to 51 fewer)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Rate of colectomy (follow-up: 90 days)
1	RCT	not serious	not serious	not serious	serious^a	none	2/53 (3.8%)	8/51 (15.7%)	OR 0.21 (0.04 to 1.04)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	2/53 (3.8%)	8/51 (15.7%)	119 fewer per 1,000 (from 149 fewer to 5 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Any adverse events
1	RCT	not serious	not serious	not serious	serious^a,b	none	13/53 (24.5%)	7/51 (13.7%)	RR 1.78 (0.77 to 4.12)	⨁⨁⨁◯ Moderate^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a,b	none	13/53 (24.5%)	7/51 (13.7%)	107 more per 1,000 (from 32 fewer to 428 more)	⨁⨁⨁◯ Moderate^a,b	CRITICAL

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CI: confidence interval; OR: odds ratio; RR: risk ratio

Explanations

^a.total events below 400

^b.Wide confidence interval.

A phase 4 TRIUMPH trial evaluated the efficacy of tofacitinib in ASUC patients and found that it may be an effective induction strategy for ASUC patients who are refractory to steroids. The study reported that 58.3% of patients achieved a clinical response by day 7, along with a marked reduction in C-reactive protein (CRP) levels. Colectomy occurred in 16.7% of patients by day 7 and 25% by 6 months. At the 6-month mark, 45.8% of patients continued on tofacitinib, with 33.3% experiencing endoscopic improvement and achieving corticosteroid-free clinical remission.[157]

The conditional recommendation for using JAKIs in ASUC patients resistant to corticosteroids is based on moderate certainty evidence, with varying desirable and undesirable effects, moderate costs, and a likely feasibility and acceptability. The panel emphasizes the need for further RCT data. According to ACG and BSG guidance, JAKIs may help treat ASUC, but evidence is limited to small RCTs and real-world series. The BSG advises using them only after risk–benefit counseling with a multidisciplinary IBD team.[31,118]

Q36. Should Standard IFX dosing regimens vs. intensive IFX dosing regimens be used for decreasing the short-term risk of colectomy in hospitalized adult patients with ASUC being treated with IFX?

Recommendation 36: In hospitalized adults with ASUC being treated with IFX, we suggest using standard IFX dosing regimens over intensive IFX dosing regimens to decrease the short-term risk of colectomy. (Conditional recommendation, moderate certainty evidence).

Remark: A significant proportion of patients with ASUC will present with low albumin and elevated CRP. In these patients, consideration should be made to use accelerated IFX dosing starting with a 10 mg/kg dose.

Rationale

This recommendation was based on the PREDICT-UC trial, which compared the intensified 10 mg/kg IFX with the standard 5 mg/kg in 138 ASUC patients who were refractory to steroids. The study demonstrated that both intensified and standard induction regimens achieved comparable clinical and biochemical remission by weeks 2–6.[158]

Efficacy outcomes were comparable between both intensified and standard induction regimens, including clinical response at 7 days (RR 0.93, [0.71 to 1.22], moderate certainty, Table S39) and a decreased risk of colectomy at 7 days with the standard regimen (RR 0.1, [0.005 to 2.06], moderate certainty, Table S39). Clinical response at 14 days was also comparable between both regimens (RR 0.95, [0.77 to 1.18], moderate certainty, Table S39).

S Table 39.

Standard infliximab dosing regimens compared to intensive infliximab dosing regimens for decreasing the short-term risk of colectomy in hospitalized adult patients with acute severe ulcerative colitis (ASUC) being treated with infliximab.

Bibliography: Choy MC, Li Wai Suen CFD, Con D, Boyd K, Pena R, Burrell K, et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol [Internet]. 2024 Nov 1 [cited 2025 Apr 16];9(11):981–96. Available from: https://www.thelancet.com/action/showFullText?pii=S2468125324002000

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Standard IFX dosing regimens	intensive IFX dosing regimens	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Standard IFX dosing regimens	intensive IFX dosing regimens	Absolute (95% CI)
Clinical response (follow-up: 7 days)
1	RCT	not serious	not serious	not serious	serious^a	none	56/92 (60.9%)	30/46 (65.2%)	RR 0.93 (0.71 to 1.22)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	56/92 (60.9%)	30/46 (65.2%)	46 fewer per 1,000 (from 189 fewer to 143 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Risk of colectomy (follow-up: 7 days)
1	RCT	not serious	not serious	not serious	serious^b	none	0/92 (0.0%)	2/46 (4.3%)	RR 0.100 (0.005 to 2.060)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	0/92 (0.0%)	2/46 (4.3%)	39 fewer per 1,000 (from 43 fewer to 46 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Clinical response (follow-up: 14 days)
1	RCT	not serious	not serious	not serious	serious^a	none	65/92 (70.7%)	34/46 (73.9%)	RR 0.95 (0.77 to 1.18)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	65/92 (70.7%)	34/46 (73.9%)	37 fewer per 1,000 (from 170 fewer to 133 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Clinical remission (follow-up: 3 months)
1	RCT	not serious	not serious	not serious	serious^a	none	46/92 (50.0%)	23/46 (50.0%)	RR 1.00 (0.70 to 1.42)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	46/92 (50.0%)	23/46 (50.0%)	0 fewer per 1,000 (from 150 fewer to 210 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Steroid free remission (follow-up: 3 months)
1	RCT	not serious	not serious	not serious	serious^a	none	38/92 (41.3%)	19/46 (41.3%)	RR 1.00 (0.65 to 1.52)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	38/92 (41.3%)	19/46 (41.3%)	0 fewer per 1,000 (from 145 fewer to 215 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Endoscopic remission (follow-up: 3 months)
1	RCT	not serious	not serious	not serious	serious^a	none	43/92 (46.7%)	21/46 (45.7%)	RR 1.02 (0.70 to 1.50)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	43/92 (46.7%)	21/46 (45.7%)	9 more per 1,000 (from 137 fewer to 228 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Risk of colectomy (follow-up: 3 months)
1	RCT	not serious	not serious	not serious	serious^b	none	11/90 (12.2%)	4/45 (8.9%)	RR 1.37 (0.46 to 4.10)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	11/90 (12.2%)	4/45 (8.9%)	33 more per 1,000 (from 48 fewer to 276 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Infectious adverse event (follow-up: range 8 days to 3 months)
1	RCT	not serious	not serious	not serious	serious^b	none	16/92 (17.4%)	2/46 (4.3%)	RR 4.00 (0.96 to 16.66)	⨁⨁⨁◯ Moderate^b	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^b	none	16/92 (17.4%)	2/46 (4.3%)	130 more per 1,000 (from 2 fewer to 681 more)	⨁⨁⨁◯ Moderate^b	IMPORTANT
Risk of colectomy (follow-up: 1 months)
1	RCT	not serious	not serious	not serious	serious^b	none	11/90 (12.2%)	3/45 (6.7%)	RR 1.83 (0.54 to 6.24)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	11/90 (12.2%)	3/45 (6.7%)	55 more per 1,000 (from 31 fewer to 349 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Risk of colectomy (follow-up: 12 months)
1	RCT	not serious	not serious	not serious	serious^b	none	16/87 (18.4%)	3/44 (6.8%)	RR 2.70 (0.83 to 8.76)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	16/87 (18.4%)	3/44 (6.8%)	116 more per 1,000 (from 12 fewer to 529 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Adverse events (follow-up: range 8 days to 3 months)
1	RCT	not serious	not serious	not serious	serious^b	none	33/92 (35.9%)	7/46 (15.2%)	RR 2.35 (1.13 to 4.91)	⨁⨁⨁◯ Moderate^b	CRITICAL
1	RCT	not serious	not serious	not serious	serious^b	none	33/92 (35.9%)	7/46 (15.2%)	205 more per 1,000 (from 20 more to 595 more)	⨁⨁⨁◯ Moderate^b	CRITICAL
Serious adverse events (follow-up: range 8 days to 3 months)
1	RCT	not serious	not serious	not serious	serious^b	none	17/92 (18.5%)	4/46 (8.7%)	RR 2.12 (0.76 to 5.95)	⨁⨁⨁◯ Moderate^b	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^b	none	17/92 (18.5%)	4/46 (8.7%)	97 more per 1,000 (from 21 fewer to 430 more)	⨁⨁⨁◯ Moderate^b	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.small sample size

