DIAGNOSIS AND MANAGEMENT OF IBD
Diagnosis and classification of IBD
Approach towards diagnosing IBD: A global assessment strategy integrating clinical, biochemical, endoscopic, histologic, and imaging findings is essential for achieving an accurate and timely diagnosis of IBD[10-12]. This approach minimizes diagnostic delays, reduces misclassification, and enhances individualized treatment planning. Given the progressive nature of IBD, early and precise diagnosis is critical in preventing complications, optimizing therapy, and improving long-term patient outcomes.
Statement 1: No single reference standard exists for diagnosing CD or UC; diagnosis requires integration of clinical history, biochemical markers, stool studies, endoscopy, histology, and imaging (evidence level: 5; strength of recommendation: Strong; consensus agreement: 100%).
Screening and early diagnosis of IBD: Delayed diagnosis of IBD is linked to worse outcomes, including complications, surgeries, and increased healthcare costs, making early detection crucial[13]. Identifying IBD within the window of opportunity allows for timely intervention, reducing bowel damage and improving long-term prognosis[14]. Several screening tools have been developed to facilitate the early detection of IBD, aiming to reduce diagnostic delays and prevent disease complications. The red flags index, developed by the International Organization for the Study of IBDs group, uses a 21-item survey to identify patients at high risk of CD based on key symptoms and clinical features[15]. However, it lacks external validation and is primarily applicable to CD rather UC. The IBD-REFER criteria, a newer screening tool designed for both CD and UC, were developed using a Delphi consensus and statistical modelling, demonstrating higher sensitivity and specificity than the red flags index[16].
Statement 2: Early detection of IBD is crucial to preventing complications and improving outcomes. Validated screening tools, such as the red flags index and IBD-REFER, may aid in triaging patients or referrals based on clinical history (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Comprehensive clinical assessment: Clinical assessment serves as the cornerstone of IBD diagnosis, helping to establish an initial suspicion of the disease based on symptomatology, disease history, and risk factors[10]. Patients with UC typically present with rectal bleeding, urgency, tenesmus, and diarrhea, with symptoms often progressing in a continuous, distal-to-proximal pattern along the colon[11]. In contrast, CD exhibits a more heterogeneous clinical presentation, with chronic diarrhea, abdominal pain, and weight loss being the most common features[12]. CD may also involve structuring and penetrating complications, with some patients experiencing perianal disease, fistulas, and abscesses at presentation. A thorough clinical history should include an assessment of extraintestinal manifestations, which can affect the musculoskeletal system, skin, eyes, and hepatobiliary tract[17,18]. These manifestations can precede gastrointestinal symptoms, highlighting the systemic nature of IBD. Family history is another critical component, as individuals with a first-degree relative affected by IBD have an increased risk of developing the disease[19]. Given the overlap between IBD and functional gastrointestinal disorders such as irritable bowel syndrome (IBS), a structured clinical evaluation is essential to differentiate IBD from other conditions[20].
Several gastrointestinal disorders can mimic IBD and need to be considering during initial clinical evaluation. Laboratory tests, with stool studies should be utilized to exclude infections like Clostridioides difficile, Salmonella, Shigella, Campylobacter, Cytomegalovirus, Mycobacterium tuberculosis and Yersinia enterocolitis[21]. Drug-induced enteritis and colitis are most commonly associated with non-steroidal anti-inflammatory drugs and immune-based therapies[22]. Non-steroidal anti-inflammatory drugs can cause ulceration throughout the gastrointestinal tract, and prolonged use may lead to chronic histologic changes, ulcerations, and strictures resembling CD. Immune checkpoint inhibitors can cause gastrointestinal toxicity in up to 64% of patients, often mimicking IBD both endoscopically and histologically[23]. Other mimics include gastrointestinal neoplasms, ischemic colitis, diverticulitis, and IBS.
Statement 3: The differentiation between CD and UC should be based on a combination of clinical, endoscopic, histologic, and radiologic findings, as no single modality is diagnostic (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 4: Diagnostic evaluation must exclude other potential causes of colitis, including infections (Clostridioides difficile, Salmonella, Shigella, Campylobacter, Cytomegalovirus, Mycobacterium tuberculosis, and Yersinia enterocolitis), ischemic colitis, drug-induced enteritis, and neoplasia (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 5: Extraintestinal manifestations and presence of perianal disease of IBD should be assessed at the time of diagnosis and during the course of the disease, as they may precede or accompany gastrointestinal symptoms (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Biochemical, serological and genetic markers in disease assessment: Biochemical markers play a crucial role in IBD diagnosis and monitoring by providing non-invasive indicators of intestinal inflammation[24]. Fecal calprotectin and lactoferrin are particularly useful in distinguishing IBD from functional disorders, as elevated levels correlate with neutrophilic infiltration in the gut. A fecal calprotectin level above 50 μg/g warrants further investigation, with values exceeding 250 μg/g being strongly suggestive of active inflammation[25]. These biomarkers are also valuable in treatment monitoring, helping to assess mucosal healing and predict relapse. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are widely used serum markers of systemic inflammation[24,26]. Although non-specific, elevated CRP levels often correlate with disease activity, particularly in CD. Other laboratory findings, including anaemia, hypoalbuminemia, and vitamin deficiencies such vitamin B12 and iron studies, can provide indirect evidence of chronic inflammation and malabsorption.
Commercially available tests known as somatic genomic information (SGI) panels (incorporating serological antibodies, genetic risk markers, and inflammatory biomarkers) have been developed to help distinguish between CD and UC by incorporating these biomarkers into a scoring system[27-29]. These panels typically include various markers such as perinuclear anti-neutrophil cytoplasmic antibody, anti-saccharomyces cerevisiae antibody-immunoglobulin A, anti-saccharomyces cerevisiae antibody-immunoglobulin G, and genetic polymorphisms like nucleotide-binding oligomerization domain containing 2 (NOD2), autophagy related 16 Like 1, signal transducer and activator of transcription 3, and extracellular matrix protein 1, which are linked to immune system dysfunction in IBD. The integration of these markers in SGI panels aims to enhance diagnostic accuracy, especially for patients with unclear clinical presentations. However, their utility remains limited to an adjunctive role, as no single test can definitively diagnose IBD without supporting clinical, endoscopic, and histological evidence. Despite their multi-marker approach, SGI panels should not be used in isolation due to their low positive predictive value in general populations, leading to frequent false positives and negatives[30]. Genetic variants alone do not confirm disease presence, as many are found in healthy individuals without IBD, limiting their diagnostic specificity[31,32]. Furthermore, studies have not demonstrated a clear clinical benefit from using SGI panels as standalone tests, and no current guidelines recommend their routine use[33]. While they may provide additional insight in complex cases where the diagnosis remains unclear, they cannot replace endoscopic visualization and histologic confirmation, which remain the gold standard for IBD diagnosis and monitoring.
Statement 6: Faecal calprotectin should be used as non-invasive screening tools for differentiating IBD from functional bowel disorders, with values > 250 μg/g strongly suggestive of active inflammation (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 7: Serum CRP should be measured at baseline for all suspected IBD cases, but their utility is limited by lack of specificity (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 8: Iron deficiency anaemia, hypoalbuminemia, and vitamin deficiencies may provide indirect evidence of chronic inflammation and should be assessed at diagnosis (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 9: Genetic and serological testing in isolation is not recommended for routine IBD diagnosis due to low predictive value and lack of clear clinical utility (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Endoscopic evaluation as the gold standard for diagnosis: Endoscopy remains the definitive diagnostic tool for IBD, allowing direct visualization of the intestinal mucosa and enabling histologic assessment through biopsies[34]. Colonoscopy with ileal intubation (ileocolonoscopy) is essential for distinguishing UC, which exhibits continuous mucosal inflammation, from CD, which may be characterized by segmental, transmural inflammation with skip lesions[35]. Endoscopic features of UC include erythema, friability, loss of vascular pattern, and ulceration, whereas CD is characterized by cobblestoning, deep ulcerations, strictures, and fistulas. Furthermore, ileocolonoscopy facilitates the staging of both activity and severity of CD and UC. For a comprehensive evaluation, biopsies should be obtained from multiple colonic segments, including macroscopically normal mucosa, specifically the rectum, sigmoid, descending, transverse, and ascending colon, as well as the terminal ileum. Flexible sigmoidoscopy would be preferred as an initial investigation in patients with presenting with acute severe UC (ASUC). Esophagogastroduodenoscopy is recommended for patients with suspected upper gastrointestinal involvement, which is observed in up to 16% of CD cases[36]. Wireless video capsule endoscopy is a non-invasive tool for visualizing the entire small intestine, particularly useful for diagnosing CD in patients with suspected isolated small bowel involvement when ileocolonoscopy is negative, provided there are no obstructive symptoms[34,37]. Video capsule endoscopy has demonstrated higher sensitivity than conventional radiology in detecting early mucosal lesions and proximal small bowel involvement, with capsule retention occurring in up to 13% of cases[37]. This risk can be mitigated with the use of patency capsules or by excluding small bowel obstruction and strictures via cross-sectional imaging.
Statement 10: Ileocolonoscopy with segmental biopsies is required for the initial diagnosis of suspected IBD, except in acute severe colitis, where sigmoidoscopy with biopsy is preferred (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 11: Endoscopic differentiation of CD and UC should be based on characteristic features: UC typically presents with continuous inflammation, loss of vascular pattern, and superficial ulceration, whereas CD is often characterized by skip lesions, cobblestoning, deep ulcerations, strictures, and fistulas (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 91%).
Statement 12: At the time of index ileocolonoscopy, if endoscopic evidence of active inflammation, two to four biopsies should be obtained from at least five segments (rectum, sigmoid, descending, transverse, and ascending colon) and the terminal ileum, including areas of both inflamed and non-inflamed mucosa (evidence level: 5; strength of recommendation: Strong; consensus agreement: 100%).
Statement 13: Upper gastrointestinal endoscopy should be performed in patients with suspected upper gastrointestinal involvement (evidence level: 4; strength of recommendation: Strong; consensus agreement: 100%).
Statement 14: Capsule endoscopy may be considered for patients with suspected small bowel CD when ileocolonoscopy and cross-sectional imaging are inconclusive with prior assessments (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Histopathology as a supportive diagnostic tool: Histologic examination may often play a pivotal role in confirming the diagnosis of IBD and distinguishing it from infectious, drug induced or ischemic colitis[38,39]. UC is characterized by continuous mucosal involvement with crypt architectural distortion, basal plasmacytosis, and diffuse chronic inflammation. In contrast, CD exhibits focal cryptitis, granulomas, transmural inflammation, and fibrosis, often in a discontinuous pattern. Noncaseating granulomas are present in CD in 9%-67% of cases but are not essential for diagnosis[38]. While histology may support the diagnosis of IBD, no single feature is pathognomonic. In cases of indeterminate colitis, where features of both UC and CD are present, histologic findings must be correlated with clinical, endoscopic, and imaging data to guide classification.
Statement 15: Histologic confirmation of IBD is essential and should include evaluation for crypt architectural distortion, basal plasmacytosis, granulomas, and transmural inflammation (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Radiological and advanced imaging modalities for comprehensive small bowel assessment: Cross-sectional imaging techniques provide complementary information that is particularly valuable in assessing small bowel involvement in CD[40,41]. Magnetic resonance enterography (MRE) is the preferred modality for evaluating disease extent, activity, and complications such as strictures, fistulas, and abscesses[42,43]. It has high sensitivity and specificity for detecting inflammation and can differentiate active disease from fibrosis using contrast enhancement patterns. The multicenter METRIC study compared MRE and ultrasound in newly diagnosed patients, reporting an MRE sensitivity of 80% for disease extent and 97% for disease presence, with a specificity of approximately 95%[44]. In patients with suspected perianal CD based on symptoms and examination findings, pelvic magnetic resonance imaging (MRI) is the most effective imaging modality, with a sensitivity of 97% and specificity of 96% for detecting perianal fistulae and collections[45,46]. Computed tomography enterography (CTE) is also an accurate diagnostic tool, however, its use is limited by the risks of repeated ionizing radiation exposure, particularly in young patients requiring lifelong monitoring[40,47]. CTE remains valuable when MRE is contraindicated, patients are acutely unwell, or access to MRE or ultrasound is limited. Imaging features of disease activity, such as bowel wall thickening and mesenteric changes, are similar across MRE and CTE[48]. For claustrophobic patients, CTE provides and alternative option. Intestinal ultrasound (IUS) is an emerging, non-invasive, radiation-free tool that provides point of care real-time, high-resolution imaging of the bowel wall, mesentery, and surrounding structures[44,49,50]. With endoscopy as the reference standard, IUS has a sensitivity of 86% and specificity of 94% for detecting disease extent in both small and large bowel CD[51]. However, its accuracy is lower in the jejunum and rectum. It serves as a valuable adjunct to cross-sectional imaging, particularly for baseline disease staging. However, its use alone is limited for diagnosing IBD and should be complemented by other diagnostic modalities.
Statement 16: Cross-sectional imaging (MRE, CTE, or IUS) should be performed in all patients with suspected small bowel CD to assess disease extent, structuring, and complications (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 17: MRE is the preferred imaging modality for small bowel assessment due to its superior soft-tissue contrast and lack of radiation exposure (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 18: CTE may be used when MRE is unavailable, contraindicated, or in acute settings requiring rapid evaluation (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 19: Pelvic MRI should be performed in patients with suspected perianal CD to evaluate fistulae and abscesses (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 91%).
Statement 20: IUS is an emerging modality that may serve as a point-of-care tool for assessing disease activity but has limited use as sole radiological investigation for diagnosis (evidence level: 3b; strength of recommendation: Conditional; consensus agreement: 100%).
Disease classification in IBD: Disease classification in IBD standardizes characterization, aiding in diagnosis, communication, and prognosis assessment[52-54]. It also guides treatment decisions through predicting disease behavior and progression. The Montreal classification was developed to provide a more detailed framework for categorizing the extent and behavior of CD while also incorporating a classification system for UC. The Montreal classification categorizes CD by age at diagnosis (A1: ≤ 16, A2: 17-40, A3: > 40), disease location (L1: Ileal, L2: Colonic, L3: Ileocolonic, L4: Upper gastrointestinal), and behavior (B1: Inflammatory, B2: Stricturing, B3: Penetrating; ± p: Perianal disease). UC is classified by extent: E1 (proctitis), E2 (left-sided), E3 (extensive/pancolitis). Multiple studies have evaluated its inter-observer reliability and validity[52]. Findings indicate strong agreement for disease location, though reliability is only moderate for upper gastrointestinal involvement. The Paris classification of UC categorizes disease extent into E1, E2, E3, and E4 based on disease location. The Paris classification also includes a severity component, categorizing disease as either S0 (never severe) or S1 (ever severe). A newer classification system, Florence classification, is currently being developed and validated.
Statement 21: The Montreal classification should be used for CD and UC in adults to enable standardization of disease characterization, aid in prognostication, and guide treatment decisions (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Assessment of disease activity and severity in IBD
Clinical scoring for UC: Clinical indices for UC primarily evaluate symptoms such as stool frequency, rectal bleeding, and urgency. The Simple Clinical Colitis Activity Index (SCCAI) is a widely used tool that includes nocturnal bowel movements and urgency, both of which significantly affect quality of life (QoL)[55]. The SCCAI has strong validity, reliability, and user friendliness in studies, with a remission cutoff of < 2. The Partial Mayo score is another commonly used index, particularly in clinical trials[56]. It assesses stool frequency, rectal bleeding, and a physician’s global assessment. Although it is sensitive to changes in disease activity, its reliance on physician input makes it subjective and less practical for routine clinical use. In cases of severe UC, the Truelove and Witts[57] criteria remain the standard for identifying acute severe colitis requiring hospitalization and intravenous (IV) corticosteroids. This index considers stool frequency, the presence of blood in stools, temperature, heart rate, haemoglobin levels, and ESR. It is particularly valuable for prognosis, as patients meeting more severe criteria at presentation face a higher risk of requiring colectomy and therefore can be stratified for early rescue therapy[58].
Biomarker-based scoring for UC: Biomarkers such as CRP and fecal calprotectin are widely used adjuncts in UC assessment. CRP is particularly useful in severe colitis, where it correlates with disease outcomes and response to therapy. The Oxford criteria, which includes CRP and stool frequency, predicts the risk of colectomy in acute severe colitis[59]. Fecal calprotectin is a highly sensitive marker of mucosal inflammation and is particularly useful for monitoring response to treatment and predicting relapse in UC. Fecal calprotectin has been shown to strongly correlates with Mayo endoscopic subscore in UC, with a cutoff of 60 μg/g effectively distinguishing subscore 0 from subscore 1-3 (area under the curve = 0.901)[60]. A target fecal calprotectin of < 150 μg/g has been proposed as a treatment goal in UC[61].
Endoscopic and histological scoring for UC: Endoscopic assessment and mucosal healing are now a key treatment target in UC. The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is the only fully validated endoscopic scoring system, developed to reduce interobserver variability[62]. It evaluates vascular pattern, bleeding, and the presence of ulcers, with scores ranging from 0 to 8. A UCEIS score of ≤ 1 is considered endoscopic remission[63,64]. While its simplicity makes it useful in clinical practice, it does not account for disease extent and lacks clear thresholds for mild, moderate, and severe disease[65]. The Mayo endoscopic subscore is widely used in clinical trials and routine practice, largely due to its familiarity among gastroenterologists[56]. It classifies disease activity from 0 to 3, with higher scores indicating more severe inflammation. However, it has not been formally validated, and significant interobserver variability exists. Despite its limitations, it remains a widely accepted measure of endoscopic disease severity. Histological assessment in UC provides prognostic value beyond endoscopy, with persistent microscopic inflammation increasing relapse risk. The Nancy index is a simple five-grade system suitable for clinical use, while the Robarts Histopathology Index is more complex and primarily used in clinical trials.
Radiological scoring for UC: Cross-sectional radiological assessment plays a limited role in UC but can on occasions be helpful in cases where endoscopic examination is not feasible or contraindicated. IUS however has been shown to be an effective tool for monitoring disease activity and treatment response in UC, offering a bedside alternative to colonoscopy[50]. IUS enables early therapy assessment, with changes detectable within two weeks of treatment initiation[66]. Bowel wall thickness reduction has been shown to correlate with endoscopic and histologic remission[67].
Statement 22: The SCCAI should be used for routine clinical assessment of UC due to its validity, reliability, and inclusion of urgency and nocturnal bowel movements. The Partial Mayo score may be used but clinicians need to be aware of its subjectivity (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 82%).
Statement 23: The Truelove and Witts[57] criteria should be used to identify ASUC requiring hospitalization and IV corticosteroids (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 82%).
Statement 24: Fecal calprotectin should be used as a non-invasive screening tool for differentiating inflammatory disorders such as IBD from functional bowel disorders, with values > 250 μg/g strongly suggestive of active inflammation (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 25: The UCEIS or Mayo endoscopic subscore should be used to endoscopic scoring of disease activity (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 26: Histological assessment should complement endoscopic assessment (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 27: IUS should be considered where available for non-invasive disease monitoring (evidence level: 3b; strength of recommendation: Conditional; consensus agreement: 100%).
Clinical scoring for CD: The CD activity index (CDAI) remains the most commonly used tool for evaluating disease activity in CD, however its complexity and reliance on a seven-day symptom diary limit its practicality in routine clinical settings[68]. The Harvey-Bradshaw Index (HBI) offers a simplified alternative, assessing five key parameters: General well-being, abdominal pain, stool frequency, abdominal mass, and complications[69]. Additionally, the patient-reported outcome 2, assessing only abdominal pain and stool frequency, has emerged as a practical, patient-reported outcome measure for use in clinical trials and may support symptom monitoring in routine care[70]. As neither of these tools sufficiently capture perianal disease severity the perianal disease activity index is a more appropriate tool for assessing perianal disease, incorporating measures of pain, discharge, induration, and the impact on sexual function[71]. More recently the TOpClass classification system for perianal CD was introduced that takes into account severity, anatomy, and treatment goals, integrating medical and surgical considerations for personalized, multidisciplinary management[72].
Biomarker-based scoring for CD: Biomarkers such as CRP and fecal calprotectin are valuable tools in CD management, particularly for monitoring response to therapy and predicting relapse. CRP is particularly useful in systemic inflammation, although it correlates modestly with endoscopic disease activity[24]. Fecal calprotectin is a reliable marker for colonic disease activity but is less sensitive for ileal disease[73]. As in UC, changes in fecal calprotectin levels over time are more informative than absolute values. It is important to benchmark CRP and fecal calprotectin at the time of colonoscopy, as this allows for correlation with endoscopic disease activity and provides a reliable reference point for tracking disease over time.
Endoscopic scoring for CD: Endoscopic remission and mucosal healing are a key treatment target in CD[61]. The CD Endoscopic Index of Severity is the currently gold standard for endoscopic assessment and is widely used in clinical trials, however, it is complex and cumbersome for routine use[65,74]. The Simple Endoscopic Score for CD (SES-CD) is a simplified version of the CD Endoscopic Index of Severity and is more practical for clinical use[75]. It assesses ulcer size, ulcerated surface area, and the presence of stenosis in five bowel segments. Rutgeerts score is specifically used postoperatively to evaluate recurrence at the anastomosis site following ileocolic resection, with scores from i0 to i4 predicting the likelihood of symptomatic recurrence[76]. Histological scoring in CD remains challenging due to its discontinuous and transmural nature. Unlike UC, standardized and validated histological indices for CD are limited, although Nancy index and Robarts Histopathology Index have been used in clinical trials[77].
Radiological scoring for CD: Radiological scoring plays a prominent role in assessing disease activity in CD, given its ability to assess transmural inflammation and complications such as strictures and fistulae. Several indices assess luminal activity, with the Magnetic Resonance Index of Activity (MaRIA) being the most widely used, incorporating bowel wall thickness, gadolinium enhancement, ulceration, and oedema. The newer simplified MaRIAs, which does not require contrast enhancement, has shown strong correlation with the CD endoscopic scoring index SES-CD[78]. IUS has been shown to correlate well with endoscopic and histologic remission in CD, particularly through bow wall thickness assessment, with a cutoff > 3 mm predicting active disease[50,79]. IUS also helps assess transmural healing, predict relapse, and monitor postoperative recurrence, making it a valuable bedside alternative to colonoscopy and MRE[80].
Statement 28: A patient-reported outcome measure such as HBI or patient-reported outcome 2 is recommended for routine clinical assessment of CD. The perianal disease activity index should be considered to assess perianal disease activity (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statemen 29: Fecal calprotectin may be considered to monitor disease activity and response to treatment in CD, with greater sensitivity for colonic involvement than ileal disease. Changes in fecal calprotectin over time should guide disease monitoring (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 30: The SES-CD should be the preferred tool for routine endoscopic assessment in CD. The Rutgeerts score should be used in CD to assess the risk of recurrence at the anastomosis site following ileocolic resection (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 31: Histological assessment should complement endoscopic assessment (evidence level: 4; strength of recommendation: Strong; consensus agreement: 100%).
Statement 32: Radiological assessment should be integrated into disease monitoring of CD, with the MaRIA as the preferred objective tool for evaluating luminal disease activity. IUS may be used where available for non-invasive monitoring (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Markers of disease severity in UC: In UC, clinical markers provide critical insights into disease severity and prognosis[81]. A younger age at diagnosis (< 40 years) is strongly associated with disease progression, steroid dependence, and increased colectomy risk[70]. Additionally, extensive colitis at diagnosis correlates with higher rates of hospitalization and colorectal cancer (CRC) risk, necessitating closer monitoring and earlier therapeutic escalation[82]. The Mayo endoscopic subscore provides a widely recognized method for assessing disease activity, with Mayo endoscopic subscore 3 (severe ulceration and friability) predicting higher rates of treatment failure and surgical intervention[81]. Similarly, patients with steroid dependence or resistance are more likely to require advanced therapies or colectomy, emphasizing the importance of early biologic or small molecule therapy initiation. The presence of extraintestinal manifestations, such as primary sclerosing cholangitis (PSC), arthritis, or pyoderma gangrenosum, is indicative of a more aggressive disease phenotype[83]. Additionally, index presentation requiring IV steroids, corticosteroid dependence or resistance suggests a more refractory disease course, often necessitating the early use of biologic or small molecule therapies. Long disease duration (> 10 years) is associated with higher risks of complications, including colorectal neoplasia, warranting closer surveillance and proactive disease management[84]. Less clinically useful prognostic markers of disease severity in UC include presence of perinuclear anti-neutrophil cytoplasmic antibodies in serology.
Markers of disease severity in CD: In CD, clinical risk factors for severe disease include young age at onset (< 40 years), perianal disease, and extensive small bowel involvement[81,85,86]. Patients with ileal, ileocolonic or upper gastrointestinal disease often exhibit an increased risk of fibrostenotic strictures and penetrating complications. Deep ulcers on endoscopy at diagnosis is strongly associated with higher rates of surgical intervention and the need for intensified therapy[70,87,88]. Additionally, smoking remains one of the most significant modifiable risk factors, contributing to treatment resistance, disease progression, higher rates of surgery and post-ileocecal resection disease recurrence in CD[89]. Higher SES-CD scores correlate with a higher risk of structuring and penetrating complications, necessitating early advanced therapy use or surgical intervention[90]. Histology as a marker is disease severity is not fully established although there is some evidence to suggest that persistent histologic inflammation in UC may predict a higher risk of relapse, hospitalization, and colectomy. NOD2 mutations and presence of anti-Saccharomyces cerevisiae antibodies in CD may have some prognostic value, although their clinical utility remains limited[84,91].
Statement 33: In UC, certain risk factors including younger age at diagnosis (< 40 years), extensive colitis (E3), steroid dependency, severe endoscopic disease activity, presence of extraintestinal manifestations including PSC a more aggressive disease course and higher colectomy risk, warranting consideration of early therapeutic escalation (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 34: In CD, certain risk factors including young age at onset (< 40 years), perianal involvement, deep ulcers on endoscopy, active smoking and extensive small bowel disease predict a more severe disease course, justifying early advanced therapy (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 91%).
Statement 35: Smoking significantly worsens CD outcomes, contributing to treatment resistance, complications, and post-surgical recurrence, making smoking cessation a key management priority (evidence level: 2b; strength of recommendation: Strong; consensus agreement: 100%).
Early disease control and disease modification in IBD
Role for early aggressive therapy in IBD: IBD management, particularly for CD, has moved from a standard step-up approach to a more personalized approach guided by patient-specific risk factors. Traditionally, IBD treatment followed a step-up approach, starting with conventional therapies such as 5-aminosalicylates (5-ASA), steroids, or immunomodulators, with escalation to biologics or small molecules only after treatment failure. This strategy aimed to minimize unnecessary immunosuppression, specifically in the case of UC and mild CD, where the focus shifts in favor of safety, cost-effectiveness, and QoL rather than progression of disease[88]. In contrast a top-down strategy involves early initiation of advanced therapies, to prevent irreversible bowel damage, induce mucosal healing, and alter the natural disease trajectory. This approach is particularly beneficial for patients with moderate-to-severe CD activity or those with unfavorable disease phenotypes, where delaying advanced therapies may lead to disease progression and complications. Key clinical trials have provided strong evidence supporting early intensive therapy. The step-up/top-down trial demonstrated that early combination therapy with infliximab and azathioprine led to significantly higher clinical remission rates at 52 weeks (62% vs 42%) compared to the conventional step-up approach[92]. Additionally, the SONIC trial confirmed that early combination therapy was superior to monotherapy with either azathioprine or infliximab alone in achieving corticosteroid-free remission[93]. More recently, the PROFILE trial confirmed that early induction with infliximab and an immunomodulator (median time from diagnosis to trial enrolment was 12 days) was superior to an accelerated step-up approach, with significantly greater sustained steroid-free and surgery-free remission and fewer adverse events[7]. Similarly, data from RCTs for other advanced therapies in CD have similarly demonstrated showed that early use of the advanced therapy led to sustained clinical and endoscopic remission, supporting the concept that advanced therapies should not be reserved only for refractory cases[94-97]. Mild CD presenting without complications, weight loss, or dietary restrictions, with normal haemoglobin and inflammatory markers, and endoscopic findings showing limited disease without ulcers (SES-CD ≤ 5 or SES-CD ≤ 3 in isolated ileal disease) may be managed with dietary modifications, smoking cessation, and periodic monitoring without immediate medical therapy in low-risk patients. If treatment is needed, budesonide may be preferred for induction, while long-term management should focus on minimizing progression risk through early risk stratification[88]. Evidence on the benefits of early advanced therapy in UC, however, remains limited, and whether more intensive treatment prevents structural and functional complications is still debated[23]. Observational studies suggest that disease duration may not impact therapy efficacy in UC[98]. There may however be an exception where steroid-responsive ASUC patients in the ACTIVE trial showed that combination therapy with infliximab and azathioprine, along with rapid steroid withdrawal, was more effective than azathioprine with a standard 8-week steroid taper[99].
Statement 36: Early initiation of advanced therapy should be prioritized in moderate-to-severe CD or high-risk phenotypes to prevent disease progression, complications, and irreversible bowel damage (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 37: In UC, the benefits of early advanced therapy remain uncertain, but combination infliximab and azathioprine may be considered as an option in steroid-responsive ASUC for superior outcomes (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 91%).
Statement 38: Mild CD, defined by the absence of complications, systemic symptoms, and significant endoscopic or biomarker evidence of inflammation, may be managed initially with conventional therapies such as dietary modification, oral budesonide and smoking cessation. However, close monitoring is essential, and advanced therapies should be considered early in patients with risk factors for disease progression (evidence level: 5; strength of recommendation: Strong; consensus agreement: 91%).
Treat to target approach: The treat-to-target strategy in IBD is a structured, proactive approach that ensures treatment adjustments when predefined therapeutic milestones are not met[100]. Unlike symptom-driven management, treat-to-target integrates objective disease monitoring, aiming for deeper remission to prevent complications such as strictures and fistulas[6]. Treatment is adjusted at each step if targets are unmet, following an algorithmic approach that may involve dose escalation, switching advanced therapies, or adding additional pharmacological agents. However, when applied effectively, this strategy aims to maximize sustained remission and long-term disease control in IBD.
The short-term goal (within the first 12 weeks of therapy) is to achieve symptomatic response, which is an essential early indicator of treatment efficacy and patient adherence. In CD, this is reflected by a reduction in abdominal pain and stool frequency as measured by HBI or PRO-2 score, whereas in UC, it is defined by a decrease in rectal bleeding and normalization of stool frequency as measured by SCCAI or Partial Mayo score. While symptom relief is an important patient-centered outcome, relying solely on clinical response can be misleading, as symptoms do not always correlate with active inflammation particularly in CD. Clinical trials such as CALM and REACT demonstrated that tight control strategies based on biomarker monitoring in addition to symptom assessment significantly improved long-term outcomes compared to symptom-driven therapy alone[101,102].
The medium-term target, as assessed between 3-6 months into therapy is biochemical remission, defined by normalization of inflammatory biomarkers such as CRP and fecal calprotectin. Persistent subclinical inflammation despite symptom improvement has been shown to increase the risk of disease progression. The STRIDE-II consensus recommends CRP levels below 5 mg/L and fecal calprotectin below 250 μg/g in UC and 150 μg/g in postoperative CD[61]. Persistent biomarker elevation, even in asymptomatic patients, suggests ongoing inflammation and indicates the need for therapy escalation. The CALM RCT demonstrated that a biomarker-driven treat-to-target strategy (dose escalation based on fecal calprotectin > 250 mg/g, CRP > 5 mg/L, CDAI > 150, or recent prednisolone use) achieved superior mucosal healing at one year compared to a symptom-based approach. The STARDUST RCT validated this approach, demonstrating that patients who intensified ustekinumab therapy based on biomarker response had better disease outcomes (without endoscopic remission) than those managed conventionally[103]. Similarly, the POCER trial found that patients with fecal calprotectin > 100 μg/g postoperatively had a significantly higher risk of recurrence, emphasizing the utility of non-invasive biomarkers for guiding therapy[104,105].
The long-term target, assessed between 6-12 months into therapy, emphasizes the importance of achieving endoscopic remission, with the addition of aspirational targets that include histologic and transmural healing. Endoscopic remission, defined as the absence of ulcers in CD and a Mayo endoscopic score of 0-1 in UC, has been linked to improved long-term outcomes. A post hoc analysis of the EXTEND trial found that achieving deep remission, defined as both the absence of ulcerations on endoscopic evaluation and clinical remission, was linked to fewer treatment modifications, hospitalizations, and surgeries, as well as improved QoL[106]. The QUOTIENT trial (NCT05230173) is currently evaluating whether therapeutic switching in asymptomatic IBD patients with ongoing endoscopic or radiological inflammation leads to improved outcomes compared to maintaining their existing treatment[107]. Histologic healing, particularly in UC, has emerged as an important but aspirational prognostic marker with its adoption as an endpoint in recent clinical trials[108]. Evidence mostly derived from uncontrolled studies suggests patients with histologic remission had a significantly lower relapse rate compared to those with only endoscopic healing[109,110]. The VERDICT trial (NCT04259138) aiming to determine the role of histologic remission in prevention of disease related complications is currently underway[111]. Transmural healing, assessed by MRE or IUS, has gained increasing recognition, signifies inflammation resolution through the entire bowel wall. It is particularly relevant in structuring and penetrating CD and provides a more comprehensive assessment of disease resolution. The STARDUST trial and other real-world studies have shown that patients who achieve transmural healing have significantly lower relapse rates, reduced steroid dependency, and lower rates of disease progression[103,112,113]. Transmural healing is however not a core target in STRIDE-II due to the lack of standardized definitions, imaging reproducibility, and routine accessibility. IBD affects physical and psychosocial well-being, with poor QoL and high disability linked to increased costs and reduced productivity[114]. STRIDE-II includes QoL normalization and disability reduction as long-term targets[61]. However, these measures correlate poorly with objective disease markers, especially in CD, requiring complementary monitoring. The IBD questionnaire is the most used QoL tool, with a shorter version for clinical use. The IBD Disability Index and IBD Disk are validated tools for disability that assess mood, sleep, fatigue, food-related QoL, and sexual function[115-117].
Statement 39: The treat-to-target strategy should be the standard approach in IBD management, integrating objective disease monitoring to optimize treatment, guide therapy escalation when targets are unmet, and prevent complications (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 91%).
Statement 40: Short-term targets should include symptomatic response within twelve weeks of therapy initiation, recognizing that symptom relief alone does not confirm inflammation control (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 41: Biochemical remission, defined by normalization of inflammatory biomarkers (for example CRP < 5 mg/L, fecal calprotectin < 250 μg/g), should be the medium-term treatment target (3 months to 6 months of initiation), guiding therapy escalation when unmet (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 91%).
Statement 42: Endoscopic remission, defined as absence of ulcers in CD and a Mayo endoscopic score of 0-1 in UC, should be the primary long-term treatment target (6 months to 12 months of initiation), with histologic and transmural healing as aspirational goals (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 43: Quality of life and disability reduction should be considered as complementary long-term targets in IBD management (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Medical therapies in IBD
Conventional therapies: 5-ASA are the first-line therapy for mild-to-moderate UC, with both oral and topical formulations available to achieve maximal mucosal delivery. Oral mesalazine is commonly administered in doses ranging from 2 g/day to 4.8 g/day, with higher doses recommended for active disease. Various formulations, including delayed-release (e.g., asacol, mezavant), pH-dependent (e.g., pentasa), and multimatrix (MMX) preparations, target different sections of the colon. Sulfasalazine, an older 5-ASA compound, is dosed at 2-6 g/day, but its use is limited due to sulfa-related side effects. Topical mesalazine is particularly effective in proctitis and left-sided colitis and is available as suppositories (1 g, daily) or enemas (2-4 g, daily), with a preference for combination therapy (oral + topical) in distal disease. Maintenance therapy is typically continued at lower doses (1.6-2 g/day oral or 1 g/day) rectal to sustain remission.
Thiopurines, including azathioprine and mercaptopurine, are immunomodulators used in steroid-dependent or immunosuppressive-requiring UC and CD. Azathioprine is dosed at 1.5-2.5 mg/kg/day, while mercaptopurine is used at 0.75-1.5 mg/kg/day. Given their delayed onset of action (8-12 weeks), they are not used for induction therapy, but rather for maintenance of remission or as part of combination therapy with anti-tumor necrosis factor (TNF) to reduce immunogenicity. Methotrexate is another immunomodulator, primarily used in CD. Subcutaneous or intramuscular methotrexate at 25 mg weekly is used for induction, with maintenance dosing at 15 mg weekly. Oral formulations (7.5-25 mg, weekly) are an alternative but are associated with lower bioavailability. Folic acid supplementation (5 mg, once or twice weekly, excluding the day of methotrexate administration) is required to reduce toxicity.
Corticosteroids remain a key component of induction therapy in moderate-to-severe flares of IBD but are not suitable for long-term maintenance due to significant adverse effects. Prednisolone is typically initiated at 40 mg daily, with a gradual taper of 5 mg per week over 8-12 weeks to minimize relapse risk. IV methylprednisolone (40-60 mg daily) or hydrocortisone (100 mg, four times a day) is used in severe colitis or complicated CD requiring hospitalization, with transition to oral steroids once improvement is noted. Budesonide offers a topically active corticosteroid with reduced systemic absorption, making it a preferred option for localized ileal and colonic inflammation. Budesonide MMX (9 mg, once daily) is used for mild-to-moderate UC, while budesonide controlled ileal release (9 mg daily, tapered over 8 weeks) is primarily used for ileal or right-sided CD. In extensive colonic disease, budesonide MMX provides an alternative to prednisolone with a better safety profile, though it remains less effective in severe cases. Budesonide foam enemas (2 mg, twice daily for 2 weeks; then once daily for 4 weeks) are effective for distal UC. Prednisolone suppositories (5 mg, once daily) can be used for proctitis, though mesalazine remains the first-line option.