^b.small sample size and wide CI.

For long-term follow-ups at 3 months, efficacy outcomes were similar in both groups, including clinical remission (RR 1.00, [0.70 to 1.42], Table S39), endoscopic remission (RR 1.02, [0.70–1.50], Table S39), and steroid-free remission (RR 1.00, [0.65 to 1.52], Table S39). Colectomy was slightly more frequent with standard IFX at 1 month (RR 1.83, [0.54 to 6.24], moderate certainty, Table S39), 3 months (RR 1.37, [0.46 to 4.10], moderate certainty, Table S39), and 12 months (RR 2.70, [0.83 to 8.76], Table S39). Infectious AEs were numerically higher with the intensive regimens (RR 4.00, [0.96 to 16.6], moderate certainty, Table S39).

The standard IFX induction regimen involves administering 5 mg/kg at weeks 0, 2, and 6. However, in ASUC, accelerated induction regimens have been explored to address the rapid clearance of IFX due to a high inflammatory burden. A retrospective study demonstrated that patients receiving the accelerated regimen had a significantly lower colectomy rate during induction therapy than those on the standard regimen (6.7% vs. 40%, P = 0.039). However, long-term colectomy rates were similar between the two groups.[159]

Based on moderate-certainty evidence, the guideline panel recommends standard IFX dosing over an intensified regimen. However, in either obese or male patients presenting or those presenting with a high inflammatory burden, elevated CRP, or low serum albumin levels, accelerated IFX dosing is recommended.[158]

Therefore, while a standard regimen is appropriate, personalized dosing based on inflammatory markers is warranted in selected high-risk patients. The panel emphasizes the acceptability and feasibility of the regimens with essential anti-TNF level post-induction monitoring. The AGA guideline panel did not recommend routine use of intensive vs. standard IFX dosing in adult patients hospitalized with ASUC refractory to IV corticosteroids.[14] This recommendation is also consistent with ACG and BSG guidance, which do not recommend routine intensive IFX dosing in ASUC. All three guidelines note that standard dosing is appropriate for most patients, but intensive dosing may be considered in those with hypoalbuminemia.[14,31,118]

Switching Formulations for Maintenance of Remission in Adults with Moderate-to-Severe UC

Q37. Should switching to SC formulation or continuing on IV formulations of IFX or VDZ vs. no treatment be used to maintain remission for stable moderate-to-severe UC patients on IV IFX or VDZ?

Recommendation 37: For maintenance of remission in stable moderate-to-severe UC patients on IV IFX or VDZ, we recommend either switching to SC formulation or continuing on IV formulations of IFX or VDZ over no treatment. (Strong recommendation, moderate certainty evidence).

Rationale

This recommendation was based on the VISIBLE 1 trial, a phase 3 RCT that evaluated the efficacy and safety of SC and IV VDZ in UC patients. Results showed higher clinical remission rates with SC VDZ compared to placebo. Endoscopic improvement and durable clinical response also favored SC VDZ over placebo. Safety profiles were similar between the SC and IV groups.[160]

Switching to SC or IV VDZ showed a trend toward benefit in clinical remission at 52 weeks (RR 1.08, [0.75 to 1.57], moderate certainty, Table S40) and endoscopic improvement (RR 1.05, [0.78 to 1.42], moderate certainty, Table S40). In contrast, a durable clinical response was slightly less frequent (RR 0.88, [0.71 to 1.10], moderate certainty, Table S40). Corticosteroid-free remission was comparable between the two groups (RR 1.00, [0.45 to 2.28], low certainty, Table S40). Switching to SC or IV VDZ was associated with a better safety profile, including fewer overall AEs (RR 0.85, [0.69 to 1.05], moderate certainty, Table S40) and fewer SAEs (RR 0.72, [0.29 to 1.80], moderate certainty, Table S40).

S Table 40.

Switching to subcutaneous formulation or continuing IV formulations of infliximab or vedolizumab compared to no treatment for maintaining remission for stable moderate-to-severe UC patients on IV infliximab or vedolizumab.

Bibliography: Sandborn WJ, Baert F, Danese S, Krznarić Ž, Kobayashi T, Yao X, et al. Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis. Gastroenterology [Internet]. 2020 Feb 1 [cited 2025 Apr 17];158(3):562-572.e12. Available from: https://pubmed.ncbi.nlm.nih.gov/31470005/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Switching to SC formulation or continuing IV formulations of IFX or VDZ	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations		no treatment	Absolute (95% CI)
Clinical remission (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	49/106 (46.2%)	23/54 (42.6%)	RR 1.08 (0.75 to 1.57)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	49/106 (46.2%)	23/54 (42.6%)	34 more per 1,000 (from 106 fewer to 243 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Endoscopic improvement (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	60/106 (56.6%)	29/54 (53.7%)	RR 1.05 (0.78 to 1.42)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	60/106 (56.6%)	29/54 (53.7%)	27 more per 1,000 (from 118 fewer to 226 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Durable clinical response (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	68/106 (64.2%)	39/54 (72.2%)	RR 0.88 (0.71 to 1.10)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	68/106 (64.2%)	39/54 (72.2%)	87 fewer per 1,000 (from 209 fewer to 72 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Durable clinical remission (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	16/106 (15.1%)	9/54 (16.7%)	RR 0.90 (0.42 to 1.91)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	16/106 (15.1%)	9/54 (16.7%)	17 fewer per 1,000 (from 97 fewer to 152 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT
Corticosteroid-free remission (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	13/45 (28.9%)	6/21 (28.6%)	RR 1.00 (0.45 to 2.28)	⨁⨁◯◯ Low^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	very serious^a,b	none	13/45 (28.9%)	6/21 (28.6%)	0 fewer per 1,000 (from 157 fewer to 366 more)	⨁⨁◯◯ Low^a,b	IMPORTANT
Any adverse events (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	69/106 (65.1%)	41/54 (75.9%)	RR 0.85 (0.69 to 1.05)	⨁⨁⨁◯ Moderate^a	CRITICAL
1	RCT	not serious	not serious	not serious	serious^a	none	69/106 (65.1%)	41/54 (75.9%)	114 fewer per 1,000 (from 235 fewer to 38 more)	⨁⨁⨁◯ Moderate^a	CRITICAL
Serious adverse events (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	serious^a	none	10/106 (9.4%)	7/54 (13.0%)	RR 0.72 (0.29 to 1.80)	⨁⨁⨁◯ Moderate^a	IMPORTANT
1	RCT	not serious	not serious	not serious	serious^a	none	10/106 (9.4%)	7/54 (13.0%)	36 fewer per 1,000 (from 92 fewer to 104 more)	⨁⨁⨁◯ Moderate^a	IMPORTANT

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CI: confidence interval; RR: risk ratio

Explanations

^a.low population number

^b.Wide confidence interval.