Advanced therapies (biologics and small molecules): TNF inhibitors remain a cornerstone of treatment in both UC and CD. Infliximab, a chimeric monoclonal antibody targeting TNF-α, is administered as an IV induction regimen of 5 mg/kg at weeks 0, 2, and 6, followed by maintenance dosing of 5 mg/kg IV every 8 weeks from week 14. Alternatively, subcutaneous infliximab can be administered from week 6 onwards as 120 mg or 240 mg every two weeks. Adalimumab, a fully human TNF inhibitor, is administered subcutaneously, with an induction regimen of 160 mg at week 0, followed by 80 mg at week 2, and maintenance dosing of 40 mg every 2 weeks. Certolizumab pegol, a pegylated, Fc-free TNF inhibitor approved for CD, is administered as 400 mg subcutaneously at weeks 0, 2, and 4, followed by maintenance of 400 mg subcutaneously every 4 weeks. Golimumab, a fully human TNF inhibitor used for UC, is administered as 200 mg at week 0, followed by 100 mg at week 2, with maintenance dosing of 100 mg subcutaneously every 4 weeks. These agents have been widely used for their rapid symptom relief and durable efficacy, although concerns about immunogenicity and loss of response (LOR) necessitate TDM and dose optimization in clinical practice.
Integrin inhibitors and IL-targeting therapies provide an alternative targeted mechanism of action. Vedolizumab, an α4β7 integrin antagonist that selectively blocks gut lymphocyte trafficking, is administered as an IV induction at 300 mg at weeks 0, 2, and 6, with an optional additional IV dose at week 10, followed by maintenance dosing of 300 mg IV every 8 weeks. The IL-12/IL-23 antagonist ustekinumab is administered as an IV induction dose based on weight (260 mg for < 55 kg, 390 mg for 55-85 kg, and 520 mg for > 85 kg), followed by subcutaneous maintenance of 90 mg at week 8 and then every 8 weeks. Selective IL-23 inhibitors have also emerged as effective treatment options. Risankizumab, which blocks IL-23p19, is administered in UC as IV induction at 1200 mg at weeks 0, 4, and 8, followed by subcutaneous maintenance of 180 mg or 360 mg every 8 weeks. In CD, IV induction consists of 600 mg at weeks 0, 4, and 8, followed by subcutaneous maintenance of 180 mg or 360 mg every 8 weeks. Mirikizumab, another IL-23p19 inhibitor, is approved for UC and under investigation for CD. In UC, induction consists of IV 300 mg at weeks 0, 4, and 8, followed by subcutaneous maintenance of 200 mg every 4 weeks, while in CD, induction consists of IV 900 mg at weeks 0, 4, and 8, followed by subcutaneous maintenance of 300 mg every 4 weeks starting at week 12. Guselkumab, which also selectively targets IL-23, is administered for both UC and CD as IV induction at 200 mg at weeks 0, 4, and 8, or alternatively, subcutaneous induction of 400 mg every 4 weeks at weeks 0, 4, and 8. Subcutaneous maintenance begins at week 12 with 200 mg every 4 weeks or 100 mg every 8 weeks starting at week 16. These biologic therapies provide a gut-selective or targeted anti-cytokine approach, offering favorable safety profiles, particularly for patients at risk of infections associated with systemic immunosuppression.
In addition to biologics, small-molecule therapies provide oral alternatives for patients with moderate-to-severe disease. Tofacitinib, a pan-JAK inhibitor, is approved for UC and administered as oral induction at 10 mg twice daily for 8 weeks, followed by maintenance dosing of 5 mg twice daily. Upadacitinib, a selective JAK1 inhibitor, is approved for UC and for CD. In UC, induction consists of 45 mg once daily for 8 weeks, followed by maintenance of 15 mg or 30 mg once daily, while in CD, induction consists of 45 mg once daily for 12 weeks, followed by maintenance of 30 mg once daily. S1PR modulators, which regulate lymphocyte trafficking, are also used in UC. Ozanimod is administered as a titrated regimen over 7 days, starting at 0.23 mg on days 1-4, 0.46 mg on days 5-7, followed by maintenance at 0.92 mg once daily from day 8 onward. Similarly, etrasimod is administered as a titrated regimen over 2 weeks, starting at 1 mg on days 1-7, followed by 2 mg once daily from day 8 onward. These regimens represent the standard induction and maintenance dosing strategies for advanced therapies in UC and CD. Treatment selection and dose optimization is guided by disease severity, safety, prior therapy exposure, comorbidities, and patient preferences and will be discussed in later sections in the guideline.
Efficacy of medical therapies in the induction and maintenance of remission in active UC: The ASCEND trials assessed the dose-response effect of delayed-release oral mesalamine in patients with mild to moderate UC. ASCEND I demonstrated no significant difference between 2.4 g/day and 4.8 g/day in overall treatment success at week 6 (51% vs 56%)[118]. However, in patients with moderate UC, the higher dose was significantly more effective (72% vs 57%, P = 0.0384). ASCEND II reinforced these findings, showing that 72% of patients with moderate UC achieved treatment success with 4.8 g/day compared to 59% with 2.4 g/day (P = 0.036)[119]. A combined analysis of ASCEND I and II found greater mucosal healing at week 6 with 4.8 g/day (80%) vs 2.4 g/day (68%, P = 0.012), particularly in patients with prior corticosteroid use[120]. The ASCEND III trial, which focused solely on moderate UC, confirmed noninferiority between the two doses in overall treatment success (70% vs 66%) but showed a higher remission rate with 4.8 g/day (43% vs 35%, P = 0.04), particularly in those previously treated with corticosteroids or multiple UC therapies[121]. Across all trials, the higher dose was well-tolerated with similar adverse event rates, suggesting that 4.8 g/day may be beneficial for patients with moderate UC, especially those with prior treatment failure or persistent symptoms. A network meta-analysis confirmed the efficacy of 5-ASA therapy in UC, emphasizing the importance of route and dose[122]. Among 40 trials for induction and 23 for maintenance, topical mesalamine ranked highest for remission, followed by combined oral and topical therapy. Combination therapy was most effective for left-sided or extensive disease, while topical mesalamine was superior for proctitis. For maintenance, combined therapy and high-dose oral mesalamine (≥ 3.3 g/day) were most effective. These findings highlight the need to tailor 5-ASA therapy based on disease extent and severity.
Statement 44: 5-ASA should be the first-line therapy for induction and maintenance of remission in mild to moderate UC (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 45: For patients with active moderate UC, a higher dose of oral mesalamine (4.8 g/day) should be considered, particularly in those with prior corticosteroid use or persistent symptoms. For maintenance of remission a lower dose may be considered once disease control is achieved (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 46: Combination therapy with oral and topical mesalamine should be preferred for left-sided or extensive UC, while topical mesalamine alone may be used for ulcerative proctitis (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 91%).
Efficacy of corticosteroids in the induction and maintenance of remission in active UC: Oral corticosteroids remain a cornerstone for inducing remission in UC, with an efficacy rate of 80% and remission achieved in 50% of patients within one month and superiority over 5-ASA[57,123,124]. Prednisolone 40 mg/day is the recommended starting dose for outpatient management. For ASUC, IV hydrocortisone has been the standard of care, achieving long-term remission in approximately two-thirds of patients. A systematic review and network meta-analysis comparing topical 5-ASA and corticosteroids for active distal UC found that most regimens were superior to placebo, except for low-dose topical budesonide and hydrocortisone[125]. Combination therapy with rectal 5-ASA (1.5-2.0 g/day) and beclomethasone dipropionate 3 mg/day ranked highest for achieving clinical and endoscopic remission, followed by monotherapy with either 5-ASA 4 g/day or beclomethasone dipropionate 3 mg/day. The safety profile was comparable across all treatments, with no significant increase in adverse events. These findings support the use of combination therapy as the most effective strategy for distal UC.
Budesonide MMX is an oral, extended-release formulation designed to deliver budesonide throughout the colon using Multi-Matrix system technology. The CORE I and CORE II trials demonstrated its efficacy in inducing remission in patients with mild to moderate UC[126]. In CORE I, budesonide MMX 9 mg achieved significantly higher remission rates (17.9%) compared to placebo (7.4%, P = 0.0143), while the 6 mg dose did not reach statistical significance. Similarly, in CORE II, the 9 mg dose showed superior combined clinical and endoscopic remission rates (17.4%) vs placebo (4.5%, P = 0.0047)[127]. Across both trials, adverse event rates were comparable to placebo, confirming a favorable safety profile. A Cochrane review of six studies (1808 participants) demonstrated that budesonide MMX 9 mg was significantly more effective than placebo for inducing remission in UC [relative risk (RR) = 2.25, 95% confidence interval (CI): 1.50-3.39], particularly in left-sided disease and in mesalamine-responsive patients[128]. However, budesonide MMX was inferior to oral mesalamine (RR = 0.72, 95%CI: 0.57-0.91) and showed no significant difference compared to prednisolone or standard budesonide. Budesonide had minimal systemic effects, with no significant increase in glucocorticoid-related side effects or study withdrawals due to adverse events.
Statement 47: Oral prednisolone may be used for inducing remission in moderate to severe UC, with a tapering strategy based on clinical response. Budesonide MMX may be considered for induction of remission for mild to moderate UC (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 48: For active distal UC, combination therapy with topical 5-ASA and topical/rectal steroids maybe considered for induction of remission (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 49: Corticosteroids should not be used for the maintenance of remission in UC due to their unfavorable long-term safety profile and lack of efficacy in preventing relapse (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of thiopurines in the induction and maintenance of remission in active UC: Thiopurine monotherapy is not recommended for induction of remission in UC due to their slow onset of action and a lack of robust evidence supporting its efficacy. A systematic review and meta-analysis found a trend favoring thiopurines for induction but did not reach statistical significance (RR = 0.85; 95%CI: 0.71-1.01)[129]. A Cochrane review of seven RCTs demonstrated the superiority of thiopurines over placebo (56% vs 35%), mesalamine (50% vs 0%), and methotrexate (50% vs 8%)[130]. UC SUCCESS trial demonstrated that corticosteroid-free clinical remission at week 16 was achieved in 39.7% of patients receiving combination therapy with infliximab and azathioprine, compared to 22.1% with infliximab alone and 23.7% with azathioprine alone, highlighting the potential benefit of thiopurines in combination regimens for induction therapy in moderate-to-severe UC[131]. The United Kingdom IBD BioResource study demonstrated that thiopurine monotherapy is effective in maintaining long-term remission in UC with 52.7% of UC patients remaining on treatment without the need for escalation to biologics or surgery[132]. The median treatment duration was 17 years, highlighting its durability as a maintenance therapy.
Statement 50: Thiopurine monotherapy is not recommended for induction of remission in UC due to its slow onset of action and lack of robust supporting evidence (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 51: Thiopurines may be used in combination with infliximab for remission in moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 52: Thiopurines may be used for long-term maintenance of remission in UC, but their use should be weighed against their safety profile relative to certain advanced therapies (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 91%).
Efficacy of methotrexate in the induction and maintenance of remission in active UC: Methotrexate has not demonstrated consistent efficacy in UC with two RCTs investigating parenteral methotrexate at 25 mg/week for induction and maintenance of remission failing to show a statistically significant difference in steroid-free clinical remission at weeks 16 or 48 compared to placebo[133,134].
Statement 53: Methotrexate as monotherapy is not recommended for the induction or maintenance of remission in UC due to a lack of consistent efficacy in clinical trials (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of infliximab in the induction and maintenance of remission in active UC: The ACT 1 and ACT 2 trials demonstrated the efficacy of infliximab for induction and maintenance therapy in moderate-to-severe UC[135]. These randomized, double-blind, placebo-controlled studies included advanced therapy naive patients who received either placebo or infliximab (5 mg/kg or 10 mg/kg) at weeks 0, 2, and 6, followed by every eight weeks through week 46 (ACT 1) or week 22 (ACT 2), with follow-up to 54 weeks (ACT 1) and 30 weeks (ACT 2). At week 8, clinical response rates in ACT 1 were 69% (5 mg/kg), 61% (10 mg/kg), and 37% (placebo) (P < 0.001), while in ACT 2, response rates were 64% (5 mg/kg), 69% (10 mg/kg), and 29% (placebo) (P < 0.001). Response was defined as a Mayo score decrease of at least 3 points and 30%, with an improvement in rectal bleeding. At week 30, infliximab-treated patients were significantly more likely to maintain a response (P ≤ 0.002). In ACT 1, clinical response at week 54 was 45% (5 mg/kg), 44% (10 mg/kg), and 20% (placebo) (P < 0.001). A separate randomized, double-blind trial (SUCCESS) assessed the efficacy and safety of infliximab monotherapy, azathioprine monotherapy, and combination therapy in advanced therapy naive adults with moderate-to-severe UC[131]. Patients received infliximab 5 mg/kg at weeks 0, 2, 6, and 14 plus placebo capsules, azathioprine 2.5 mg/kg daily plus placebo infusions, or combination therapy. The primary endpoint was corticosteroid-free remission at week 16. Combination therapy was superior, achieving corticosteroid-free remission in 39.7% of patients, compared to 22.1% with infliximab alone (P = 0.017) and 23.7% with azathioprine alone (P = 0.032). Mucosal healing at week 16 was also higher with combination therapy (62.8%) compared to infliximab (54.6%, P = 0.295) and azathioprine (36.8%, P = 0.001). The LIBERTY phase 3 trials evaluated the efficacy and safety of subcutaneous infliximab (CT-P13 SC) as maintenance therapy in moderate-to-severe CD and UC[136]. After an IV induction phase (5 mg/kg at weeks 0, 2, and 6), clinical responders at week 10 were randomized 2:1 to CT-P13 SC (120 mg, every 2 weeks) or placebo through week 54. In UC, clinical remission rates at week 54 were 43.2% for CT-P13 SC vs 20.8% for placebo (P < 0001), with superiority observed across key secondary endpoints. The REMSWITCH study demonstrated that switching from IV to subcutaneous infliximab (120 mg every other week) in IBD patients in remission was safe, well tolerated, and led to increased drug levels, except in those previously on 10 mg/kg every 4 weeks[137]. Patients on this intensified regimen had a significantly higher relapse risk (66.7%) but responded well to dose escalation (93.3% recaptured remission on 240 mg every other week).
Statement 54: Infliximab is recommended for the induction and maintenance of remission in moderate-to-severe UC based on robust evidence from RCTs (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 55: Combination therapy with infliximab and azathioprine is superior to monotherapy for corticosteroid-free remission and mucosal healing in advanced therapy-naive patients with moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 56: CT-P13 SC is an effective maintenance therapy following IV induction in moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 57: Switching from IV to subcutaneous infliximab (120 mg, every other week) is safe and effective in UC, but patients on intensified IV dosing (10 mg/kg, every 4 weeks) have a higher relapse risk. These patients may require upfront dose escalation (240 mg, every other week) to maintain remission (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 91%).
Efficacy of adalimumab in the induction and maintenance of remission in active UC: The efficacy and safety of adalimumab in moderately to severely active UC have been evaluated in three key trials. The ULTRA 1 trial assessed induction of remission in anti-TNF-naive patients over 8 weeks[138]. Patients received adalimumab 160 mg at week 0, 80 mg at week 2, and 40 mg at weeks 4 and 6, or a lower induction regimen (80 mg/40 mg) vs placebo. At week 8, remission rates were 18.5% with the 160 mg/80 mg regimen vs 9.2% with placebo (P = 0.031), while the 80 mg/40 mg regimen (10.0%) did not significantly differ from placebo (P = 0.833). The ULTRA 2 trial evaluated adalimumab for both induction and maintenance therapy over 52 weeks, and included patients who had been exposed to anti-TNF previously[139]. At week 8, 16.5% of adalimumab-treated patients achieved remission vs 9.3% with placebo (P = 0.019). By week 52, remission rates were 17.3% with adalimumab vs 8.5% with placebo (P = 0.004). Anti-TNF-naive patients showed higher response rates (week 8: 21.3% vs 11%, P = 0.017; week 52: 22% vs 12.4%, P = 0.029), while previously exposed patients had lower remission rates (week 8: 9.2% vs 6.9%, P = 0.559; week 52: 10.2% vs 3%, P = 0.039). The ULTRA 3 trial, an open-label extension, assessed long-term adalimumab therapy for up to 4 years[140]. Among 600 patients initially randomized, 199 remained on treatment at year 4, with 24.7% achieving remission, 27.7% achieving mucosal healing, and 59.2% discontinuing corticosteroids. Among patients followed up in ULTRA 3, remission and mucosal healing were maintained in 63.6% and 59.9%, respectively, after 3 additional years of treatment.
Statement 58: Adalimumab may be considered for the induction and maintenance of remission in moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of golimumab in the induction and maintenance of remission in active UC: The PURSUIT-SC trial evaluated subcutaneous golimumab for induction of remission in TNF-naive patients with moderate-to-severe UC who had failed conventional therapy[141]. This integrated phase 2 and phase 3 study randomized patients to receive golimumab 200 mg followed by 100 mg, 400 mg followed by 200 mg, or placebo at weeks 0 and 2. At week 6, the primary outcome of clinical response was achieved in 51.0% (200 mg/100 mg) and 54.9% (400 mg/200 mg) compared to 30.3% with placebo (P ≤ 0.0001). Golimumab also significantly improved clinical remission, mucosal healing, and QoL (P ≤ 0.0014). The PURSUIT-M trial evaluated golimumab as maintenance therapy in patients who achieved clinical response during induction[142]. Responders were randomized to receive 50 mg, 100 mg, or placebo every 4 weeks through week 52. At week 54, clinical response was maintained in 47.0% (50 mg), 49.7% (100 mg), and 31.2% (placebo) (P = 0.010 and P < 0.001, respectively). Secondary endpoints of clinical remission and mucosal healing were also significantly higher in the 100 mg group at weeks 30 and 54 (27.8% and 42.4% vs 15.6% and 26.6%, P = 0.004 and P = 0.002, respectively).
Statement 59: Golimumab is recommended for the induction and maintenance of remission in moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 82%).
Efficacy of vedolizumab in the induction and maintenance of remission in active UC: The GEMINI 1 RCT trial demonstrated vedolizumab’s efficacy in patients with moderate-to-severe UC who had an inadequate response to conventional therapy[143]. At week 6, 47.1% of vedolizumab-treated patients achieved a clinical response compared to 25.5% with placebo (P < 0.001). Clinical remission rates were 16.9% vs 5.4% (P = 0.001), and mucosal healing rates were 40.9% vs 24.8% (P = 0.001). At week 52, clinical remission was maintained in 41.8% of patients receiving vedolizumab every 8 weeks and 44.8% receiving it every 4 weeks, compared to 15.9% with placebo (P < 0.001 for both comparisons). The GEMINI long-term safety study further assessed vedolizumab’s long-term efficacy, with patients receiving vedolizumab every 4 weeks for up to 152 weeks. Among those who responded to induction therapy and had data available, 88% were in remission at week 104, and 96% at week 152, indicating sustained clinical benefit over time[144].