A real-world study concluded that switching to SC VDZ is as effective, safe, and well tolerated as continued IV treatment, maintaining comparable disease control and QoL at 52 weeks.[161] More recently, a prospective cohort study indicated that SC IFX therapy induced higher remission rates than continued IV IFX administration in patients with IBD over 1 year.[162]

The guideline panel strongly recommends switching SC or IV IFX or VDZ over no treatment for remission maintenance in UC patients. This recommendation is based on moderate-certainty evidence, with a benefit–risk profile that likely favors treatment. The undesirable effects are considered minimal, and the associated costs are moderate. The panel also highlights the importance of incorporating patient preferences when selecting the route of administration.

This is consistent with ACG guidance, which considers SC IFX and VDZ similar to IV for maintenance, and with BSG guidance, which favors switching while emphasizing collaborative decision-making, monitoring, and local practicality.[31,118]

Q38. Should switching to biosimilars vs. the originator version be used for maintaining the remission for stable moderate-to-severe UC patients on the originator biologic?

Recommendation 38: For adults with moderate-to-severe UC who are in stable remission on the originator biologic, we suggest either switching to a biosimilar version or continuing the originator version. (Conditional recommendation, low certainty evidence).

Remark: Biosimilars are typically substantially less expensive than originator biologics, offering significant cost savings. This cost advantage, combined with the lack of evidence of inferior efficacy, supports the conditional recommendation.

Rationale

This recommendation was based on the NOR-SWITCH trial, a government-funded phase 4 RCT, which assessed the disease worsening rate and remission after switching from originator IFX to biosimilar (CT-P13) in 93 UC patients for ≥6 months.[163]

Despite the biosimilar (CT-P13) having a higher disease worsening rate (RR 1.31, [0.34 to 5.08, low certainty, Table S41), it was associated with higher remission at week 52 (RR 1.06, [0.91 to 1.23, low certainty, Table S41).

S Table 41.

Switching to Biosimilars compared to continuing the Originator version for maintaining the remission for stable moderate-to-severe UC patients on the originator biologic.

Bibliography: Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet (London, England) [Internet]. 2017 Jun 10 [cited 2025 Apr 17];389(10086):2304–16. Available from: https://pubmed.ncbi.nlm.nih.gov/28502609/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	switching to Biosimilars	continuing the Originator version	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	switching to Biosimilars	continuing the Originator version	Absolute (95% CI)
UC remission difference (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	very serious^a	none	206	202	-	⨁⨁◯◯ Low^a	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a	none	206	202	MD 6.1 higher (9.6 lower to 21.9 higher)	⨁⨁◯◯ Low^a	CRITICAL
Disease worsening Rates
1	RCT	not serious	not serious	not serious	very serious^a	none	3/33 (9.1%)	5/42 (11.9%)	RR 1.31 (0.34 to 5.08)	⨁⨁◯◯ Low^a	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a	none	3/33 (9.1%)	5/42 (11.9%)	37 more per 1,000 (from 79 fewer to 486 more)	⨁⨁◯◯ Low^a	CRITICAL
Remission (follow-up: 52 weeks)
1	RCT	not serious	not serious	not serious	very serious^a	none	29/33 (87.9%)	39/42 (92.9%)	RR 1.06 (0.91 to 1.23)	⨁⨁◯◯ Low^a	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a	none	29/33 (87.9%)	39/42 (92.9%)	56 more per 1,000 (from 84 fewer to 214 more)	⨁⨁◯◯ Low^a	CRITICAL

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CI: confidence interval; MD: mean difference; RR: risk ratio

Explanations

^a.CI crosses null effect (0).

A long-term study found no significant difference in treatment persistence, loss of response rates, or AEs between patients continuing the originator ADA and those switching to biosimilars.[164] Another prospective multicenter cohort study found that multiple switches between the originator IFX and biosimilars were effective and safe for IBD patients, including UC.[165] A study found that reverse switching from the biosimilar (SB₂) to the originator IFX did not impact efficacy, immunogenicity, or safety in IBD patients, including UC.[166]

Biosimilars are typically substantially less expensive than originator biologics, offering significant cost savings, and may improve access to biologic therapies for more patients, potentially promoting equity. This cost advantage and the lack of evidence of inferior efficacy support the conditional recommendation.

This recommendation is consistent with ACG guidance, which supports that biosimilars to anti-TNF agents and ustekinumab are appropriate alternatives to originators and advises against delaying switching. The BSG also promotes switching but emphasizes that the local clinical commissioning setting should influence the decision between originator and biosimilar.[31,118]

Despite the available international evidence supporting the safety and cost-effectiveness of switching to approved biosimilars, the panel elected to adopt a cautious stance in the local context and emphasized shared decision-making, balancing potential cost benefits against uncertain efficacy differences, and underscoring the need to monitor postswitch to assess for loss of response and AEs, including immunogenicity.

Management of Adults with Complex/Refractory UC

Q39. Should advanced therapies vs. no treatment be used to treat recurrent pouchitis in patients with UC who have undergone IPAA and experience recurrent pouchitis that responds to antibiotics but relapses shortly after stopping the antibiotics?

Recommendation 39: In patients with UC who have undergone IPAA and experience recurrent pouchitis that is antibiotic-dependent or refractory, we suggest the use of advanced therapies over no treatment to treat recurrent pouchitis (Conditional recommendation, low certainty evidence).

Rationale

This recommendation was based on a phase 4 double-blinded RCT that evaluated VDZ 300 mg IV compared to placebo in 102 UC patients with chronic pouchitis following ileal pouch-anal anastomosis (IPAA). VDZ demonstrated superior efficacy outcomes compared to placebo, including clinical remission assessed by the modified Pouchitis Disease Activity Index (mPDAI) (defined as a score ≤4 with a ≥2-point reduction from baseline) at both 14 and 34 weeks.[167]

Advanced therapy, such as VDZ, demonstrated higher mPDAI remission at 34 weeks (RR 2.01, [0.99 to 4.10, low certainty, Table S42). Safety outcomes were comparable between the VDZ and placebo groups. VDZ showed less frequent SAEs (RR 0.76, [0.13 to 4.53, low certainty, Table S42), and AEs led to discontinuation (RR 0.20, [0.01 to 3.63, low certainty, Table S42). In contrast, the overall incidence of AEs was numerically slightly higher with VDZ (RR 1.07, [0.75 to 1.53, low certainty, Table S42).[167]

S Table 42.

Advanced therapies compared to no treatment for treating recurrent pouchitis in patients with UC who have undergone IPAA and experience recurrent pouchitis that responds to antibiotics but relapses shortly after stopping the antibiotics.

Bibliography: Travis S, Silverberg MS, Danese S, Gionchetti P, Löwenberg M, Jairath V, et al. Vedolizumab for the Treatment of Chronic Pouchitis. N Engl J Med [Internet]. 2023 Mar 30 [cited 2025 Apr 16];388(13):1191–200. Available from: https://pubmed.ncbi.nlm.nih.gov/36988594/

Certainty assessment							№ of patients		Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	advanced therapies	no treatment	Relative (95% CI)
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	advanced therapies	no treatment	Absolute (95% CI)
mPDAI-Defined Remission (follow-up: mean 34 weeks; assessed with: Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a	none	18/51 (35.3%)	9/51 (17.6%)	RR 2.01 (0.99 to 4.10)	⨁⨁◯◯ Low^a	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a	none	18/51 (35.3%)	9/51 (17.6%)	178 more per 1,000 (from 2 fewer to 547 more)	⨁⨁◯◯ Low^a	CRITICAL
Change from baseline in PDAI total score (follow-up: mean 34 weeks; assessed with: Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	51	51	-	⨁⨁◯◯ Low^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	very serious^a,b	none	51	51	MD 1.7 lower (3.7 lower to 0.2 higher)	⨁⨁◯◯ Low^a,b	IMPORTANT
Change from baseline in IBDQ total score (follow-up: mean 34 weeks; assessed with: Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	51	51	-	⨁⨁◯◯ Low^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	very serious^a,b	none	51	51	MD 9.9 higher (4.8 lower to 24.6 higher)	⨁⨁◯◯ Low^a,b	IMPORTANT
Change from baseline in CGQL score (follow-up: mean 34 weeks; assessed with: Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	51	51	-	⨁⨁◯◯ Low^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	very serious^a,b	none	51	51	MD 0.03 higher (0.05 lower to 0.11 higher)	⨁⨁◯◯ Low^a,b	IMPORTANT
Any adverse event (follow-up: mean 34 weeks; assessed with: Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	47/51 (92.2%)	44/51 (86.3%)	RR 1.07 (0.75 to 1.53)	⨁⨁◯◯ Low^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a,b	none	47/51 (92.2%)	44/51 (86.3%)	60 more per 1,000 (from 216 fewer to 457 more)	⨁⨁◯◯ Low^a,b	CRITICAL
Adverse event leading to discontinuation (follow-up: mean 34 weeks; assessed with: Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	1/51 (2.0%)	5/51 (9.8%)	RR 0.20 (0.01 to 3.63)	⨁⨁◯◯ Low^a,b	CRITICAL
1	RCT	not serious	not serious	not serious	very serious^a,b	none	1/51 (2.0%)	5/51 (9.8%)	78 fewer per 1,000 (from 97 fewer to 258 more)	⨁⨁◯◯ Low^a,b	CRITICAL
Serious adverse events (follow-up: mean 34 weeks; assessed with: Vedolizumab)
1	RCT	not serious	not serious	not serious	very serious^a,b	none	3/51 (5.9%)	4/51 (7.8%)	RR 0.76 (0.13 to 4.53)	⨁⨁◯◯ Low^a,b	IMPORTANT
1	RCT	not serious	not serious	not serious	very serious^a,b	none	3/51 (5.9%)	4/51 (7.8%)	19 fewer per 1,000 (from 68 fewer to 277 more)	⨁⨁◯◯ Low^a,b	IMPORTANT

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CI: confidence interval; MD: mean difference; RR: risk ratio

Explanations

^a.downgrade two levels for a small number of events

^b.Wide CI

Based on low certainty evidence, minor desirable and undesirable effects, and feasibility of this class of medication, the guideline panel conditionally recommends advanced therapy in UC patients post-IPAA with antibiotic-dependent relapses for recurrent pouchitis. The conditional recommendation emphasized the further local/regional real-world evidence. The AGA guidelines align with this recommendation and indicate that advanced therapies, including anti-TNF agents, such as IFX, ADA, golimumab, CZP, VDZ, ustekinumab, RZB, ozanimod, tofacitinib, and upadacitinib, are recommended for patients with pouchitis who have an inadequate response to antibiotics.[168] This is also in line with the BSG guidance, which suggests VDZ as a first-line advanced therapy for chronic pouchitis [Table 2].[31]

Table 2.

Treatment recommendations for ulcerative colitis

Final recommendation	Strength of recommendation	Certainty of evidence	Percentage of panel agreement
Treatment of Advanced Therapy Bio-Naïve or Exposed Adults with Moderate-to-Severe UC
For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend anti-TNF agents (IFX, ADA, golimumab) over no treatment. Remarks: IFX is the favored anti-TNF agent in terms of efficacy in moderate-to-severe UC.	Strong	Moderate	100%
For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend using anti-integrins (VDZ) over no treatment.	Strong	Moderate	93%
For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend using anti-IL12/23 over no treatment.	Strong	Moderate	100%
For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend using anti-IL-23 (RZB, Mirikizumab, Guselkumab) over no treatment.	Strong	Moderate	100%
For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend the treatment with JAK inhibitors (tofacitinib, upadacitinib, and filgotinib) over no treatment.	Strong	Moderate	100%
For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend using S1P-R modulators (Ozanimod and Etrasimod) over no treatment.	Strong	Moderate	100%
For induction and maintenance of remission in bio-naïve adults with moderate-to-severe UC, we suggest using VDZ over ADA.	Conditional	Moderate	93%
For induction and maintenance of remission in adults with moderate-to-severe UC, we recommend using anti-TNF or IL-12/23 biosimilars over no treatment.	Strong	High	100%
For induction and maintenance of remission in adults with moderate-to-severe UC, we suggest combining IFX with AZA over IFX monotherapy.	Conditional	Very low	93%
Treatment Optimization Strategies for Adults with UC and Secondary Loss of Response to Advanced Therapy
For adults with UC and secondary loss of response to anti-TNF therapy, we suggest measurement of anti-TNF trough levels and dose optimization based on these levels over maintaining the standard anti-TNF dose without trough level monitoring.	Conditional	Moderate	93%
For adults with moderate-to-severe UC who have achieved partial remission on a standard dose of advanced therapies (VDZ and Ustekinumab), we suggest dose escalation over standard dosing.	Conditional	Very low	87%
In UC patients with loss of response to anti-TNF therapy despite adequate serum drug levels and negative ADAs, we suggest switching to a different class, such as anti-IL-12/23, anti-IL-23, anti-Integrins, JAKi, or S1P-R modulators for optimizing the management of the disease over switching to another anti-TNF.	Conditional	Very low	87%
Management of Adults with Acute Severe UC
In hospitalized adults with ASUC refractory to IV corticosteroids, we recommend using rescue therapy with IFX or cyclosporine over no treatment to reduce the short-term risk of colectomy. Remarks: We suggest using IFX or cyclosporine as rescue therapy in patients admitted with ASUC and who have failed adequate doses and duration of IV steroids.	Strong	Moderate	100%
In adults with ASUC who had an inadequate response or intolerance to at least one therapy, including IV corticosteroids, cyclosporine, or IFX, we suggest using JAK inhibitors over no treatment to induce remission. Remarks: A cautious risk and benefit approach should be considered to not delay colectomy in patients who are unlikely to benefit from further sequential medical rescue therapy.	Conditional	Moderate	87%
In hospitalized adults with ASUC being treated with IFX, we suggest using standard IFX dosing regimens over intensive IFX dosing regimens to decrease the short-term risk of colectomy. Remarks: A significant proportion of patients with ASUC will present with low albumin and elevated CRP. In these patients, consideration should be made to use accelerated IFX dosing starting with a 10 mg/kg dose.	Conditional	Moderate	93%
Switching Formulations for Maintenance of Remission in Adults with Moderate-to-Severe UC
For maintenance of remission in stable moderate-to-severe UC patients on IV IFX or VDZ, we recommend either switching to SC formulation or continuing on IV formulations of IFX or VDZ over no treatment.	Strong	Moderate	93%
For adults with moderate-to-severe UC who are in stable remission on the originator biologic, we suggest either switching to a biosimilar version or continuing the originator version.	Conditional	Low	93%
Remarks: Biosimilars are typically substantially less expensive than originator biologics, offering significant cost savings. This cost advantage, combined with the lack of evidence of inferior efficacy, supports the conditional recommendation.
Management of Adults with Complex/Refractory UC
In patients with UC who have undergone IPAA and experience recurrent pouchitis that is antibiotic-dependent or refractory, we suggest the use of advanced therapies over no treatment to treat recurrent pouchitis.	Conditional	Low	93%