Statement 60: Vedolizumab is recommended for the induction and maintenance of remission in moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of ustekinumab in the induction and maintenance of remission in active UC: The UNIFI induction trial enrolled patients with moderate-to-severe UC, randomizing them to a single IV dose of ustekinumab (130 mg or approximately 6 mg/kg based on body weight) or placebo[145]. At week 8, clinical remission was achieved in 15.6% (130 mg) and 15.5% (approximately 6 mg/kg) of ustekinumab-treated patients vs 5.3% in the placebo group (P < 0.001 for both comparisons). Responders at week 8 were re-randomized to maintenance therapy with subcutaneous ustekinumab 90 mg every 8 or 12 weeks or placebo through week 44. Clinical remission at week 44 was significantly higher with ustekinumab every 8 weeks (43.8%) and every 12 weeks (38.4%) compared to placebo (24.0%) (P < 0.001 and P = 0.002, respectively). Patients who completed 44 weeks of maintenance therapy were eligible to continue treatment in the UNIFI long-term extension study, receiving ustekinumab 90 mg every 12 weeks for up to 152 weeks. At week 200 (approximately four years), 55.2% of patients remained in symptomatic remission, with higher rates in biologic-naive patients (67.2%) compared to those with prior biologic failure (41.6%)[146,147]. Among patients in symptomatic remission, 96.4% were corticosteroid-free at week 200. Endoscopic improvement was observed in 81.6% of patients receiving ustekinumab every 12 weeks and 79.8% of those on an 8-week dosing schedule, demonstrating sustained mucosal benefit over long-term treatment.
Statement 61: Ustekinumab is recommended for the induction and maintenance of remission in moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of risankizumab in the induction and maintenance of remission in active UC: In the UC induction study INSPIRE, patients with moderately to severely active UC receiving IV risankizumab 1200 mg at weeks 0, 4, and 8 achieved significantly higher clinical remission rates at week 12 (20.3%) compared to placebo (6.2%) [adjusted difference: 14.0% (95%CI: 10.0-18.0), P < 0.001][148]. Those achieving a clinical response were re-randomized in the maintenance trial (COMMAND), where subcutaneous risankizumab (180 mg and 360 mg every 8 weeks) maintained remission at significantly higher rates (40.2% and 37.6%, respectively) compared to placebo (25.1%), confirming its long-term efficacy (P < 0.001 for 180 mg, P = 0.002 for 360 mg)[148]. Interim results from the COMMAND open-label extension study show that risankizumab maintains sustained efficacy and a stable safety profile in UC patients up to 96 weeks[149]. Higher-dose maintenance (360 mg, every 8 weeks) showed continued clinical and endoscopic improvements over time, with no new safety concerns.
Statement 62: Risankizumab is recommended for the induction and maintenance of remission in moderate-to-severe UC with both 180 mg and 360 mg every 8 weeks as effective maintenance dosing options (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of mirikizumab in the induction and maintenance of remission in active UC: The LUCENT-1 (induction) and LUCENT-2 (maintenance) phase 3 trials evaluated the efficacy of mirikizumab, in moderate-to-severe UC[150]. In LUCENT-1, 1281 patients were randomized 3:1 to receive IV mirikizumab (300 mg) or placebo every 4 weeks for 12 weeks. Clinical remission at week 12 was significantly higher in the mirikizumab group (24.2% vs 13.3%, P < 0.001). In LUCENT-2, 544 responders from induction were re-randomized 2:1 to subcutaneous mirikizumab (200 mg) or placebo every 4 weeks for 40 weeks. At week 40 (52 weeks total), 49.9% of mirikizumab-treated patients achieved clinical remission vs 25.1% with placebo (P < 0.001). All major secondary endpoints, including clinical response, endoscopic remission, and improvement in bowel urgency, were met in both trials. The LUCENT-3 open-label extension study evaluated the long-term efficacy of mirikizumab in moderate-to-severe UC over 152 weeks[151]. At week 152, 81.6% of week 52 responders maintained clinical response, with 56.1% achieving clinical remission, 54.5% remaining corticosteroid-free, and 61.0% achieving endoscopic remission. Among week 52 remitters, 85.4% maintained clinical response, with 70.1% in clinical remission, 68.9% corticosteroid-free, and 72.0% achieving endoscopic remission.
Statement 63: Mirikizumab is recommended for the induction and maintenance of remission in moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of guselkumab in the induction and maintenance of remission in active UC: The QUASAR phase 3 induction and maintenance trials evaluated guselkumab, in moderate-to-severe UC[152]. In the induction trial, patients were randomized 3:2 to receive guselkumab 200 mg IV at weeks 0, 4, and 8 or placebo. At week 12, clinical remission rates were significantly higher with guselkumab (23%) compared to placebo (8%) (P < 0.0001), confirming its superior induction efficacy. In the maintenance trial, responders to induction were re-randomized 1:1:1 to subcutaneous guselkumab 200 mg every 4 weeks, subcutaneous guselkumab 100 mg every 8 weeks, or placebo for 44 weeks. Clinical remission at week 44 was achieved in 50% of patients on subcutaneous 200 mg (P < 0.0001) and 45% on subcutaneous 100 mg (P < 0.0001), compared to 19% on placebo, demonstrating strong maintenance efficacy with both dosing regimens. The ASTRO phase 3 trial evaluated subcutaneous guselkumab as an alternative induction strategy in moderately to severely active UC. At week 12, clinical remission was achieved in 27.6% of patients receiving SC guselkumab vs 6.5% with placebo (P < 0.001). Significant improvements were also seen in clinical response (65.6% vs 34.5%), symptomatic remission (51.3% vs 20.9%), endoscopic improvement (37.3% vs 12.9%), and histo-endoscopic mucosal improvement (30.5% vs 10.8%), all P < 0.001. As of now, only data up to week 12 have been publicly reported; longer-term outcomes from ASTRO are awaited[153].
Statement 64: Guselkumab is effective for the induction and maintenance of remission in moderate-to-severe UC, with both IV and subcutaneous induction strategies available (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 65: For maintenance therapy, guselkumab should be administered subcutaneously, with both 200 mg every 4 weeks and 100 mg every 8 weeks as effective dosing options (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of tofacitinib in the induction and maintenance of remission in active UC: The OCTAVE induction 1 and 2 trials demonstrated that tofacitinib 10 mg twice daily was significantly more effective than placebo in inducing clinical remission at 8 weeks in patients with moderate-to-severe UC[154]. In OCTAVE induction 1, remission rates were 18.5% with tofacitinib vs 8.2% with placebo (P = 0.007), and in OCTAVE induction 2, 16.6% vs 3.6% (P < 0.001), confirming the drug’s efficacy as an induction therapy. The OCTAVE sustain trial evaluated maintenance therapy over 52 weeks in patients who responded to induction treatment. Remission was achieved in 34.3% of patients on tofacitinib 5 mg twice daily and 40.6% on 10 mg twice daily, compared to 11.1% in the placebo group (P < 0.001 for both doses vs placebo). The OCTAVE open study, an open-label extension of the OCTAVE program, evaluated the long-term safety and efficacy of tofacitinib in patients with moderate-to-severe UC for up to seven years[155]. Efficacy outcomes were reported through 36 months, at which point 58.9% of patients on 5 mg twice daily and 33.7% on 10 mg twice daily were in clinical remission, with endoscopic improvement observed in 64.6% and 37.1%, respectively.
Statement 66: Tofacitinib is effective for the induction and maintenance of remission in moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of upadacitinib in the induction and maintenance of remission in active UC: The U-ACHIEVE and U-ACCOMPLISH trials demonstrated that upadacitinib (45 mg once daily) was significantly more effective than placebo in inducing remission in moderate-to-severe UC with remission rates at week 8 of 26% vs 5% (U-ACHIEVE) and 34% vs 4% (U-ACCOMPLISH) (P < 0.0001)[156]. The U-ACHIEVE maintenance study further showed that after 52 weeks, remission rates were 42% with upadacitinib 15 mg, 52% with upadacitinib 30 mg, and 12% with placebo (P < 0.0001), highlighting the dose-dependent efficacy of the 30 mg dose. The U-ACTIVATE LTE study evaluated the four-year efficacy and safety of upadacitinib in UC patients who completed the one-year U-ACHIEVE maintenance study[157]. Patients in clinical remission at week 52 continued their assigned maintenance dose of 15 mg or 30 mg, while non-remitters on 15 mg were eligible for dose escalation. At LTE week 144, more than half of patients maintained clinical and endoscopic remission, confirming sustained long-term efficacy.
Statement 67: Upadacitinib is effective for the induction and maintenance of remission in moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of ozanimod in the induction and maintenance of remission in active UC: The True North phase 3 trial evaluated ozanimod for moderate-to-severe UC[158]. Patients were randomized to 0.92 mg ozanimod daily or placebo for a 10-week induction, followed by a 52-week maintenance phase for responders. Clinical remission was higher with ozanimod in both induction (18.4% vs 6.0%; P < 0.001) and maintenance (37.0% vs 18.5%; P < 0.001). Clinical response rates were also superior during induction (47.8% vs 25.9%; P < 0.001) and maintenance (60.0% vs 41.0%; P < 0.001). Ozanimod also significantly improved endoscopic and histologic outcomes, confirming its efficacy as an oral therapy for UC induction and maintenance.
Statement 68: Ozanimod is effective for the induction and maintenance of remission in moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of etrasimod in the induction and maintenance of remission in active UC: The ELEVATE UC 52 and ELEVATE UC 12 phase 3 trials evaluated the efficacy and safety of etrasimod in moderate-to-severe UC[159]. Patients were randomized to etrasimod 2 mg once daily or placebo. In ELEVATE UC 52, which included a 12-week induction and 40-week maintenance period, clinical remission rates were significantly higher with etrasimod than placebo at both week 12 (27% vs 7%; P < 0.0001) and week 52 (32% vs 7%; P < 0.0001). ELEVATE UC 12, a separate 12-week induction study, also showed higher remission with etrasimod (25% vs 15%; P = 0.026). In isolated proctitis, etrasimod 2 mg once daily demonstrated significant efficacy in the ELEVATE UC studies, with higher clinical remission rates than placebo at weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), along with improved endoscopic outcomes and bowel urgency scores[160].
Statement 69: Etrasimod is effective for the induction and maintenance of remission in moderate-to-severe UC (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 70: Etrasimod may be considered as a treatment option for patients with moderate-to-severe isolated proctitis who require advanced therapy (evidence level: 1b; strength of recommendation: Conditional; consensus agreement: 100%).
Efficacy of aminosalicylates in the induction and maintenance of remission in active CD: Multiple RCTs and systematic reviews have consistently demonstrated no significant benefit of oral 5-ASAs over placebo for inducing or maintaining remission in CD, with relapse rates at 12 months and 24 months being nearly identical[161-163]. A Cochrane review of 20 studies found only a modest trend favoring sulfasalazine over placebo for remission induction, with benefits primarily in Crohn’s colitis, but overall, 5-ASAs were significantly less effective than corticosteroids[164]. Another Cochrane analysis of 12 trials with 2146 participants concluded that oral 5-ASAs did not prevent relapse in quiescent CD, showing no significant difference in remission rates compared to placebo at both 12 months and 24 months[165].
Statement 71: Oral 5-ASA are not recommended for the induction or maintenance of remission in CD due to a lack of significant benefit over placebo (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 72: Sulfasalazine (not mesalazine) may provide modest benefit for induction of remission in mild Crohn’s colitis (evidence level: 1a; strength of recommendation: Weak; consensus agreement: 91%).
Efficacy of corticosteroids in the induction and maintenance of remission in active CD: Corticosteroids are effective for inducing remission in active CD but are not suitable for long-term maintenance. A Cochrane review demonstrated that systemic corticosteroids, administered orally or intravenously, were nearly twice as effective as placebo (RR = 1.99, 95%CI: 1.51-2.64, P < 0.00001) and superior to 5-ASA when used for more than 15 weeks (RR = 1.65, 95%CI: 1.33-2.03, P < 0.00001)[166]. However, corticosteroids were associated with higher adverse event rates compared to placebo (RR = 4.89, 95%CI: 1.98-12.07, P = 0.0006) and low-dose 5-ASA (RR = 2.38, 95%CI: 1.34-4.25, P = 0.003), though these did not lead to increased study withdrawals. A double-blind, multicenter trial evaluated the efficacy of oral controlled-ileal-release budesonide in patients with active CD[167]. Budesonide 9 mg/day induced remission in 51% of patients, significantly superior to placebo (20%, P < 0.001), with improvements in QoL. While budesonide reduced plasma cortisol levels, it was well tolerated without significant corticosteroid-related adverse effects.
Statement 73: Systemic corticosteroids are effective for inducing remission in active CD but should not be used for long-term maintenance due to safety concerns and lack of sustained efficacy (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 74: Budesonide 9 mg once daily is an effective induction therapy for mild to moderate ileal and right colonic CD, offering a better safety profile than systemic corticosteroids (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of thiopurines in the induction and maintenance of remission in active CD: Thiopurine monotherapy has shown limited efficacy in the treatment of CD, particularly in moderate to severe cases. A Cochrane review of 13 RCTs demonstrated only a modest difference in induction of clinical remission rates between azathioprine or 6-mercaptopurine and placebo (RR = 1.23, 95%CI: 0.97-1.55)[168]. For maintenance of remission, thiopurines have demonstrated a modest benefit in CD, particularly in corticosteroid-dependent patients. A Cochrane review of six studies found that azathioprine (1.0-2.5 mg/kg/day) was superior to placebo in maintaining corticosteroid-free remission (RR = 1.19, 95%CI: 1.05-1.34)[169]. The United Kingdom IBD BioResource study, which analyzed long-term data from 11928 patients, confirmed that thiopurine monotherapy was markedly less effective in CD than in UC, with only 34.2% of CD patients achieving sustained benefit without requiring escalation to biologic therapy or surgery[132]. The SONIC trial further highlighted that combination therapy with infliximab and azathioprine was significantly more effective than either agent alone in achieving clinical remission and mucosal healing[93].
Statement 75: Thiopurine monotherapy is not recommended for the induction of remission in CD due to limited efficacy (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 76: Thiopurines may be considered for maintenance of remission in CD, particularly in corticosteroid-dependent patients, but their effectiveness is lower compared to advanced therapies (evidence level: 1a; strength of recommendation: Weak; consensus agreement: 91%).
Statement 77: Combination therapy with infliximab and azathioprine is more effective than either agent alone for achieving clinical remission and mucosal healing in CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of methotrexate in the induction and maintenance of remission in active CD: Methotrexate has demonstrated efficacy in CD, particularly when used parenterally[170]. A placebo-controlled trial showed that intramuscular injection methotrexate at 25 mg/week for 16 weeks was superior to placebo in achieving remission, whereas lower oral doses (12.5-15 mg/week) were ineffective[171]. For maintenance, continued intramuscular injection methotrexate at 15 mg/week sustained remission at week 40[172]. A Cochrane review of five trials (n = 333) found moderate-quality evidence that intramuscular injection methotrexate at 15 mg/week was superior to placebo for maintenance (65% vs 39%; RR = 1.67, 95%CI: 1.05-2.67)[173]. However, oral methotrexate at 12.5 mg/week was not effective for maintenance. Comparisons with thiopurines showed similar efficacy, both being superior to 5-ASA for maintenance. In combination therapy, methotrexate did not improve remission rates with infliximab but reduced anti-drug antibody formation and improved drug levels[174]. A pooled analysis of two trials (n = 145) found no difference in maintenance rates between infliximab monotherapy and infliximab with methotrexate (54% vs 53%; RR = 1.02, 95%CI: 0.76-1.38)[173]. While thiopurines appear more effective in combination, methotrexate remains an alternative in thiopurine-intolerant or Epstein-Barr virus-naive patients and may reduce immunogenicity in anti-TNF therapy.
Statement 78: Intramuscular methotrexate may be considered for inducing and maintaining remission in CD; however, its use should be weighed against its safety profile relative to certain advanced therapies (evidence level: 1a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 79: Methotrexate may be used in combination with anti-TNF therapy to reduce immunogenicity in patient’s intolerant or unsuitable for thiopurines (evidence level: 1b; strength of recommendation: Weak; consensus agreement: 100%).
Efficacy of infliximab in the induction and maintenance of remission in active CD: Infliximab has been established as a key therapy for the management of moderate-to-severe CD, with strong evidence supporting its role in both luminal and fistulizing disease. The ACCENT I trial investigated the efficacy of maintenance infliximab therapy in biologic-naive patients with active CD who responded to an initial 5 mg/kg infusion[175]. Responders at week 2 (58%) were randomized to continued infliximab (5 mg/kg or dose escalation to 10 mg/kg every 8 weeks) or placebo. At week 30, clinical remission rates were significantly higher in patients receiving maintenance infliximab (39% and 45% in the 5 mg/kg and 10 mg/kg groups, respectively) compared to 21% with placebo (P = 0.003, P = 0.0002). Additionally, the median time to LOR was significantly longer in the maintenance groups (over 38 weeks vs 19 weeks with placebo, P = 0.002), confirming infliximab’s role in sustaining remission and delaying disease progression. For patients with fistulizing CD, the ACCENT II trial investigated the benefit of infliximab maintenance therapy in achieving and sustaining fistula closure[176]. Following induction therapy, responders were randomized to maintenance infliximab every 8 weeks or placebo through week 54. The median time to LOR was significantly longer in the infliximab group (over 40 weeks vs 14 weeks with placebo, P < 0.001), and at week 54, complete fistula closure was observed in 36% of infliximab-treated patients compared to 19% with placebo (P = 0.009). A post hoc analysis focusing on rectovaginal fistulas further supported these findings, demonstrating that 72.2% of responders-maintained closure at week 14, with a longer median closure duration in the infliximab group (46 weeks vs 33 weeks with placebo)[177]. The SONIC trial provided further evidence supporting infliximab’s efficacy, particularly when used in combination with azathioprine[93]. In this study, biologic- and immunosuppressant-naive patients with moderate-to-severe CD were randomized to infliximab monotherapy, azathioprine monotherapy, or combination therapy. At week 26, corticosteroid-free remission was significantly higher in the combination group (56.8%) compared to infliximab monotherapy (44.4%, P = 0.02) and azathioprine monotherapy (30.0%, P < 0.001 vs combination, P = 0.006 vs infliximab). Mucosal healing rates followed a similar trend, favoring combination therapy (43.9%) over infliximab (30.1%, P = 0.06) and azathioprine (16.5%, P < 0.001). The LIBERTY phase 3 trials evaluated the efficacy and safety of CT-P13 SC as maintenance therapy in moderate-to-severe CD following IV induction with 5 mg/kg at weeks 0, 2, and 6[136]. Clinical responders at week 10 were randomized to receive CT-P13 SC 120 mg every 2 weeks or placebo through week 54. In patients with CD, clinical remission at week 54 was achieved in 62.3% of those receiving CT-P13 SC compared to 32.1% with placebo (P < 0.0001), and endoscopic response was also significantly higher (51.1% vs 17.9%, P < 0.0001). Similar to UC, the REMSWITCH study demonstrated that switching from IV to subcutaneous infliximab in the CD subgroup-maintained efficacy and was well tolerated, with dose escalation effectively recapturing remission in patients requiring intensified dosing[137].