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ADA=Adalimumab, ADAs=Anti-drug antibodies, ASUC=Acute Severe Ulcerative Colitis, AZA=Azathioprine, CD=Crohn’s Disease, CRP=C-reactive protein, IFX=Infliximab, IPAA=Ileal Pouch–Anal Anastomosis, IV=Intravenous, JAK=Janus Kinase, JAKi=Janus Kinase inhibitors, RZB=Risankizumab, SC=Subcutaneous, S1P-R=Sphingosine-1-phosphate receptor, TNF=Tumor Necrosis Factor, UC=Ulcerative Colitis, VDZ=Vedolizumab

Treatment Recommendations for Moderate to Severe IBD with uncontrolled extraintestinal manifestations

Q40. Should advanced combination therapy (e.g., biologic + small molecule, or biologic + biologic) vs. advanced monotherapy (e.g., biologic alone or small molecule alone) be used for adults with refractory IBD or those with uncontrolled extraintestinal manifestations (EIMs)?

Recommendation 40: The use of combined advanced therapy (e.g., biologics + small molecules) in adults with IBD should be reserved for patients with severely active disease that is refractory to multiple lines of single advanced therapy, where surgery is not an acceptable option, for patients with EIMs (Good practice statement).

This good practice statement is based on limited data and expert opinion due to the lack of direct evidence. Previous studies have indicated that 60% of CD patients do not achieve long-term remission.[169] Similarly, a significant proportion of UC patients do not achieve long-term remission with current treatments. In a UK study, only 53.9% of patients achieved remission within 12 months of starting advanced therapies.[170] Similar results were found in a German study, which reported that 47.2% of patients achieved clinical remission after 12 months, while 37.6% experienced an inadequate response.[171]

Therefore, advanced combination therapy may be appropriate in various situations, including cases with uncontrolled EIMs, patients with concurrent immune-mediated diseases, and those with a refractory IBD phenotype where surgical options are not viable. When dealing with refractory disease, combining agents that have previously led to at least a partial response without causing adverse side effects is reasonable.[172]

Advanced combination use should consider the specific clinical situation to manage EIMs. This includes any previous evidence of partial effectiveness from a particular agent, available research indicating potential benefits from other relevant treatments, and considerations regarding safety.[173] While targeting multiple mechanistic pathways may be beneficial for patients, from bio-naïve to advanced therapies, there is currently limited evidence supporting the use of upfront advanced combination therapy, even in those at high risk of disease progression or complications.[173]

A recent SR and MA of 30 studies with 279 patients compared the efficacy and safety of a dual biologic or biologic therapy with those of tofacitinib in IBD.[169] The advanced combination therapy, which includes biologics and small molecules, showed higher rates of clinical response and remission, with an RR of 1.83, [1.60 to 2.09] for clinical response and an RR of 2.05, [1.67 to 2.51] for remission. Additionally, the combination therapy group had higher rates of corticosteroid-free remission (RR 0.46, [0.31 to 0.61] and response to EIMs (RR 0.50, [0.14 to 0.06]. There was also a greater reduction in the need for surgery in the combination therapy group, with an RR of 0.12 (95% CI: 0.04 to 0.24).[169] In contrast, endoscopic response and remission rates were higher with the advanced monotherapy, with risk ratios of 0.60 (95% CI: 0.27 to 0.89) for response and 0.24 (95% CI: 0.10 to 0.42) for remission, respectively.[169]

Another SR and MA has shown that dual biologic therapy or small molecule combined with a biologic therapy was safe and effective among refractory IBD patients with pooled SAEs rates ranging from 0% to 12.3% and pooled clinical remission rates ranging from 40.4% to 80.0% and endoscopic/radiologic remission rates ranging from 18.0% to 37.4%.[174]

Recent evidence supports the potential utility of combination therapy in cases of high refractoriness. The phase 2a VEGA trial evaluated the combination of guselkumab (an anti-IL-23 agent) and golimumab (an anti-TNF agent) in UC patients. The trial demonstrated that combination therapy was more effective than monotherapy with either agent alone. Specifically, 83.1% of patients receiving combination therapy achieved clinical response at 12 weeks, compared to 74.6% with guselkumab monotherapy and 61.1% with golimumab monotherapy.[175] Additionally, mucosal healing, a composite endpoint of endoscopic improvement and histologic remission, was achieved in 40.8% of patients receiving combination therapy, which is significantly higher than the rates observed with monotherapy (26.8% for guselkumab and 15.3% for golimumab).[175]

Similarly, in CD, the EXPLORER (VDZ-ADA-methotrexate trials) open-label design and absence of a control arm limit conclusions on efficacy, requiring phase 3 trials with comparator arms (e.g., monotherapy) to validate findings and evaluate long-term safety, particularly in biologically experienced patients.[176]

Based on a good practice statement, the guideline panel recommends using biologics-small-molecule combination therapy in refractory luminal or EIMs IBD patients. The panel emphasizes the need for further RCTs and cost-effectiveness analyses to support the combination therapy.

According to ECCO guidelines, advanced combination therapy should be considered for CD patients with uncontrolled EIMs, symptomatic immune-mediated disorders requiring multiple agents for remission, or refractory CD [Table 3].[51]

Table 3.

Treatment recommendations for Refractory IBD or for those with uncontrolled extraintestinal manifestations

Final recommendation	Strength of recommendation/certainty of evidence	Percentage of panel agreement
The use of combined advanced therapy (e.g., biologics + small molecules) in adults with IBD should be reserved for patients with severely active disease that is refractory to multiple lines of single advanced therapy, where surgery is not an acceptable option, for patients with EIMs.	Good practice statement	100%

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DISCUSSION

Our comprehensive IBD guidelines established 38 evidence-based recommendations for managing moderate-to-severe adult patients with CD and UC and two good practice statements based on our experts’ clinical practice. Our recommendations addressed the different aspects of the induction and maintenance of remission and treatment optimization. The guideline was developed using the GRADE approach, with systematic reviews, meta-analyses, and RCTs prioritized, followed by observational studies when none are available.

Regarding CD management, the guideline strongly recommends early initiation of biological therapy for induction and maintenance of remission in adults, which has proven to be associated with favorable outcomes compared to delayed initiation of advanced therapy (or step-up therapy). When focusing on specific advanced therapies, our guidelines strongly recommend anti-TNF agents such as IFX, IFX biosimilars, ADA, ADA biosimilars, or CZP over no treatment.

Additionally, SC IFX is strongly recommended as a maintenance therapy as it has proved highly efficacious, nearly twice as effective as a placebo, and has a comparable safety profile to IV IFX. Ustekinumab, an IL-12/23 inhibitor, is strongly recommended for induction and maintenance therapy, with higher response rates than placebo. More selective IL-23 inhibitors such as RZB, mirikizumab, and guselkumab are also strongly recommended.

The panel strongly recommends the use of IL23 inhibitors over ustekinumab particularly in advanced therapy exposed CD patients. Due to the limited head-to-head clinical trial data in CD, further positioning or sequencing recommendations could not be made. However, positioning advanced therapies should employ shared-decision making with the patient and include factors such as drug efficacy, drug safety, patient profile, comorbidities, extraintestinal manifestations, and previous exposure to advanced therapies.

For combination therapy approaches, the guidelines conditionally recommend thiopurine when starting IFX over IFX monotherapy for both CD and UC; on the other hand, SC IFX was superior as monotherapy over combination therapy. For the use of ADA, the guidelines suggest against routine combination with thiopurine, but to consider combination therapy, including those with prior immunogenic failure to other anti-TNF. For treatment optimization in patients with secondary loss of response to anti-TNF therapy, the guidelines conditionally recommend measurement of anti-TNF trough levels and dose optimization based on these levels over empirical dose adjustment for both CD and UC.

At specific treatment failure scenarios, the guidelines conditionally recommend switching to another anti-TNF agent over switching to another class of medications in patients with secondary loss of response to anti-TNF therapy, due to developing anti-drug antibodies. When choosing between IL-23 and IL-12/23 inhibition for patients who have previously failed anti-TNF therapy, the guidelines strongly recommend anti-IL-23 over anti-IL-12/23. Dose escalation by shortening the dosing interval to every 4 weeks was suggested for patients with partial or secondary loss of response to standard 8-weekly anti-integrins or anti-IL-12/23 inhibitors. The dose escalation showed high clinical response rates and endoscopic response rates.

Managing complex perianal fistulizing CD requires a multidisciplinary approach integrating surgical and medical therapies. Strong evidence supports the use of combination therapy, including seton placement, antibiotics, and anti-TNF combination with immunomodulators, for optimal clinical healing. In cases requiring fistula closure, adding immunomodulators to anti-TNF therapy may offer added benefit over monotherapy. While anti-IL-12/23, anti-IL-23, anti-integrin, and JAKIs remain conditionally recommended, emerging data, particularly for upadacitinib, show promise in achieving fistula closure. For prevention of POR in high-risk CD, advanced therapy is conditionally recommended, with the strongest evidence supporting anti-TNF, followed by VDZ and upadacitinib.

Regarding advanced combination therapy, the guideline pointed out that combination advanced therapies (biologics with small molecules or biologics with biologics) should be reserved for patients with severely active luminal disease refractory to multiple lines of single advanced therapy or patients with uncontrolled EIMs. Such patients should be managed in highly specialized IBD practices or centers.

Regarding UC management, the guidelines conditionally recommend VDZ over ADA for the induction and maintenance of remission in bi-naïve patients to biological agents. For patients with UC following failure or intolerance to advanced therapies, the guidelines strongly recommend anti-IL-12/23, and IL-23 inhibitors such as RZB, mirikizumab, and guselkumab.

JAKIs are strongly recommended for the induction and maintenance of remission in UC following advanced therapy failure. When considering formulation preferences, the guidelines strongly recommend either SC or IV formulations of IFX or VDZ maintenance over no treatment.

For hospitalized adults with ASUC refractory to IV corticosteroids, the guidelines strongly recommend using IFX or cyclosporine to decrease the short-term risk of colectomy, with evidence showing a significant reduction in colectomy rates at 1 month.

Our guidelines had several limitations that should be considered, as the evidence used was primarily derived from global Western studies involving non-Saudi or Middle Eastern patients. Detailed analysis of resource implications and cost-effectiveness within the Saudi healthcare system remains limited. The guidelines may not fully address the variability in healthcare delivery systems across different regions of Saudi Arabia, which impacts the feasibility of implementation. The guidelines provide limited specific recommendations for special populations, including pregnant women, elderly patients, and those with significant comorbidities.

The guideline aims to address current limitations by providing future recommendations and identifying key research priorities for medical professionals, with a focus on generating Saudi-specific evidence, optimizing treatment strategies, and enhancing implementation across diverse healthcare settings. The guideline panel proposes establishing a systematic update system that adheres to the GRADE methodology, with comprehensive reviews conducted every 3–5 years and interim updates provided as significant new data emerge. Priority will be given to novel therapeutics, comparative effectiveness studies, and Saudi-specific outcomes through a national IBD registry capturing treatment effectiveness and safety profiles. Future updates should incorporate biomarker validation for personalized approaches, Saudi-specific cost-effectiveness analyses, and assessments of patient-reported outcomes. We recommend developing post-marketing surveillance for advanced therapies, with a focus on understudied populations. At the same time, implementation studies and international collaborations will address barriers to guideline adherence and enhance the relevance of research for Saudi patients.

Implementation considerations

Implementing these evidence-based recommendations requires a coordinated approach across the Saudi healthcare system. Healthcare facilities should establish multidisciplinary IBD teams to ensure comprehensive care. A tiered referral system should be developed to facilitate access to specialized IBD centers for complex cases while maintaining follow-up care at regional centers when appropriate. Implementing biological and small-molecule therapies requires a cost-effectiveness analysis specific to the Saudi context to prioritize interventions for each scenario. Clinical decision support and monitoring could be performed through electronic record integration with IBD-specific tools, standardized TDM protocols, regular clinical audits, development of Saudi IBD registries, and quality initiatives to reduce treatment delays. Research should prioritize addressing the gaps through Saudi-specific clinical research networks, studies on the effectiveness of biological therapy, research on predictive biomarkers, assessments of combination therapies, and local cost-effectiveness analyses.

CONCLUSION

These guidelines represent an advancement in standardizing care for moderate to severe IBD in Saudi Arabia through a rigorous GRADE methodology. We provide guidance for biological and small-molecule therapies in both CD and UC. Acknowledging equity concerns in the implementation of advanced therapies, we suggest pragmatic strategies, including multidisciplinary teams, tiered referral systems, and standardized protocols. Despite the limitations of relying primarily on Western evidence, our systematic update framework, with scheduled reviews and a proposed national IBD registry, will progressively incorporate Saudi-specific data for both CD and UC. Through these guidelines, coordinated implementation efforts, and continued research, we aim to improve care quality, accessibility, and equity for all IBD patients throughout Saudi Arabia.