Statement 80: Infliximab is recommended for the induction and maintenance of remission in moderate-to-severe CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 81: Combination therapy with infliximab and azathioprine is superior to monotherapy for corticosteroid-free remission and mucosal healing in biologic-naive CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 82: Infliximab is recommended for achieving and sustaining fistula closure in perianal and rectovaginal fistulizing CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 83: CT-P13 SC is an effective maintenance therapy following IV induction in moderate-to-severe CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 84: Switching from IV to subcutaneous infliximab (120 mg, every other week) is safe and effective in CD, but patients on intensified IV dosing (10 mg/kg, every 4 weeks) have a higher relapse risk. These patients may require upfront dose escalation (240 mg, every other week) to maintain remission (evidence level: 2b; strength of recommendation: Strong; consensus agreement: 91%).
Efficacy of adalimumab in the induction and maintenance of remission in active CD: The efficacy and safety of adalimumab for the treatment of moderate-to-severe CD have been established through three key RCTs: CLASSIC-I, CLASSIC-II, and CHARM. The CLASSIC-I trial evaluated adalimumab as an induction therapy in anti-TNF-naive patients[178]. Patients were randomized to receive placebo or adalimumab at varying doses (40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg) at weeks 0 and 2. At week 4, remission rates were highest in the 160 mg/80 mg group (36%) compared to 24% (80 mg/40 mg) and 18% (40 mg/20 mg), while placebo achieved 12% remission (P = 0.001). These findings established 160 mg at week 0 followed by 80 mg at week 2 as the optimal induction regimen for adalimumab in CD. For long-term maintenance, the CLASSIC-II trial followed patients from CLASSIC-I who achieved remission at weeks 0 and 4 after induction therapy[179]. These patients were re-randomized to adalimumab 40 mg every other week, adalimumab 40 mg weekly, or placebo for 56 weeks. By week 56, 79% of patients on adalimumab every other week and 83% on adalimumab weekly remained in remission, compared to 44% in the placebo group (P < 0.05). The CHARM trial further confirmed the efficacy of adalimumab maintenance therapy in patients with moderate-to-severe CD who had an initial response to induction treatment[180]. At week 4, responders were randomized to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. By week 26, 40% (adalimumab, every other week) and 47% (adalimumab weekly) were in remission, compared to 17% with placebo (P < 0.001). At week 56, remission rates were 36%, 41%, and 12%, respectively (P < 0.001). There were no significant differences in efficacy between every other week and weekly dosing.
Statement 85: Adalimumab is recommended for the induction and maintenance of remission in moderate-to-severe CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 91%).
Efficacy of certolizumab in the induction and maintenance of remission in active CD: The PRECISE 1 trial evaluated certolizumab pegol for induction and maintenance in moderate-to-severe CD stratified by baseline CRP[181]. Patients were randomized to receive 400 mg certolizumab or placebo at weeks 0, 2, and 4, then every 4 weeks. Among patients with CRP ≥ 10 mg/L, response rates at week 6 were 37% with certolizumab vs 26% with placebo (P = 0.04), and at weeks 6 and 26, 22% vs 12% (P = 0.05). In the overall population, response rates were 35% vs 27% at week 6 (P = 0.02) and 23% vs 16% at weeks 6 and 26 (P = 0.02), but remission rates did not differ significantly. The PRECISE 2 trial assessed certolizumab as maintenance therapy in patients who responded to induction[182]. Of 668 patients, 428 (64%) achieved response at week 6 and were randomized to certolizumab 400 mg or placebo every 4 weeks through week 24. Among those with CRP ≥ 10 mg/L, 62% maintained response at week 26 with certolizumab vs 34% with placebo (P < 0.001). Remission (CDAI ≤ 150) at week 26 was achieved in 48% with certolizumab vs 29% with placebo (P < 0.001).
Statement 86: Certolizumab is recommended for the induction and maintenance of remission in moderate-to-severe CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 91%).
Efficacy of vedolizumab in the induction and maintenance of remission in active CD: The GEMINI 2 trial evaluated vedolizumab (300 mg IV) in moderate to severe CD, assessing induction (week 6) and maintenance (week 52) efficacy[183]. At week 6, clinical remission was achieved in 14.5% of vedolizumab-treated patients vs 6.8% on placebo (P = 0.02), though CDAI-100 response rates were similar (31.4% vs 25.7%, P = 0.23). At week 52, remission rates were 39.0% (8-weekly vedolizumab), 36.4% (4-weekly), and 21.6% (placebo, P < 0.001 and P = 0.004). The GEMINI 3 trial, which specifically assessed patients with prior anti-TNF failure, did not show a significant difference in remission at week 6 (15.2% vs 12.1%; P = 0.433), but a benefit emerged at week 10 (26.6% vs 12.1%; P = 0.001)[184]. Patients who did not achieve response at week 6 appeared to benefit from an additional administration at week 10[185]. The GEMINI long-term safety trial evaluated vedolizumab’s long-term efficacy in CD over 152 weeks[186]. Among initial responders, 83% remained in remission at week 104, increasing to 89% by week 152. In patients who had withdrawn from GEMINI 2, increasing dosing from every 8 weeks to every 4 weeks improved clinical response (39% to 47%) and remission rates (4% to 32%) by week 52, with consistent benefits regardless of prior TNF antagonist exposure. A validated clinical decision support tool, developed from the GEMINI, GETAID, and VICTORY cohorts, stratifies patients with CD into low, intermediate, and high probability groups for vedolizumab response based on five clinical variables: Prior surgery, TNF exposure, fistulizing phenotype, baseline CRP, and albumin[187]. This tool may aid in personalized treatment selection and optimization of vedolizumab use in clinical practice.
Statement 87: Vedolizumab is recommended for the induction and maintenance of remission in moderate-to-severe CD. Patients who do not achieve response at week 6 may benefit from an additional IV dose at week 10. The clinical decision support tool may be used to guide patient selection for its use in CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 91%).
Efficacy of ustekinumab in the induction and maintenance of remission in active CD: Its efficacy in moderate to severe CD was established in the UNITI-1, UNITI-2, and IM-UNITI trials. UNITI-1 enrolled patients with prior anti-TNF failure, while UNITI-2 included those who had failed conventional therapies[188]. Patients received a single IV dose of ustekinumab (130 mg or weight-based 6 mg/kg) or placebo. At week 6, the primary endpoint of clinical response, was significantly higher with ustekinumab in both UNITI-1 (34.3% and 33.7% vs 21.5%, P < 0.003) and UNITI-2 (51.7% and 55.5% vs 28.7%, P < 0.001). Clinical remission was also significantly improved. Patients who responded were re-randomized in the IM-UNITI maintenance trial to subcutaneous ustekinumab 90 mg every 8 or 12 weeks or placebo. At week 44, remission rates were higher with ustekinumab (53.1% for 8-weekly and 48.8% for 12-weekly dosing) compared to 35.9% in the placebo group. The long-term (five year) efficacy and safety of ustekinumab maintenance therapy were further evaluated in the IM-UNITI long-term extension study, which followed patients for up to five years[189]. Patients who completed week 44 of the maintenance study were eligible to continue ustekinumab at the same dosing schedule (90 mg every 8 or 12 weeks). At week 252, intent-to-treat analysis from week 0 of IM-UNITI showed clinical remission rates of 34.4% in the 8-weekly group and 28.7% in the 12-weekly group. Among patients who entered the long-term extension, remission rates were higher, reaching 54.9% and 45.2%, respectively.
Statement 88: Ustekinumab is recommended for the induction and maintenance of remission in moderate-to-severe CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of risankizumab in the induction and maintenance of remission in active CD: The ADVANCE and MOTIVATE induction trials evaluated the efficacy of IV risankizumab (600 mg or 1200 mg) over 12 weeks in patients with moderately to severely active CD[190]. Both studies demonstrated significantly higher clinical remission and endoscopic response rates compared to placebo (P ≤ 0.0001). In ADVANCE, clinical remission was achieved in 45% of patients receiving 600 mg and 42% receiving 1200 mg, vs 25% in the placebo group. Similarly, in MOTIVATE, remission rates were 42% for 600 mg and 40% for 1200 mg, compared to 20% with placebo. The FORTIFY maintenance trial confirmed the durability of response, with the 360 mg dose achieving clinical remission in 52% of patient’s vs 41% with placebo, and endoscopic response in 47% vs 22%, respectively[191]. The 180 mg dose also showed strong efficacy, with clinical remission rates of 55% and endoscopic response rates of 47%, supporting a dose-response relationship. Long-term outcomes were evaluated in the FORTIFY open-label extension, which assessed risankizumab’s efficacy beyond 52 weeks[192]. Clinical remission based on CDAI remained stable from week 56 to 152, while stool frequency and abdominal pain remission improved from 64.4% to 71.0%. Endoscopic outcomes also improved over time, with response rates increasing from 53.4% to 74.2%, remission from 37.5% to 58.9%, and ulcer-free endoscopy from 31.0% to 50.0%.
Statement 89: Risankizumab is recommended for the induction and maintenance of remission in moderate-to-severe CD colitis with both 180 mg and 360 mg every 8 weeks as effective maintenance dosing options (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of mirikizumab in the induction and maintenance of remission in active CD: The VIVID-1 phase 3 trial evaluated the efficacy of mirikizumab in moderate-to-severe CD[193]. The study randomized 6:3:2 to receive mirikizumab (900 mg IV at weeks 0, 4, and 8; followed by subcutaneous 300 mg, every 4 weeks), ustekinumab (6 mg/kg IV at week 0; then 90 mg subcutaneously, every 8 weeks), or placebo. Mirikizumab met both co-primary endpoints, demonstrating superior efficacy compared to placebo. The endoscopic response-composite endpoint (defined as patient-reported outcome clinical response at week 12 and endoscopic response at week 52) was achieved in 38.0% of mirikizumab-treated patients vs 9.0% of placebo-treated patients (P < 0.0001). The CDAI clinical remission-composite endpoint (defined as patient-reported outcome clinical response at week 12 and CDAI clinical remission at week 52) was significantly higher in the mirikizumab group (45.4%) compared to placebo (19.6%, P < 0.0001). Mirikizumab was non-inferior to ustekinumab for clinical remission (CDAI-treat-through) at week 52 [54.1% vs 48.4%; difference: 5.7% (95%CI: -1.4 to 12.8)]. However, mirikizumab did not achieve superiority for endoscopic response [48.4% vs 46.3%; difference: 2.3% (95%CI: -4.7 to 9.3)]. In the long-term extension of the VIVID-2 study, mirikizumab maintained high rates of endoscopic response and remission in CD patients who were responders at one year, with over 30% of initial non-responders achieving endoscopic response after reinduction[194].
Statement 90: Mirikizumab is recommended for the induction and maintenance of remission in moderate-to-severe CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of guselkumab in the induction and maintenance of remission in active CD: The GALAXI 2 and 3 phase 3 trials evaluated guselkumab, in patients with moderate-to-severe CD using two co-primary endpoints: Clinical response at week 12 plus clinical remission at week 48, and clinical response at week 12 plus endoscopic response at week 48[195]. Patients were randomized to receive guselkumab 200 mg IV every 4 weeks (for a total of 3 times) followed by either subcutaneous guselkumab 200 mg every 4 weeks or subcutaneous guselkumab 100 mg every 8 weeks, ustekinumab approximately 6 mg/kg IV (for a total of 1 time) followed by subcutaneous ustekinumab 90 mg every 8 weeks, or placebo with a treat through study design. For the clinical response at week 12 plus clinical remission at week 48, guselkumab demonstrated superiority over placebo. In GALAXI 2, 49.0% of patients receiving guselkumab 200 mg IV followed by 100 mg subcutaneously every 8 weeks achieved the composite endpoint, compared to 11.8% of placebo-treated patients (P < 0.001). The subcutaneous guselkumab 200 mg every 4 weeks regimen yielded an even higher response of 54.8%. Similarly, in GALAXI 3, guselkumab-treated patients had clinical remission rates of 46.9% and 48.0% with subcutaneous guselkumab 100 mg (every 8 weeks) and subcutaneous guselkumab 200 mg (every 4 weeks), respectively, compared to 12.5% with placebo (P < 0.001). For the clinical response at week 12 plus endoscopic response at week 48, guselkumab again showed significant benefit. In GALAXI 2, 39.2% (subcutaneous guselkumab 100 mg every 8 weeks) and 38.4% (subcutaneous guselkumab 200 mg every 4 weeks) of guselkumab-treated patients achieved the endpoint, vs 5.3% with placebo (P < 0.001). In GALAXI 3, the results were comparable, with 33.6% and 36.0% of guselkumab-treated patients achieving clinical plus endoscopic response, compared to 5.6% with placebo (P < 0.001). At week 48, pooled analyses demonstrated that both guselkumab maintenance doses were superior to ustekinumab for endoscopic response, endoscopic remission and clinical remission plus endoscopic response.
The GRAVITI phase 3 trial evaluated the efficacy of subcutaneous guselkumab induction and maintenance in moderate-to-severe CD[196]. A total of 347 patients with inadequate response or intolerance to corticosteroids, immunomodulators, or biologics were randomized 1:1:1 to receive subcutaneous guselkumab 400 mg every 4 weeks (for a total of 3 times) followed by subcutaneous guselkumab 200 mg every 4 weeks, subcutaneous guselkumab 400 mg (for a total of 3 times) followed by subcutaneous guselkumab 100 mg every 8 weeks, or placebo. At week 12 clinical remission was achieved in 56.1% of patients receiving subcutaneous guselkumab 400 mg every 4 weeks, compared to 21.4% in the placebo group (Δ = 34.9%, P < 0.001). Similarly, endoscopic response was observed in 41.3% of guselkumab-treated patients vs 21.4% with placebo (Δ = 19.9%, P < 0.001). At week 48, both maintenance regimens of guselkumab sustained clinical and endoscopic efficacy. Clinical remission was achieved in 60.9% of patients receiving 100 mg every 8 weeks and 66.1% of those receiving 200 mg every 4 weeks, compared to 17.1% in the placebo group (Δ = 37.0% and Δ = 48.9%, both P < 0.001). Similarly, endoscopic response was observed in 44.3% of patients on 100 mg every 8 weeks and 51.3% on 200 mg every 4 weeks, compared to 6.8% with placebo (Δ = 37.5% and Δ = 44.6%, both P < 0.001).
Statement 91: Guselkumab is effective for the induction and maintenance of remission in moderate-to-severe CD, with both IV and subcutaneous induction strategies available (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 92: For maintenance therapy in CD, guselkumab should be administered subcutaneously, with both 200 mg every 4 weeks and 100 mg every 8 weeks as effective dosing options (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Efficacy of upadacitinib in the induction and maintenance of remission in active CD: The efficacy of upadacitinib for CD was evaluated in U-EXCEL and U-EXCEED (induction) and U-ENDURE (maintenance)[197]. In U-EXCEL (n = 526) and U-EXCEED (n = 495), patients with moderate-to-severe disease were randomized (2:1) to upadacitinib 45 mg or placebo once daily for 12 weeks. Remission rates were 49.5% vs 29.1% (U-EXCEL) and 38.9% vs 21.1% (U-EXCEED), with endoscopic response rates of 45.5% vs 13.1% and 34.6% vs 3.5%, respectively (P < 0.001). In U-ENDURE (n = 502), responders from induction were randomized (1:1:1) to upadacitinib 15 mg, 30 mg, or placebo for 52 weeks. Remission rates at week 52 were 37.3% (15 mg), 47.6% (30 mg), and 15.1% (placebo), with endoscopic response rates of 27.6%, 40.1%, and 7.3% (P < 0.001). The U-ENDURE long-term extension demonstrated sustained efficacy, with patients continuing upadacitinib treatment maintaining stable clinical remission and endoscopic response over an additional 48 weeks, whereas those on placebo experienced worsening disease[198].
Statement 93: Upadacitinib is recommended for the induction and maintenance of remission in moderate-to-severe CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Safety and monitoring of medical therapies for IBD
Ensuring the safe use of medical therapies in IBD requires comprehensive pre-treatment screening, risk assessment, and structured monitoring to prevent complications. This section of the guideline outlines key recommendations for pre-advanced therapy safety screening, infection risk mitigation, and drug-specific monitoring protocols. The aim is to minimize adverse events, optimize therapy selection, and enhance long-term patient safety.
Pre-advanced therapy initiation safety screening: Both the European and United Stated guidelines recommend a comprehensive pre-advanced therapy safety screening to reduce the risk of opportunistic infections and complications associated with immunosuppression[199-201]. This standardized assessment should ideally be conducted at IBD diagnosis and repeated before starting advanced therapy. It includes a detailed medical history focusing on past microbial infections, particularly tuberculosis, herpes simplex virus, varicella-zoster virus, human immunodeficiency virus (HIV), and hepatitis A, B, and C, alongside a travel history to identify risks from endemic infections. Immunization status should be reviewed to ensure protection against diphtheria, tetanus, poliomyelitis, pertussis, measles-mumps-rubella, human papillomavirus (HPV), and hepatitis B, along with annual influenza and pneumococcal vaccines as recommended for IBD patients. A thorough physical examination should be conducted. Baseline laboratory tests should assess for concomitant immunodeficiency or infection, including full blood count with neutrophil and lymphocyte counts, CRP, hepatitis B and hepatitis C serologies. Cytomegalovirus and Epstein-Barr virus serologies testing maybe performed if indicated. Tuberculosis screening with tuberculin skin test and/or interferon-gamma release assay, and a chest X-ray if needed, is mandatory before starting immunosuppressive therapy. HIV testing is not mandatory but should be strongly considered in vulnerable individuals as defined by the World Health Organization. If measles-mumps-rubella or varicella-zoster virus immunity is uncertain, serology should be checked, and vaccination administered if appropriate, ensuring no contraindications to live vaccines. Vaccination programme is covered in greater detailed in the health maintenance section of this guideline.
Statement 94: A comprehensive pre-advanced therapy safety screening (that includes hepatitis B, hepatitis C, and tuberculosis) should be performed before initiating advanced therapy to minimize the risk of opportunistic infections and complications associated with immunosuppression. HIV testing should be considered in vulnerable individuals as defined by World Health Organization (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Management of specific co-existing infections prior to initiation of advanced therapies: While infection prevention strategies, including vaccination, antimicrobial prophylaxis, and monitoring and management of co-existing infections, are comprehensively addressed in the ECCO guidelines on the prevention, diagnosis, and management of infections in IBD, this section focuses specifically on the management of tuberculosis, hepatitis B, and hepatitis C - three key infections routinely screened before the initiation of advanced therapies[199].
Tuberculosis: According to the ECCO guidelines, all patients with latent tuberculosis should receive a full chemoprophylaxis regimen before initiating biologic or small-molecule therapy, or prolonged high-dose corticosteroids. Standard treatment involves isoniazid for 6-9 months, although shorter regimens such as 3 months of rifapentine and isoniazid or 4 months of rifampicin have demonstrated comparable efficacy with better adherence. Liver function should be monitored regularly, and therapy should be modified if transaminases exceed three times the upper limit of normal with symptoms or five times without symptoms. Biologic or small-molecule therapy should be delayed for at least 4 weeks after initiating tuberculosis treatment, unless clinically urgent, in which case specialist advice is required. For active tuberculosis, advanced therapies should be postponed for at least 2 months after starting full anti-tuberculosis treatment, ensuring compliance and confirmation of the drug susceptibility profile. Thiopurines may be continued during tuberculosis treatment, but careful monitoring is necessary due to potential infectious and hepatotoxic risks.
Statement 95: Patients with latent tuberculosis should receive full chemoprophylaxis before initiating biologic or small-molecule therapy, following treatment protocols and durations as per institutional antimicrobial policies and appropriate referral to infectious disease specialists. Biologic or small-molecule therapy should be delayed for at least 4 weeks after initiating tuberculosis treatment, unless clinically urgent, in which case specialist advice is required (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Hepatitis B and hepatitis C: According to the 2025 AGA guidelines on hepatitis B reactivation prevention and the 2021 ECCO guidelines on prevention of infection, all patients with chronic hepatitis B (positive hepatitis B surface antigen) should receive antiviral prophylaxis before initiating immunosuppressive therapy, including biologics and small molecules, to prevent reactivation[199,202]. Preferred agents include tenofovir or entecavir, which should be initiated at least two weeks before starting immunosuppressive therapy and continued for at least 12 months after stopping therapy, with regular monitoring of liver function tests and hepatitis B virus (HBV) DNA every 3 months to 6 months. In contrast, patients with resolved hepatitis B infection (positive hepatitis B core antibody but negative hepatitis B surface antigen) do not require routine antiviral prophylaxis but should have hepatitis B surface antigen and HBV DNA monitored every 1-3 months during immunosuppressive therapy and for at least 6 months after stopping treatment. If HBV reactivation occurs, immediate antiviral therapy is required. The 2025 AGA guideline further refines risk stratification, recommending universal screening for hepatitis B in all patients prior to starting immunosuppressive therapy, replacing previous stratified approaches. In patients receiving advanced therapies, those at high risk (positive hepatitis B surface antigen) should receive antiviral prophylaxis, while those at moderate risk (positive hepatitis B core antibody only) should have close monitoring or prophylaxis based on risk factors. Given that prolonged steroid use (> 20 mg/day for more than four weeks) in IBD also increases HBV reactivation risk, screening and prophylaxis should be strongly considered in such cases[202]. For hepatitis C, patients with IBD should be treated with direct-acting antiviral agents according to national and international guidelines, with close monitoring during antiviral therapy due to limited data on its impact in immunosuppressed IBD patients[199,203].
Statement 96: Patients with chronic hepatitis B (positive hepatitis B surface antigen) should receive antiviral prophylaxis, preferably with tenofovir or entecavir, initiated at least two weeks before therapy and continued for at least 12 months after cessation, while those with resolved infection should undergo regular monitoring for reactivation (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 91%).
Statement 97: Patients with IBD and hepatitis C should be treated with direct-acting antiviral agents according to national and international guidelines, with close monitoring during antiviral therapy due to limited data on its impact in immunosuppressed patients (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Safety considerations and monitoring with aminosalicylates: Mesalazine is widely used for the treatment of UC and is generally well tolerated but requires appropriate safety monitoring. Common adverse effects include gastrointestinal symptoms, headache, and mild allergic reactions, while rare but serious risks include pancreatitis, nephrotoxicity, hepatotoxicity, pericarditis, and hypersensitivity pneumonitis[204-206]. Routine monitoring of renal function is essential, as interstitial nephritis can occur, necessitating baseline serum creatinine assessment before initiation and periodic renal function tests during treatment. Hepatic function should be evaluated in patients with unexplained liver enzyme elevations, while routine liver enzyme monitoring is recommended annually[205]. Importantly, there is no dose-dependent increase in adverse events, meaning that high-dose mesalazine (> 2.4 g/day) does not carry a significantly greater risk than lower doses. Given its safety profile, mesalazine remains a first-line therapy for mild-to-moderate UC, with proper monitoring ensuring early detection and management of adverse effects.
Statement 98: Regular renal and hepatic function monitoring is essential during mesalazine therapy to detect potential adverse effects, including interstitial nephritis and hepatotoxicity, with baseline serum creatinine assessment and periodic renal and liver function tests recommended (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Safety considerations and monitoring with corticosteroids: Corticosteroids have long been a cornerstone of IBD treatment due to their rapid ability to induce remission, but their role in maintaining remission is limited by significant adverse effects. Prolonged steroid use is associated with serious complications, including osteoporosis, infections, adrenal insufficiency, mental health complications, immunosuppression, hyperglycaemia, and increased mortality. As a result, both the BSG and ECCO strongly advocate for reducing steroid dependence and emphasize treatment escalation to biologics or immunomodulators for patients requiring prolonged corticosteroid therapy[200,207,208]. The increasing availability of advanced therapies has challenged the historical reliance on corticosteroids, shifting clinical practice towards steroid-sparing strategies to minimize harm. Steroid excess in IBD is now recognized as a critical issue, encompassing steroid dependence (symptom recurrence upon tapering or the need for another course within three months), prolonged steroid use (continuous therapy beyond three months), and frequent steroid courses (two or more courses within a year). Inappropriate steroid use occurs when patients continue corticosteroid therapy despite clear indications for transitioning to more effective maintenance options. Given these risks, minimizing steroid exposure has become a key quality indicator in IBD care[209,210]. Guidelines emphasize restricting corticosteroid use to short induction courses with rapid tapering, ensuring early treatment escalation in steroid-dependent patients. In clinical practice, this requires a structured approach, prioritizing steroid-sparing therapies, regular monitoring, and proactive decision-making to prevent unnecessary corticosteroid prescriptions.
For patients requiring a short course of corticosteroids, topical is preferred over systemic and should be used at the lowest effective dose for the shortest duration to minimize adverse effects. While there is no strict maximum dose in IBD, initiation should not exceed 1 mg/kg or 60 mg/day of prednisolone. Calcium and vitamin D (1500-2000 IU/day) supplementation should be given during steroid treatment. Abrupt withdrawal of ≤ 40 mg/day for up to three weeks is generally safe, but gradual tapering is necessary for higher doses or prolonged use, with reductions of 5-7.5 mg/day during chronic treatment[207]. Caution is needed for patients with repeated steroid courses over three weeks, recent steroid use within a year of stopping long-term therapy, or doses > 40 mg/day. Those at risk of adrenal insufficiency and should undergo adrenal function assessment before complete withdrawal[211].
Statement 99: Corticosteroid use in IBD should be limited to short induction courses with rapid tapering, and prolonged or repeated use should be avoided due to risks including osteoporosis, infections, adrenal insufficiency, and increased mortality (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 100: Patients requiring corticosteroid therapy should receive calcium and vitamin D supplementation, and those at risk of adrenal insufficiency after prolonged use should undergo adrenal function assessment before withdrawal with appropriate referral to endocrinology services (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 82%).
Safety considerations and monitoring with thiopurines and methotrexate: Thiopurines (azathioprine and mercaptopurine) and methotrexate remain widely used immunomodulators in IBD particularly as combination with anti-TNFs to reduce immunogenicity. Despite their efficacy, these agents require careful safety monitoring due to risks of infection, malignancy, hepatotoxicity, and hematologic toxicity. Thiopurines and methotrexate increase susceptibility to opportunistic infections due to their immunosuppressive effects[212,213]. The risk is further amplified when combined with biologics, particularly anti-TNFs[199,214]. Studies indicate that thiopurines are associated with a higher risk of viral reactivations, including Epstein-Barr virus associated lymphoproliferative disorders and HPV related cervical dysplasia[215-217]. A 4-6-fold increased risk of lymphoma has been observed, especially when combined with anti-TNFs as demonstrated with the CESAME and other population wide cohort studies[218,219]. Thiopurine use is also associated with a 2-3-fold increased risk of nonmelanoma skin cancers and a possible increased risk of myeloid neoplasm[220-224]. Thiopurines have been linked to an increased risk of lymphoma, particularly hepatosplenic T-cell lymphoma, a rare but fatal malignancy that predominantly affects young males on long-term therapy[225]. Methotrexate has not been consistently linked to lymphoma in IBD patients, but its use in rheumatoid arthritis (RA) has been associated with lymphoproliferative disorders, particularly Epstein-Barr virus-related cases that may regress upon drug withdrawal[226]. Both thiopurines and methotrexate can cause hepatotoxicity, but the mechanisms differ. Hepatic injury may occur with thiopurines due to direct toxicity (dose-dependent) or idiosyncratic reactions, such as nodular regenerative hyperplasia and vascular complications[227-229]. Long-term use of methotrexate has been associated with fibrosis and cirrhosis, particularly in patients with additional risk factors like obesity, diabetes, or excessive alcohol intake; however, more recent studies suggest this risk may be overstated[170,229]. Thiopurines and methotrexate can induce bone marrow suppression, leading to leukopenia, anaemia, and thrombocytopenia. This is particularly important for patients with thiopurine methyltransferase (TPMT) or nudix hydrolase 15 (NUDT15) deficiencies, which predispose to severe cytopenia with thiopurines TPMT and NUDT15 genotyping may be considered before initiating thiopurines to guide dosing[230-232]. Methotrexate can cause macrocytosis and megaloblastic anaemia due to folate antagonism, which can be mitigated with folic acid supplementation (1-5 mg daily). Complete blood count (CBC) should be monitored frequently when initiated especially thiopurines, followed by 3 months to detect cytopenias[233]. Thiopurines are generally well tolerated but can cause nausea, vomiting, and pancreatitis, which occurs in up to 4% of patients and necessitates discontinuation. Methotrexate occasionally causes nausea and gastrointestinal discomfort, often requiring dose reduction or switching to subcutaneous administration. Rare but serious pulmonary toxicity, including pneumonitis and fibrosis, has been reported with methotrexate, warranting immediate discontinuation if respiratory symptoms develop[170]. Thiopurines are generally safe in pregnancy, with no clear evidence of teratogenicity. They should however not be commenced in pregnancy due to risk of hepatotoxicity and myelosuppression post-initiation[234]. They are compatible with breastfeeding. Methotrexate on the other hand is highly teratogenic and contraindicated in pregnancy due to risks of fetal malformations[235]. It should be discontinued at least 3 months before conception in both men and women. Effective contraception is mandatory during treatment.
Statement 101: Thiopurines require regular monitoring due to risks of opportunistic infections, hepatotoxicity, bone marrow suppression, and malignancy, including an increased risk of lymphoma and nonmelanoma skin cancer; TPMT and NUDT15 genotyping may be considered before initiation to guide dosing (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 91%).
Statement 102: Methotrexate requires routine monitoring for hepatotoxicity, bone marrow suppression, and pulmonary toxicity, with folic acid supplementation recommended to mitigate hematologic toxicity; it is contraindicated in pregnancy and should be discontinued at least three months before conception (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Safety considerations and monitoring with anti-TNF therapies (infliximab, adalimumab, golimumab, certolizumab): Anti-TNF agents whilst being highly effective and pivotal in the management of IBD, their safety profile necessitates thorough monitoring due to potential risks of infection, malignancy, immunogenicity, and metabolic effects. Anti-TNFs carry a black box warning for serious infections, including opportunistic and viral infections[236]. Tuberculosis screening is mandatory before initiation, with and annual re-screening maybe considered in high-risk patients. HBV screening is essential due to risks of viral reactivation. Despite initial concerns, their use has not been associated with severe coronavirus disease 2019 outcomes [adjusted odds ratio (OR) = 0.9; 95%CI: 0.4-2.2][237]. The association between anti-TNFs and malignancy remains debated. Some studies suggest an increased risk of lymphoma (1.5-fold to 4-fold higher), particularly with concomitant thiopurines[219,238]. A potential increased risk of melanoma has also been reported, though this may reflect an intrinsic disease-related predisposition rather than a drug. Data do not support an increased risk of solid organ malignancies[239,240]. The ECCO guidelines suggest avoiding anti-TNFs in active cancer and delaying initiation for at least two years in low-risk malignancies and five years in high-risk cases[241]. Anti-TNFs are contraindicated in patients with New York Heart Association class III/IV heart failure due to increased mortality risks[242]. Furthermore, due to an associated risk with demyelination, anti-TNFs are relatively contraindicated in patients with preexisting multiple sclerosis or other forms of demyelinating diseases[243].
Statement 103: Anti-TNF agents require thorough safety monitoring due to risks of serious infections, malignancy, immunogenicity, and metabolic effects (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 104: Anti-TNFs should be avoided in patients with New York Heart Association class III/IV heart failure, active malignancy, or demyelinating disorders, with treatment initiation delayed for at least two years in low-risk malignancies and five years in high-risk cases (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 91%).
Safety considerations and monitoring with anti-integrins (vedolizumab): Vedolizumab, a gut-selective anti-integrin monoclonal antibody, reduces systemic immunosuppression and has demonstrated a favourable safety profile in both UC and CD compared to other advanced therapies for IBD, with data from randomized trials and long-term extension studies showing no safety signals for infections, malignancies, or hepatic toxicity[244,245]. Long-term safety data from the GEMINI long-term safety program, encompassing 4811 patient-years of exposure, identified no new or unexpected safety signals[244]. A meta-analysis has however suggested a higher incidence of upper respiratory tract infections including nasopharyngitis particularly in UC patients (OR = 1.63; 95%CI: 1.07-2.49)[246]. Theoretical concerns exist regarding its role in modulating immune responses in the lung, as cases of vedolizumab-associated pneumonitis have been reported but remain rare. Progressive multifocal leukoencephalopathy, a serious complication associated with natalizumab, an anti-integrin (a4B1), has not been observed with vedolizumab[247]. Malignancy rates with vedolizumab remain low, with data from GEMINI LTS reporting rates of 17.2 per 1000 patient-years in UC and 20.8 per 1000 patient-years in CD[244]. The most commonly reported malignancies were basal cell carcinoma, lung neoplasms, and colon carcinoma, with no significant increase in overall cancer risk. Notably, in patients with a history of malignancy, vedolizumab has not been linked to increased cancer recurrence [adjusted hazard ratio (HR) = 1.36; 95%CI: 0.27-7.01]. Vedolizumab therefore offers a superior safety profile in patients with prior or active cancer[239]. Vedolizumab has not been associated with significant cardiovascular risks. However, some cases of hepatobiliary events, predominantly cholelithiasis, have been reported in long-term follow-up studies (3.2% in UC, 4.7% in CD). Liver enzyme elevations are usually transient but warrant routine monitoring, and vedolizumab should be discontinued in cases of significant hepatic dysfunction or jaundice. No significant risks with venous thromboembolism (VTE) have been observed with vedolizumab.
Statement 105: Vedolizumab has a favorable safety profile with no significant increased risk of infections, malignancies, or hepatic toxicity; however, routine monitoring of liver function is recommended due to rare hepatobiliary events (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 106: Vedolizumab may be a preferred advanced therapy in patients with a history of malignancy due to its gut-selective mechanism and lack of observed increased cancer recurrence risk (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 91%).
Safety considerations and monitoring with anti-IL-12/IL-23 and anti-IL-23 agents (ustekinumab, risankizumab, mirikizumab, guselkumab): IL-12/IL-23 inhibitors and IL-23s inhibitors have emerged as effective biologics for IBD particularly in refractory cases. The most frequently reported adverse events in trials of these therapies (occurring in approximately 3%-14% of cases) include upper respiratory tract infections, joint pain, injection site reactions, rash, headache, and urinary tract infections, though in clinical practice, these have occasionally been dose-limiting. Hypersensitivity reactions are uncommon (< 1%). A similarly reassuring safety profile has been observed in studies on psoriasis. In registration trials ustekinumab was well tolerated, with adverse events comparable to placebo[145,188]. There were no reported malignancies, opportunistic infections, or tuberculosis cases in the trial cohorts. In both the UNIFI and UNITI long-term extension study, ustekinumab maintained a favorable safety profile, with no new safety signals observed over the follow up periods[146,189]. Long-term extension studies for ustekinumab in CD and UC report malignancy rates of 0.99 and 0.64 events per 100 patient-years, respectively, primarily driven by nonmelanoma skin cancers. No increased risk of lymphoma has been observed. In a cohort study of 390 IBD patients with prior malignancy exposure, ustekinumab did not elevate the risk of cancer recurrence (adjusted HR = 0.96; 95%CI: 0.17-5.41)[248]. Risankizumab demonstrated a favorable safety profile in clinical trials, with no new risks identified during induction or maintenance treatment[148,190,191]. The overall incidence of adverse events was comparable between risankizumab and placebo groups, reinforcing its tolerability as a long-term therapy for UC. Mirikizumab was generally well tolerated in the phase 3 trials, with nasopharyngitis and arthralgia reported more frequently than in the placebo group[150,193]. The overall incidence of adverse events and treatment discontinuations was lower in the mirikizumab group compared to placebo in the VIVID-1. Slight increase in opportunistic infections, specifically herpes zoster and a few cases of malignancy (thought to be unrelated) were observed in the LUCENT trial. Guselkumab was well tolerated in the phase 3 trials, with a safety profile consistent with that observed within the anti-IL-23 class[152]. In the induction study for UC, adverse events were comparable in both guselkumab and placebo-treated patients, with serious adverse events reported in 3% and 7%, respectively. Discontinuation due to adverse events was lower with guselkumab vs placebo. As transient elevation of liver enzymes is observed routine liver enzyme monitoring is recommended during risankizumab induction and up to 12 weeks into maintenance therapy, with discontinuation if there is significant liver dysfunction.
Statement 107: IL-12/IL-23 and IL-23 inhibitors have a favorable safety profile in IBD; however, herpes zoster infections and transient liver enzyme elevations may occur, necessitating routine liver function monitoring evidence level: 2a; strength of recommendation: Strong; consensus agreement: 91%).