Ethical approval

Not applicable.

Conflict of interest

Dr. Mahmoud Mosli has served on advisory boards, and received speaker fees, and/or consultation fees from AbbVie, Takeda, Janssen, Ferring, Falk, Sandoz, Hikma, Pfizer, Bristol-Myers Squibb, Amgen, and Organon. Dr. Mosli has received research funding from Celgene, Pfizer, and Takeda. Dr. Abdulelah Almutairdi has served on advisory boards for Janssen, Abbvie, Amgen,Takeda, Pfizer, Bristol Meyers Squibb, Lilly. He has received speaker fees, and/or consultation fees from Janssen, Abbvie, Takeda, Bristol Meyers Squibb, Ferring. Dr. Nahla Azzam has served on advisory boards for Johnson&Johnson, Abbvie, Amgen, Takeda, Hikma, Pfizer, and Lilly. Dr. Azzam has received speaker fees from Johnson& Johnson, Abbvie, Takeda, Ferring, Acino, Sandoz, Hikma and Pfizer. She has received research grants from Abbvie, Johnson&Johnson. Dr. Turki Alameel has received consultation and speaker’s fees from Janssen, AbbVie, Takeda, Hikma, Pfizer, Amgen, BMS, Sandoz, Lilly, Ferring, Tabuk and New bridge. Dr. Shakir Bakkari has received speaker fees, and/or consultation fees from Janssen, AbbVie, Takeda, Hikma, Pfizer, BMS, Eli Lilly, Ferring. Dr. Badr Al-Bawardy has received speaker fees, and/or consultation fees from Janssen, AbbVie, Takeda, Hikma, Pfizer, BMS, Eli Lilly, Ferring. Dr. Othman Alharbi has received speaker fees, and/or consultation fees from Janssen, AbbVie, Takeda, Hikma, Pfizer, Amgen, BMS, Sandoz, Lilly, Ferring, Pentax, Tillotts Pharma, Tabuk and New bridge. Dr. Majid Almadi has served on advisory boards, and received speaker fees, and/or consultation fees from Abbvie, Takeda, Janssen, Ferring, Hikma, Pfizer. Dr. Yaser Meeralam received consultation and speaker’s fees from Janssen, AbbVie, Takeda, Hikma, Pfizer, Eli Lilly, Ferring. Dr. Bedor AlOmari served on advisory boards and received speaker’s fees from Abbvie, Janssen and Takeda. All other authors declare that they have no conflicts of interest, and the work was not supported or funded by any drug company. The manuscript has not been partially or fully published in English or Arabic in any other journals or websites.

Acknowledgments

The authors wish to express their sincere gratitude to Riyadh Home Company and its dedicated team for their valuable contributions to this project. Their support in medical writing, workflow coordination, and assistance with the analysis of voting results was crucial in the successful completion of this manuscript. Their involvement was limited to administrative and editorial support, with no involvement in the study design, formulation of recommendations, or any decision-making processes.

Supplementary tables of the “Practical Guidelines on Medical Management of Adults with Moderate-to-Severe Inflammatory Bowel Disease study”

S Table 1. Critical Outcomes According to PICO Questions ............................................................................................................................................. 5

S Table 2. Search Strategy for Crohn's Disease Recommendations .................................................................................................................................. 9

S Table 3. Search Strategy for Ulcerative Colitis Recommendations .............................................................................................................................. 35

S Table 4. Implications of the recommendation.s strength. ............................................................................................................................................. 53

S Table 5. Early initiation of biologic therapy compared to no treatment for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD. .................................................................................................................................................................................................... 54

S Table 6. Anti-TNFα [infliximab (IFX), adalimumab (ADA), or certolizumab pegol (CZP)] compared to no treatment for induction and maintenance of remission in bio-naive patients with moderate-to-severe CD. ..................................................................................................................................... 56

S Table 7. Vedolizumab compared to no treatment for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD. .. 58

S Table 8. Ustekinumab compared to no treatment for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD. .. 61

S Table 9. Anti-IL-23 agents (risankizumab (RZB), guselkumab, and mirikizumab) compared to no treatment for induction and maintenance of remission in bio-naïve patients with moderate-to-severe CD. .......................................................................................................................................... 63

S Table 10. Upadacitinib compared to no treatment for induction and maintenance of remission in bio-naive patients with moderate-to-severe CD. . 67

S Table 11. Subcutaneous infliximab (CT-P13) compared to no treatment for maintenance of remission in bio-naïve patients with moderate-to-severe CD. .................................................................................................................................................................................................................................... 70

S Table 12. Treatment with biosimilars of anti-tumor necrosis factor [TNF] agents or Anti-IL-12/23 compared to no treatment for inducing and maintaining remission in conventional therapy-exposed patients with moderate-to-severe CD. ..................................................................................... 73

S Table 13. Switching to another anti-TNF agent compared to no treatment for optimizing the management of the disease in CD patients with secondary loss of response to anti-TNF therapy (and not primary treatment failure) due to developing Anti-Drug Antibodies (ADAs) ...................... 75

S Table 14. Switching outside the anti-TNF class to another advanced therapy compared to no treatment for clinical remission in CD patients who do not respond to anti-TNF therapy, although having adequate serum drug levels and negative ADAs. ............................................................................. 77

S Table 15. Anti-IL23 compared to anti-IL 12/23 for induction and maintenance of remission in patients with moderate-to-severe CD who have previously failed anti-TNF therapy. .................................................................................................................................................................................. 79

S Table 16. Combination therapy with an immunomodulator and IFX compared to IFX monotherapy for the induction of remission in patients with moderate-to-severe CD. .................................................................................................................................................................................................... 81

S Table 17. Combination therapy with immunomodulators (thiopurine) with subcutaneous (SC) infliximab (CT-P13) compared to subcutaneous infliximab (CT-P13) without immunomodulators for maintaining remission in patients with moderate-to-severe CD.................................................. 83

S Table 18. Combination of adalimumab with immunomodulators (thiopurine) compared to adalimumab monotherapy for inducing and maintaining remission in patients with moderate-to-severe CD. .......................................................................................................................................................... 85

S Table 19. Adjusting the dose based on measured anti-TNF trough levels compared to empirically optimizing the dose without measuring anti-TNF trough levels for CD patients with secondary loss of response to anti-TNF therapy. ...................................................................................................... 87

S Table 20. Combination therapy including seton placement, antibiotics, and anti-TNF agents (e.g., infliximab, adalimumab) compared to Standard care or alternative treatments such as antibiotics alone, surgical drainage without seton, or other immunosuppressive therapies for the induction of remission in patients with complicated perianal fistula associated with abscess. ............................................................................................................ 89

S Table 21. combination of immunomodulators & anti-TNF compared to anti-TNF monotherapy for fistula healing in patients with CD and complex perianal fistula. .................................................................................................................................................................................................................. 90