Safety considerations and monitoring with JAK inhibitors (tofacitinib, upadacitinib): JAK inhibitors, represent an important class of small molecules for the treatment of IBD. Their safety profile does however necessitate close monitoring due to risks of infection, malignancy, cardiovascular complications, and metabolic disturbances[242]. JAK inhibitors are associated with an increased risk of infections, particularly herpes zoster reactivation, which is dose-dependent[249]. Long-term data from the OCTAVE open study for tofacitinib reported herpes zoster incidence rates of 3.55 per 100 patient-years with 10 mg twice daily dosing[155]. Upadacitinib trials similarly reported herpes zoster in up to 6 per 100 patient-years with 30 mg daily dosing with lower incidence with 15 mg once daily dosing[156,197]. The extended induction period (16 weeks) was associated with an increased incidence of herpes zoster compared to the standard 8-week induction, consistent with the immunosuppressive effects of JAK inhibition. Risk factors for herpes zoster include older age, prior anti-TNF failure, and lower body weight. Recombinant zoster vaccine (Shingrix) is therefore recommended for patients, receiving JAK inhibitors. Other infections, including opportunistic fungal infections and cytomegalovirus, have been observed, though tuberculosis reactivation remains rare. Tofacitinib and upadacitinib carry black box warnings by Food and Drug Administration in the United States for malignancy based on post-marketing surveillance studies in RA. The ORAL surveillance trial, a large safety study in RA patients aged ≥ 50 years with cardiovascular risk factors, reported a higher incidence of malignancies, particularly lung cancer and nonmelanoma skin cancers, in patients receiving tofacitinib compared to TNF inhibitors, although this risk may not be present in IBD patients[250]. Upadacitinib’s pooled safety data show malignancy rates of 1 per 100 patient-years for 30 mg and 0.6 per 100 patient-years for 15 mg, with no observed lymphoma cases. JAK inhibitors have been associated with major adverse cardiovascular events, particularly in older patients with pre-existing cardiovascular disease. The ORAL surveillance trial also demonstrated an increased risk of myocardial infarction, stroke, and cardiovascular death with tofacitinib compared to anti-TNFs, prompting a class-wide warning[250]. In UC clinical trials, upadacitinib did not show a significantly elevated risk of major adverse cardiovascular events[251]. The risk of VTE (deep vein thrombosis and pulmonary embolism) is also dose-dependent, with most cases occurring in patients with pre-existing risk factors such as prior VTE, obesity, or cancer. JAK inhibitors however have been used considered in patients with prior thromboembolic events alongside an anti-coagulant without any additional VTE events, however, the lowest effective dose should be used[252,253]. Dose-dependent elevations in lipid levels, including increased low-density lipoprotein and total cholesterol have been observed which appears reversible with statin therapy. Consequently, lipid monitoring is recommended 8 weeks to 12 weeks after initiation. Elevated liver enzymes (≥ 3 times the upper limit of normal) have been observed in up to 8% of patients receiving tofacitinib and 4% of those on upadacitinib necessitating periodic monitoring of liver enzymes. JAK inhibitors can cause dose-dependent cytopenias, including neutropenia, lymphopenia, and anaemia in which case treatment should be interrupted and the lowest possible dose used. JAK inhibitors have been associated with onset of acne. Gastrointestinal perforations occurred in a few patients. Acne is a known side effect of JAK inhibitors, particularly higher-dose upadacitinib, affecting up to 20% of patients. Studies suggest a 4.8-fold increased risk compared to placebo, with higher rates in younger patients (15-40 years), females, and non-White individuals[254]. While no clear risk factors have been identified, the incidence appears dose-dependent. Counselling patients about this potential side effect can support treatment adherence. JAK inhibitors are contraindicated in pregnancy due to teratogenicity[234].
Statement 108: JAK inhibitors require close monitoring due to potential risks of infections, malignancy, cardiovascular events, thromboembolism, and metabolic disturbances, with recommended screening for CBC, liver function, herpes zoster, lipid levels, and liver function before and during treatment (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 109: JAK inhibitors are contraindicated in pregnancy due to teratogenicity and should be discontinued before conception, with effective contraception advised during treatment (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Safety considerations and monitoring with S1PR modulators (ozanimod, etrasimod): S1PR modulators are safe and effective therapies for UC, however have specific risks unique to this class that warrants additional monitoring[255]. In the True North clinical trial, overall infection rates were comparable between ozanimod (23%) and placebo (12%) in maintenance therapy[158]. However, herpes zoster incidence was higher with ozanimod (2.2% vs 0.4% in placebo). No tuberculosis reactivation cases were reported. Malignancy rates with S1PR modulators low, with True North reporting isolated cases of basal cell carcinoma, colorectal adenocarcinoma, and breast cancer. An interim analysis of the True North open-label extension study found that long-term ozanimod treatment for up to four years in moderately to severely active UC remains well tolerated, with no new safety concerns[256]. Cumulative safety data from 2536 patient-years of exposure showed stable adverse event rates and no increased risk of serious infections or cardiac events.
CBC should be monitored periodically as ozanimod may cause a reversible significant decrease in lymphocyte counts often needing treatment cessation[257]. A small subset of patients may develop severe lymphopenia (< 0.2 × 109/L), in which case discontinuation of therapy is recommended. Upon stopping ozanimod, lymphocyte count typically returns to normal within a median of 30 days, with 90% of patients achieving normalization by 12 weeks although this improvement is much early with etrasimod due to its shorter half-life. S1PR modulation can uniquely cause transient bradycardia and conduction abnormalities, particularly upon initiation[258]. Consequently, baseline electrocardiogram evaluation is recommended in patients and ozanimod should be avoided in patients with significant conduction disorders (Mobitz type II second-degree or third-degree atrioventricular block), pre-existing cardiovascular conditions, stroke, decompensated heart failure, or significant conduction disorders. Blood pressure should be monitored periodically, as hypertension has been reported in clinical trials. Monoamine oxidase inhibitors are contraindicated due to the risk of hypertensive crisis. Ozanimod is associated with liver enzyme elevations (transaminitis) with ≥ 3 × the upper limit of normal occurring in up to 5% of patients necessitating baseline and periodic liver enzymes assessments are recommended before initiation and periodically during therapy[257]. Macular oedema has been reported with S1PR modulators, particularly in patients with diabetes, uveitis, or a history of retinal disease. Patients at risk should undergo baseline ophthalmologic evaluation before starting ozanimod and be monitored for visual disturbances. For patients planning pregnancy, ozanimod should be discontinued at least three months before conception, while etrasimod should be stopped one month prior[259]. Since S1PR modulators are excreted in breast milk, their use during breastfeeding is not recommended due to uncertain clinical effects.
Statement 110: S1PR modulators require monitoring for lymphopenia, liver enzyme elevations, hypertension, and cardiac conduction abnormalities, with baseline and periodic assessments of CBC, liver function, blood pressure, ophthalmic examination and electrocardiogram in at-risk patients (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 111: S1PR modulators are contraindicated in patients with significant cardiac conduction disorders, pre-existing cardiovascular disease, decompensated heart failure, recent stroke, or uncontrolled hypertension, and should not be used in patients taking monoamine oxidase inhibitors (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 112: S1PR modulators are contraindicated in pregnancy due to teratogenicity and should be discontinued before conception, with effective contraception advised during treatment (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
RESPONSE ASSESSMENT, TDM, AND OPTIMIZATION OF ADVANCED THERAPIES IN IBD
Post-induction response assessment and the management of LOR are critical in optimizing long-term outcomes in IBD. This section addresses the assessment and management of inadequate post-induction response and secondary LOR across different biologic and small-molecule therapies, incorporating evidence-based recommendations to optimize treatment durability and patient outcomes.
Post-induction response assessment and management
Response assessment following induction is typically performed between week 10 and week 14, depending on the therapeutic agent, with decisions primarily based on clinical and biomarker response, and less frequently on endoscopic evaluation[61,207]. Ideally, patients should enter clinical remission before transitioning to a maintenance regimen, but in clinical practice, this is not often achievable. The primary objective of induction therapy is to ensure that patients achieve a significant clinical response, allowing them to move forward with maintenance treatment while minimizing disease burden[286,287]. Primary non-response or delayed response to advanced therapies however remains a significant challenge in the management of IBD and affects nearly one third of patients[288]. In cases of primary non-response to advanced therapies, a decision must be made to either switch to a different mechanism of action or consider extended induction. The latter may be appropriate with certain agents where clinical trials have shown benefits, particularly if there is some clinical improvement or an evolving objective response. For instance, fecal calprotectin and CRP trends can help identify delayed responders, who may still benefit from continued therapy, as opposed to true primary non-responders, who require a therapy switch. Extended induction is especially relevant in biologic-experienced patients, where prior exposure may attenuate response rates, and in those with severe disease burden, where remission may take longer to achieve. The rationale lies in pharmacokinetic and pharmacodynamic variability, as some patients require additional time to reach therapeutic drug levels or optimal immune modulation. However, this approach must be carefully balanced against the risk of prolonging active disease and worsening outcomes in true non-responders, where delaying a necessary switch could lead to sustained inflammation, complications, and a poorer disease trajectory. Certain biologics and small molecules have demonstrated benefit with prolonged induction in clinical trials and real-world practice, as outlined later in this guideline.
Statement 117: Response to induction therapy should be assessed between weeks 10 and 14, guided primarily by clinical and biomarker response, with endoscopic evaluation reserved for selected cases (evidence level: 5; strength of recommendation: Strong; consensus agreement: 100%).
Statement 118: Patients should ideally achieve clinical remission before transitioning to maintenance therapy, though in practice, a significant clinical response is an acceptable goal to proceed with maintenance (evidence level: 5; strength of recommendation: Strong; consensus agreement: 100%).
Statement 119: Extended induction may be considered with certain advanced therapies for patients who exhibit an inadequate response following the standard induction phase (evidence level: 2a; strength of recommendation: Conditional; consensus agreement: 91%).
Assessment and management of LOR during maintenance therapy
Non-inflammatory causes can mimic LOR in IBD, leading to unnecessary treatment changes. Functional disorders like IBS and pelvic floor dysfunction are common, with studies estimating that nearly one-third of IBD patients in remission have IBS-like symptoms[289]. Persistent urgency in UC or perianal discomfort in Crohn’s may stem from these issues rather than inflammation. Objective markers such as fecal calprotectin and endoscopy help differentiate functional symptoms from active disease, preventing inappropriate therapy escalation. Conditions such as celiac disease, bile acid malabsorption and small intestinal bacterial overgrowth are frequent in IBD, especially post-surgery[21,22]. Bile acid malabsorption results from impaired bile acid reabsorption, leading to diarrhoea that responds to bile acid sequestrants. Small intestinal bacterial overgrowth, common in patients with strictures or resected bowel, causes bloating and malabsorption and often improves with antibiotics. Recognizing these conditions can prevent misclassification of LOR and unnecessary medication adjustments. Pancreatic exocrine insufficiency and post-surgical complications can also mimic IBD flares. Pancreatic exocrine insufficiency may be seen in Crohn’s patients with extensive small bowel disease, leads to diarrhoea and weight loss but improves with enzyme replacement. Post-surgical issues like anastomotic strictures or pouchitis in UC patients may present with cramping and urgency, requiring imaging or endoscopy to guide management. Differentiating these structural problems from active inflammation is crucial for appropriate treatment[290]. Non-adherence and infections must also be considered. Missed doses of biologics or small-molecule therapies are a major cause of apparent LOR, often revealed by TDM. Infections like Clostridioides difficile or cytomegalovirus colitis can mimic disease flares, particularly in immunosuppressed patients[199]. Properly addressing these issues ensures that therapy adjustments are made based on true disease activity rather than confounding factors.
Once true loss of LOR to an advanced therapy is confirmed, management follows a structured algorithm that includes dose optimization, immunomodulator combination, and therapy switching. Non-immune mediated pharmacokinetic failure, characterized by subtherapeutic drug levels without significant immunogenicity (i.e., absence of neutralizing and non-neutralizing anti-drug antibodies), is typically managed through dose escalation or interval shortening, particularly with monoclonal antibodies. Anti-drug antibodies mediated pharmacokinetic failure is managed by switching within class ideally with the addition of an immunomodulator to prevent further immunogenicity[291]. TDM plays a central role in guiding these decisions in particular for identifying mechanistic failure, where therapeutic drug levels are achieved but the treatment remains ineffective, indicating a need to switch to a different mechanism of action (mechanistic failure)[200]. Reactive TDM, performed in response to LOR or clinical relapse, helps determine whether dose escalation, a switch within class, or a change in mechanism is warranted[292-295]. Proactive TDM, involving routine monitoring regardless of symptoms, aims to maintain therapeutic drug levels while minimizing immunogenicity and treatment failure. If dose intensification and immunomodulator co-therapy fail, switching therapy within or across drug classes is necessary. Within-class switching (e.g., infliximab to adalimumab) is most effective when LOR is immunogenic, as antibodies to one agent do not necessarily cross-react with others in the class[291]. However, if mechanistic failure is suspected - where the targeted inflammatory pathway is insufficient - an out-of-class switch is required. Real-world data suggest diminishing response rates with successive biologic failures, but meaningful clinical remission is still achievable[296,297].
Dual advanced therapy, the concurrent use of two biologic agents or a biologic with a small molecule, is an emerging strategy for patients with highly refractory IBD who have failed multiple lines of therapy[298]. This approach is reserved for the most complex cases, including difficult-to-treat IBD and severe, refractory perianal CD, where conventional monotherapy has been exhausted. The rationale is to target multiple, distinct inflammatory pathways simultaneously to achieve a synergistic effect and overcome treatment resistance. The evidence for dual advanced therapy is primarily derived from observational studies and case series, with RCTs currently lacking. A 2022 systematic review and meta-analysis by which included 279 patients, found that dual therapy was associated with a pooled clinical remission rate of 59% and endoscopic remission of 34%[299]. More recent retrospective data reinforces these findings. A study of 79 patients, primarily on a biologic combined with a JAK inhibitor, reported endoscopic improvement in 69% and clinical improvement in 73% of patients, along with significant reductions in inflammatory markers[300]. Another small case series demonstrated that combining ustekinumab and upadacitinib was effective for both refractory luminal CD and associated extraintestinal manifestations[301].
While these initial results are promising, this strategy is considered off-label and requires careful consideration of safety. The 2022 meta-analysis reported a pooled rate of serious adverse events of 6.5%[299]. The long-term safety profile remains uncertain, and therefore, the decision to initiate dual advanced therapy should be made within a multidisciplinary team at a specialized IBD center. It requires a thorough discussion with the patient about the potential benefits and unknown long-term risks, and close safety monitoring is mandatory. In patients with limited ileal disease, early ileocecal resection has been shown to be a viable alternative to biologic therapy, offering similar long-term outcomes while avoiding prolonged immunosuppression[208,302,303]. For those with refractory or complicated disease, surgery should be considered proactively rather than as a last resort, ideally with bowel-sparing techniques where feasible, as delays can lead to worsening complications, malnutrition, and more extensive resections.
Difficult-to-treat IBD has recently been defined through international consensus as IBD that persists despite optimal use of at least two advanced therapies with different mechanisms of action, recurrent post-operative CD after two bowel resections, chronic antibiotic-refractory pouchitis, complex perianal disease, or psychosocial comorbidities that interfere with care[304]. These patients account for nearly one in four of those receiving biologic or small molecule therapies and often have complex disease phenotypes, including stricturing, penetrating, or perianal CD, or extensive UC[305]. Once such patients are identified, management requires a highly individualized and multidisciplinary approach. Strategies may include combination biologic therapy, advanced TDM, early and proactive surgical intervention, psychological support, and consideration for clinical trial enrolment. Despite limited randomized trial data, observational series and registry data suggest meaningful clinical, biochemical, and even endoscopic responses can still be achieved in difficult-to-treat IBD with appropriate escalation and personalization of care. Proactive referral of such patients to tertiary IBD centers with established multidisciplinary teams capable of offering access to complex treatment strategies, surgical input and clinical trials is encouraged.
Statement 120: LOR is defined as the recurrence of clinical symptoms or objective markers of active disease after an initial response to therapy. In suspected LOR, non-inflammatory conditions such as IBS, bile acid malabsorption, small intestinal bacterial overgrowth, structural complications, and infections should be ruled out before adjusting treatment (evidence level: 5; strength of recommendation: Strong; consensus agreement: 100%).
Statement 121: In confirmed LOR, if pharmacokinetic failure is suspected, ideally guided by TDM, therapy should be intensified or switched within class, particularly for anti-TNF agents. If mechanistic failure is suspected, switching to a therapy with a different mechanism of action should be prioritized (evidence level: 2a; strength of recommendation: Conditional; consensus agreement: 100%).
Statement 122: Dual advanced therapy may be considered in highly refractory cases, particularly for perianal CD with close safety monitoring and informed consent (evidence level: 3b; strength of recommendation: Conditional; consensus agreement: 100%).
Statement 123: Difficult-to-treat IBD should be defined by failure of at least two advanced therapies with different mechanisms of action, recurrent CD following two or more resections, chronic antibiotic-refractory pouchitis, complex perianal CD, or significant psychosocial comorbidities that interfere with management (evidence level: 5; strength of recommendation: Strong; consensus agreement: 100%).
Statement 124: Patients meeting criteria for difficult-to-treat IBD should be referred to a specialized IBD center with access to multidisciplinary care and clinical trials. Early referral ensures timely optimization of complex treatment strategies and access to therapies beyond standard practice (evidence level: 5; strength of recommendation: Strong; consensus agreement: 100%).
Strategies for managing LOR to infliximab
Role of TDM with infliximab: TDM plays a crucial role in optimizing infliximab therapy for patients with UC and CD. Reactive TDM has been the traditional approach, primarily used when patients experience primary non-response or secondary LOR to infliximab. Studies such as personalized anti-TNF therapy in CD (PANTS) have demonstrated that low infliximab trough levels following induction strongly predict treatment failure at one year[306]. Additionally, the CALM study, which used biomarker-based monitoring (CRP and fecal calprotectin) alongside clinical assessments, showed that tight control strategies resulted in higher rates of mucosal healing compared to symptom-based decisions alone[101]. This suggests that early reactive TDM, guided by objective markers rather than symptoms alone, can optimize treatment before clinical deterioration occurs. Furthermore, reactive TDM is more cost-effective than empiric dose escalation and helps guide appropriate therapeutic adjustments, such as dose intensification, interval shortening, or switching therapies[307]. Proactive TDM aims to prevent treatment failure by maintaining adequate drug trough levels throughout therapy. The TAXIT study found no significant improvement in clinical remission rates at one year with proactive TDM compared to standard dosing, though post hoc analyses suggested optimal infliximab levels reduced treatment discontinuation[308]. Similarly, TAILORIX showed no clear advantage of concentration-based dosing over symptom-based adjustments, but delayed dose modifications until week 14, potentially missing an early intervention window[309]. The Norwegian Drug Monitoring trial, which included patients with various immune-mediated diseases, found that proactive TDM improved disease control during infliximab maintenance therapy, though subgroup analyses in IBD were underpowered[310]. Pooled data from RCTs in systematic reviews concluded that proactive TDM did not significantly reduce the risk of failing to maintain clinical remission (RR = 0.96), though it was associated with a higher likelihood of dose escalation[311,312]. The PANTS-extension study, a 3-year follow-up of PANTS, showed that only one-third of infliximab-treated patients remained in remission by year 3, with remission rates dropping from 40.2% at year 1 to 34.7% at year 3 and a 60% LOR[313]. Week 14 drug levels (6.1-10.0 mg/L) strongly predicted long-term remission, while low levels were the strongest predictor of failure (HR = 0.45). By year 3, 44% developed anti-drug antibodies leading to undetectable drug levels, but this was significantly reduced by concomitant immunomodulators (HR = 0.40). HLA-DQA1*05 carriers had a higher risk of anti-drug antibodies (HR = 1.46) and poorer drug persistence, reinforcing the importance of early TDM and possible pharmacogenomic risk stratification. Subcutaneous infliximab provides a more stable pharmacokinetic profile than IV dosing. In the LIBERTY RCT, ADA positivity in the CT-P13 SC groups peaked at week 30 before stabilizing, with rates of 65.1% in CD and 63.8% in UC, compared to 76.2% and 91.8% in placebo groups[136]. Higher anti-drug antibodies titers were associated with lower infliximab trough levels, yet clinical remission and endoscopic response rates remained superior to placebo. For perianal CD, infliximab levels correlate with fistula healing. In ACCENT-II, higher post-induction infliximab concentrations at weeks 2 (≥ 20.2 μg/mL), 6 (≥ 15 μg/mL), and 14 (≥ 7.2 μg/mL) were associated with improved fistula response and composite remission at week 54[273]. Further studies have demonstrated that fistula healing was more likely in patients with trough infliximab levels ≥ 10.1 μg/mL, with a significant stepwise increase in response rates at higher concentrations[314].