S Table 22. Anti-IL-12/23, anti-IL23, anti-integrin, or selective JAKi compared to no treatment for fistula healing in complex perianal fistulae in CD patients. ............................................................................................................................................................................................................................. 91

S Table 23. Subcutaneous or IV infliximab or subcutaneous or IV vedolizumab compared to no treatment for maintaining remission for stable moderate-to-severe CD patients. ....................................................................................................................................................................................... 94

S Table 24. Advanced therapy compared to no treatment for preventing the postoperative recurrence for high-risk CD. ............................................. 96

S Table 25. Treatment with anti-tumor necrosis factor [TNF] agents [IFX, adalimumab, and golimumab] compared to no treatment for induction and maintenance of remission in patients with moderate-to-severe UC. ................................................................................................................................ 97

S Table 26. Treatment with Anti-Integrins (vedolizumab) compared to no treatment for induction and maintenance of remission in patients with moderately to severely active UC. .................................................................................................................................................................................... 99

S Table 27. Treatment with Anti-IL-12/23 compared to no treatment for induction and maintenance of remission in patients with moderate-to-severe UC. .................................................................................................................................................................................................................................. 103

S Table 28. Anti-IL-23 (Risankizumab, Mirikizumab, Guselkumab) compared to no treatment for induction and maintenance of remission in patients with moderately-to-severely active UC. ......................................................................................................................................................................... 106

S Table 29. Treatment with JAK Inhibitors (JAKIs) (Tofacitinib, Upadacitinib, Filgotinib) compared to no treatment for induction and maintenance of remission in patients with moderate-to-severe UC..................................................................................................................................................... 110

S Table 30. S1P-R modulators (Ozanimod, Etrasimod) compared to no treatment for induction and maintenance of remission in patients with moderate-to-severe UC. .................................................................................................................................................................................................. 118

S Table 31. Vedolizumab compared to Adalimumab for induction and maintenance of remission in moderate-to-severe ambulatory UC patients bionaïve to advanced therapies. ........................................................................................................................................................................................... 120

S Table 32. Treatment with biosimilars of anti-tumor necrosis factor [TNF] agents or Anti-IL-12/23 compared to no treatment for induction and maintenance of remission in patients with moderate-to-severe UC. .............................................................................................................................. 121

S Table 33. Combining infliximab with thiopurine compared to infliximab monotherapy for induction and maintenance of remission in patients with moderate-to-severe UC. .................................................................................................................................................................................................. 123

S Table 34. Adjusting the dose based on measured anti-TNF trough levels compared to empirically optimizing the dose without measuring anti-TNF trough levels for UC patients with secondary loss of response to anti-TNF therapy. .................................................................................................... 124

S Table 35. Dose escalation (by shortening dosing intervals) used for advanced therapies (Vedolizumab and Ustekinumab) compared to the standard dose for maintaining the remission of patients with moderate-to-severe UC who demonstrated a partial response to standard 8-weekly dosing. ...... 125

S Table 36. Switching to a different class, such as Anti-IL-12/23, Anti-IL-23, Anti-Integrins, JAKi, or S1P-R modulators, compared to no treatment, for optimizing the management of the disease in UC patients with secondary loss of response to anti-TNF therapy based on therapeutic drug monitoring (TDM). ......................................................................................................................................................................................................... 126

S Table 37. Infliximab or cyclosporine compared to no treatment for decreasing the risk of short-term colectomy in hospitalized adult patients with acute severe ulcerative colitis (ASUC) refractory to intravenous corticosteroids. ......................................................................................................... 129

S Table 38. JAK Inhibitors (JAKIs) compared to no treatment for remission induction in adults with acute severe ulcerative colitis (ASUC) who had an inadequate response or intolerance to at least one therapy, including IV corticosteroids, cyclosporine, or infliximab. ........................................... 131

S Table 39. Standard infliximab dosing regimens compared to intensive infliximab dosing regimens for decreasing the short-term risk of colectomy in hospitalized adult patients with acute severe ulcerative colitis (ASUC) being treated with infliximab. ................................................................... 132

S Table 40. Switching to subcutaneous formulation or continuing IV formulations of infliximab or vedolizumab compared to no treatment for maintaining remission for stable moderate-to-severe UC patients on IV infliximab or vedolizumab. .......................................................................... 135

S Table 41. Switching to Biosimilars compared to continuing the Originator version for maintaining the remission for stable moderate-to-severe UC patients on the originator biologic. ................................................................................................................................................................................. 137

S Table 42. Advanced therapies compared to no treatment for treating recurrent pouchitis in patients with UC who have undergone IPAA and experience recurrent pouchitis that responds to antibiotics but relapses shortly after stopping the antibiotics. ............................................................ 138

Recommendation Questions

Funding Statement

All authors declare that none of them has received any financial support for the research, authorship, and publication of this article.

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PERMALINK

Practical guidelines on medical management of adults with moderate-to-severe inflammatory bowel disease

Mahmoud H Mosli

Badr Al-Bawardy

Turki AlAmeel

Nahla A Azzam

Shakir A Bakkari

Othman R Alharbi

Abdulelah Almutairdi

Yaser K Meeralam

Omar I Saadah

Majid A Almadi

Waleed Alhazzani

Haifa F Alotaibi

Khalidah A Alenzi

Bedor A Al-Omari

Hajer Y Almudaiheem

Ahmed H Al-Jedai

Abstract

INTRODUCTION

Scope and purpose

Goal

Objectives

Guidelines, scope

End-users

Process of guideline development and guidance on their implementation

METHODOLOGY

Panel composition

Group interaction and process

Selection of questions and outcomes’ prioritization

S Table 1.

Evidence synthesis

S Table 2.

S Table 3.

Assessing the certainty of evidence

S Table 4.

TREATMENT RECOMMENDATIONS FOR MODERATE-TO-SEVERE CROHN’S DISEASE

Initial Treatments for Bio-Naïve Adults with Moderate-to-Severe CD

S Table 5.

S Table 6.

S Table 7.

S Table 8.

S Table 9.

S Table 10.

S Table 11.

S Table 12.

Treatment for Advanced Therapy Exposed Adults with Moderate-to-Severe CD

S Table 13.

S Table 14.

S Table 15.

Combination Therapies for Adults with Moderate-to-Severe CD

S Table 16.

S Table 17.

S Table 18.

Treatment Optimization Strategies for Adults with CD and Secondary Loss of Response to Advanced Therapy

S Table 19.

Management of Complex Perianal Fistula among Adults with CD

S Table 20.

S Table 21.

S Table 22.

Switching Formulations for Maintenance of Remission in Adults with Stable Moderate-to-Severe CD

S Table 23.

Prevention of Postoperative Recurrence (POR) among Adults with High-Risk CD

S Table 24.

Table 1.

TREATMENT RECOMMENDATIONS FOR MODERATE TO SEVERE UC

Treatment of Advanced Therapy Exposed Adults with Moderate-to-Severe UC

S Table 25.

S Table 26.

S Table 27.

S Table 28.

S Table 29.

S Table 30.

S Table 31.

S Table 32.

S Table 33.

Treatment Optimization Strategies for Adults with UC and Secondary Loss of Response to Advanced Therapy

S Table 34.

S Table 35.

S Table 36.