Combination therapy with infliximab and an immunomodulator, such as azathioprine or methotrexate, has been shown to reduce immunogenicity and improve drug durability in IBD. The SONIC trial in CD and SUCCESS trial in UC demonstrated that combination therapy led to higher rates of clinical remission and mucosal healing than infliximab monotherapy, primarily by reducing the formation of anti-drug antibodies[93,131]. A post hoc analysis of the SONIC trial demonstrated that the superior remission rates observed with combination infliximab and azathioprine therapy were primarily driven by higher infliximab concentrations and reduced anti-infliximab antibody formation, rather than a true synergistic effect between the two drugs[315]. This effect was further supported by the PANTS study, which found that concomitant immunomodulator use significantly reduced anti-drug antibodies formation and improved infliximab persistence[306]. This was further confirmed through a systematic review that immunomodulator co-therapy was beneficial in preventing LOR to anti-TNF therapy but did not provide additional benefits for non-TNF biologics, such as vedolizumab or ustekinumab[316]. Patients carrying the HLA-DQA1*05 allele, who are at higher risk for anti-drug antibodies development, may particularly benefit from combination therapy. However, the long-term risks of dual immunosuppression, including infections and malignancies, must be carefully balanced against its benefits. Proactive TDM at week 14 post-induction and during maintenance is recommended with infliximab to optimize drug exposure, reduce immunogenicity, and improve long-term outcomes.
Role for dose optimization of infliximab: LOR to infliximab occurs in approximately one-third of CD patients within a year, with an annual risk of 20.9% per patient-year requiring dose intensification[317]. A systematic review found that 38% of infliximab-treated patients required escalation, either by increasing the dose or shortening the infusion interval[317]. A retrospective study reported that 45.7% of patients on long-term infliximab required intensification, with 75.9% regaining response and remaining on therapy[318]. High-dose infliximab (> 10 mg/kg, every 4-7 weeks) has shown clinical benefit in refractory cases, with 84.9% achieving response and significant CRP reductions, but with an increased infection risk (7.41 events per 100 patient-years)[319].
In ASUC, dose intensification of infliximab is often used to improve outcomes in steroid-refractory cases. Standard induction (5 mg/kg at weeks 0, 2, and 6) has modest efficacy, leading to exploration of accelerated induction regimens with higher doses or shortened intervals. A retrospective multicenter study and meta-analysis found no significant difference in colectomy rates between standard and accelerated infliximab induction, though an initial 10 mg/kg dose was associated with lower colectomy rates than 5 mg/kg-based regimens[320]. Similarly, the PREDICT-UC RCT found no advantage of 10 mg/kg over 5 mg/kg in achieving clinical response at day 7, and neither intensified nor accelerated regimens improved remission or colectomy rates at month 3[321]. However, infectious adverse events were more common with early additional doses, emphasizing the need for careful patient selection. While dose intensification remains a widely used strategy, particularly in patients at high risk of early colectomy, randomized data do not currently support routine escalation to 10 mg/kg induction. Dose intensification is an effective strategy to restore response in infliximab-treated CD patients, particularly when guided by TDM and inflammatory biomarkers. High-dose regimens should be reserved for those with persistent inflammation despite standard intensification, balancing efficacy with infection risk. These findings reinforce the value of proactive TDM, particularly early during induction, to optimize infliximab exposure, prevent immunogenicity, and improve long-term outcomes. However, proactive TDM alone may not be sufficient for all patients, underscoring the need for personalized treatment strategies integrating TDM, pharmacogenomics, and disease severity assessments.
Statement 125: Proactive TDM at week 14 post-induction and during maintenance is recommended with infliximab to optimize drug exposure, reduce immunogenicity, and improve long-term outcomes. Reactive TDM should be used to guide dose adjustments in cases of primary nonresponse or secondary LOR (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 126: Dose intensification with infliximab, either through interval shortening or higher dosing, is effective for secondary LOR due to low drug levels in absence of anti-drug antibodies and should be guided by TDM (evidence level: 2a; strength of recommendation: Conditional; consensus agreement: 100%).
Statement 127: In acute severe UC, accelerated induction or higher initial doses of infliximab may be considered in steroid-refractory cases, but randomized data do not support routine escalation to 10 mg/kg induction. Patient selection should be guided by clinical and biomarker indicators (evidence level: 1b; strength of recommendation: Conditional; consensus agreement: 82%).
Strategies for managing LOR to adalimumab
Role of TDM with adalimumab: While proactive TDM has been widely studied for infliximab, data on adalimumab remain limited[294,322]. The CLASSIC I and CLASSIC II studies demonstrated that patients achieving remission had significantly higher median adalimumab concentrations than non-responders, particularly in the early weeks of treatment[323]. However, considerable interpatient variability and overlapping drug levels between responders and non-responders highlighted the limitations of using fixed concentration cutoffs to predict clinical outcomes reliably. The PAILOT study, a RCT in paediatric CD, demonstrated that children undergoing proactive TDM achieved higher rates of sustained corticosteroid-free remission from week 8 through week 72 compared to those managed with reactive TDM[324]. A multi-center retrospective study found that at least one proactive TDM measurement during adalimumab maintenance therapy was independently associated with a lower risk of treatment failure (HR = 0.4, P = 0.022)[325]. The PANTS-extension study reported that by the end of year 3, only 28.9% of adalimumab-treated patients remained in remission[313]. Low week 14 adalimumab concentrations (optimal range: 10.1-12.0 mg/L) were strongly predictive of LOR by year 3 (HR = 0.39). ADA formation was lower with adalimumab (20.3%) than infliximab (44.0%) but was linked to undetectable drug levels rather than directly to treatment failure. HLA-DQA1*05 carriers had a higher risk of LOR (HR = 1.95), while concomitant immunomodulator use significantly reduced ADA formation (HR = 0.42).
The SERENE CD and SERENE UC trials explored adalimumab’s exposure-response relationship, highlighting its pharmacokinetic complexities[326,327]. While higher drug concentrations within treatment arms correlated with better outcomes, escalating the induction dose did not improve short-term remission or endoscopic response. Patients with lower baseline drug clearance responded better, emphasizing individual pharmacokinetics in treatment success. During maintenance, higher average drug concentrations were linked to improved outcomes at week 52, reinforcing the importance of dose optimization in this phase. Observational data suggest adalimumab trough levels ≥ 8-12 μg/mL improve endoscopic outcomes in CD. Proactive TDM, with individualized adjustments rather than fixed cutoffs or dose escalation, is crucial for long-term treatment success.
Role for dose optimization of adalimumab: Adalimumab dose intensification remains a key strategy for managing LOR in IBD, but its efficacy is variable. The SERENE CD and SERENE UC trials evaluated whether higher induction doses of adalimumab improved clinical and endoscopic outcomes in CD and UC[328,329]. Despite increasing drug exposure, higher induction dosing did not result in superior short-term efficacy compared to standard induction, with similar rates of clinical remission and endoscopic response. In the maintenance phase, no significant differences were observed between a clinically adjusted strategy and a proactive TDM strategy at week 56. However, the trials used a relatively low target trough concentration of 5 μg/mL for dose adjustments, which may have limited the potential benefit of proactive TDM. Studies such as PANTS suggest that higher trough levels (≥ 12 μg/mL) are associated with better long-term remission, and the SERENE trials’ cap on dose escalation at 10 μg/mL may have constrained optimization[313,330]. While higher maintenance dosing (40 mg weekly) in SERENE UC showed a trend toward improved remission at week 52, this did not reach statistical significance, and the exploratory TDM arm did not outperform fixed dosing. Adalimumab dose intensification is therefore recommended with post-induction proactive TDM targeting adalimumab trough levels > 12 μg/mL to optimize drug exposure and reduce the risk of early LOR. This approach allows for timely dose adjustments before clinical deterioration. In the maintenance phase, reactive TDM can guide effective dose intensification in patients experiencing secondary LOR, ensuring individualized therapy adjustments based on pharmacokinetics and inflammatory burden.
Statement 128: TDM for adalimumab is recommended, as higher drug levels correlate with improved long-term outcomes. Proactive TDM, post-induction, may optimize drug exposure and reduce early LOR (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 82%).
Statement 129: Dose intensification with adalimumab to 40 mg weekly may be considered for LOR, guided by reactive TDM. Higher induction dosing has not demonstrated superior efficacy, but maintenance dose adjustments based on pharmacokinetics and inflammatory burden may improve outcomes (evidence level: 1b; strength of recommendation: Conditional; consensus agreement: 100%).
Strategies for managing LOR to golimumab
Role of TDM with golimumab: Golimumab TDM in UC remains an evolving area with limited data compared to infliximab and adalimumab. The PURSUIT induction study found that higher serum golimumab concentrations at week 6 were associated with improved clinical and endoscopic outcomes, with a suggested target concentration of ≥ 2.5 μg/mL[331]. Similarly, in the PURSUIT maintenance study, steady-state trough concentrations ≥ 1.4 μg/mL were linked to sustained clinical remission, with golimumab concentrations stabilizing after week 14 regardless of the induction regimen. Immunomodulator use had no significant effect on serum golimumab concentrations with the 100 mg dose but was associated with slightly higher drug levels in the 50 mg group. Notably, antibodies to golimumab were rare (approximately 3%), suggesting a lower immunogenicity risk than other anti-TNF agents. Additional real-world studies further support the exposure-response relationship of golimumab in UC. The GO-LEVEL study identified 3.8 μg/mL at week 6 as the optimal threshold for achieving clinical and biochemical remission, with patients above this level having significantly better outcomes[332]. During maintenance, a trough concentration of ≥ 2.4 μg/mL was associated with sustained remission, reinforcing the potential role of TDM in optimizing long-term efficacy. An observational study demonstrated that week 6 golimumab levels > 5.1 μg/mL correlated with a higher likelihood of clinical response at week 14, while lower levels were linked to non-response[333]. Overall, these studies highlight that higher drug exposure is associated with better clinical outcomes, and while golimumab TDM remains investigational, early proactive monitoring to ensure adequate trough levels may be beneficial in optimizing response and preventing secondary loss of efficacy.
Role for dose optimization of golimumab: Golimumab dose intensification has been explored as a strategy to recapture response in patients with UC experiencing LOR or insufficient initial response. The PURSUIT-M post-hoc analysis demonstrated that non-responders to induction who were escalated to 100 mg maintenance dosing at week 6 had a 28.1% response rate at week 14, with long-term outcomes similar to early responders, suggesting that early intensification may be beneficial, particularly in patients with high drug clearance[334]. A prospective study further highlighted the need for dose optimization, showing that 76% of patients < 80 kg required intensification to 100 mg every 4 weeks and that week 6 golimumab levels > 10.7 μg/mL predicted higher endoscopic remission rates at week 14 and year 1, whereas levels < 5.1 μg/mL identified non-responders[335]. A prospective multicentric study evaluating dose intensification, found that 44% of patients recaptured response and 41% achieved endoscopic improvement following escalation to 100 mg every 4 weeks or 100 mg every 2 weeks[336]. However, baseline drug levels and anti-drug antibodies did not predict response. These findings collectively advocate for a proactive dose escalation strategy in UC patients with an inadequate response to golimumab, incorporating reactive TDM to guide optimization[337].
Statement 130: The role of TDM in golimumab remains unclear, though higher drug levels correlate with improved outcomes. While early proactive monitoring may help optimize response, routine TDM is not currently recommended (evidence level: 3b; strength of recommendation: Conditional; consensus agreement: 82%).
Statement 131: Dose intensification with golimumab to 100 mg every 4 weeks may be considered for UC patients with inadequate response, as it can recapture response in select cases. Proactive optimization strategies incorporating TDM may further enhance outcomes (evidence level: 2a; strength of recommendation: Conditional; consensus agreement: 82%).
Strategies for managing LOR to certolizumab
Role of TDM with certolizumab: TDM for certolizumab pegol in CD remains less established due to limited data compared with infliximab and adalimumab. A post hoc analysis of the endoscopic mucosal improvement trial demonstrated that higher certolizumab plasma concentrations at week 8 were associated with improved endoscopic response and remission at weeks 10 and weeks 54[338]. A seven-year longitudinal study found that while 22.6% of patients exhibited transient ADA with no significant impact on drug levels or inflammatory markers, 77.4% developed persistent ADA, which were associated with significantly lower certolizumab concentrations and higher CRP and fecal calprotectin levels[339]. An exposure-response study utilizing a population pharmacokinetic model across nine clinical trials found that higher certolizumab concentrations at weeks 6 and weeks 12 correlated with better clinical remission, biomarker responses (CRP ≤ 5 mg/L, fecal calprotectin ≤ 250 μg/g), and composite disease control at weeks 6 and weeks 26[340]. Although no definitive therapeutic thresholds have been established, certolizumab levels of ≥ 36.1 μg/mL at week 6 and ≥ 14.8 μg/mL at week 12 were associated with improved outcomes[341].
Role for dose optimization of certolizumab: Dose intensification of certolizumab pegol in CD has shown mixed results. A compassionate-use study found that intensifying certolizumab to 200 mg every other week successfully achieved remission in 5 of 6 refractory patients who had previously failed infliximab and/or adalimumab. However, the WELCOME trial, a 26-week open-label study, evaluated certolizumab in 539 patients with moderate-to-severe CD who had lost response to infliximab[342]. After an induction phase of certolizumab 400 mg at weeks 0, 2, and 4, patients in response at week 6 (62%) were randomized to maintenance therapy every 2 or 4 weeks. By week 26, 40% of patients on 4-weekly certolizumab and 37% on 2-weekly certolizumab maintained clinical response (P = 0.55), while remission rates were 29% and 30%, respectively (P = 0.81). These findings indicate that while certolizumab remains an option for patients failing infliximab, empirical/non-TDM based dose intensification does not universally improve outcomes[343].
Statement 132: TDM for certolizumab pegol in CD remains exploratory, with emerging evidence suggesting higher drug levels correlate with improved outcomes. However, no definitive therapeutic thresholds have been established, and its routine use is not recommended (evidence level: 3b; strength of recommendation: Conditional; consensus agreement: 91%).
Statement 133: Dose intensification with certolizumab may be considered for refractory CD, but available data show mixed results, and non-TDM-based escalation does not consistently improve outcomes (evidence level: 3b; strength of recommendation: Conditional; consensus agreement: 91%).
Strategies for managing LOR to vedolizumab
Role of TDM with vedolizumab: The exposure-efficacy relationship for vedolizumab was reported in the post hoc analysis of the GEMINI trials[344]. In UC, patients achieving trough levels > 35.7 μg/mL at week 6 had higher clinical remission and mucosal healing rates, while levels above 30-38 μg/mL have been linked to better long-term outcomes, including deep remission at week 52. In CD, the exposure-response relationship is less pronounced, but higher trough levels (≥ 10-15 μg/mL during maintenance) have been associated with improved outcomes. A further post hoc comparative analysis of the GEMINI and VISIBLE studies found that exposure-efficacy relationships for IV and subcutaneous injection vedolizumab were comparable in both UC and CD. Predicted steady-state concentrations were similar for IV (once every 8 weeks) and subcutaneous injection-every other week, while IV (once every 4 weeks) resulted in higher exposure which correlated with greater efficacy. The LOVE-CD trial of vedolizumab for patients with active CD demonstrated that higher vedolizumab concentrations at weeks 2, 10, and 22 correlated with improved endoscopic outcomes in CD, with week 22 trough levels > 10 μg/mL predicting endoscopic remission at week 26[345]. A multicenter prospective study found that vedolizumab trough levels > 18 μg/mL at week 6 were predictive of mucosal healing within the first year of treatment[346]. A retrospective study found that 61.1% of vedolizumab trough levels during maintenance therapy were < 20 μg/mL, with 81.5% of patients on once every 8 weeks dosing having low levels. Increasing to once every 4 weeks dosing improved trough levels, but 30.6% remained below 20 μg/mL, suggesting some patients may require alternative therapy[347]. Unlike anti-TNF agents, vedolizumab has a lower rate of immunogenicity (< 5%), and combination therapy with immunomodulators does not appear to significantly alter drug levels or improve efficacy.
Role for dose optimization of vedolizumab: In CD patients with primary non-response to vedolizumab, a week 10 dose may help optimize treatment by allowing additional time for response. In GEMINI 2, enhanced clinical response rates improved at week 10 (16%) and week 14 (22%), compared to placebo (7% and 12%), though clinical remission differences were not significant[183]. However, week 52 data suggest that patients who responded at week 10 or 14 had better long-term outcomes, supporting the week 10 dose as a strategy to extend induction for delayed responders before discontinuing treatment. The role of an additional week 10 dose in UC has not been reported or confirmed, and its clinical benefit in UC remains uncertain. The GEMINI trials established the efficacy and safety of vedolizumab 300 mg IV infusions for moderate-to-severe UC and CD, with maintenance dosing every 4 weeks (once every 4 weeks) or 8 weeks (once every 8 weeks) showing comparable remission rates[143,183]. While dose intensification to once every 4 weeks is commonly used in clinical practice for patients with inadequate or lost response on once every 8 weeks, it has not been systematically studied in a controlled setting[348,349]. The phase 4 ENTERPRET trial assessed vedolizumab dose optimization in UC patients with early nonresponse and high drug clearance[350]. Patients with serum levels < 50 μg/mL at week 5 and nonresponse at week 6 were randomized to standard dosing (300 mg, every 8 weeks) or dose intensification (600 mg at week 6; then 300 mg or 600 mg, every 4 weeks). At week 30, endoscopic improvement (18.9% vs 14.5%) and clinical remission (9.4% vs 9.1%) were similar between groups, suggesting dose intensification may not be necessary in early non-responders. In the VISIBLE OLE study, patients with UC (n = 70) and CD (n = 131) who had treatment failure on vedolizumab SC every other week were dose-escalated to once a week. At 8 weeks post-escalation, 61.7% of UC and 45-51.5% of CD patients achieved a clinical response, with 17%-33.3% (UC) and 32.4%-33.3% (CD) in clinical remission[351]. By week 48, response rates declined to 34.2% (UC) and 25%-51.5% (CD), with remission in 13.2%-19.0% (UC) and 14.8%-22.2% (CD). A systematic review and meta-analysis of 10 cohort studies found LOR rates of 47.9 per 100 person-years in CD and 39.8 per 100 person-years in UC, with dose intensification restoring response in 53.8% of secondary non-responders[352]. However, high variability in response rates (I2 = 77%) suggests that not all patients benefit from this strategy. More recently, the LOVE-CD trial evaluated vedolizumab dose intensification in CD patients with endoscopic primary non-response after 26 weeks of standard dosing. Despite higher trough levels in the intensified group (46.4 μg/mL vs 16.3 μg/mL, P < 0.001), no improvement was seen in endoscopic or clinical remission at week 52, indicating ineffectiveness in primary endoscopic non-responders[353]. These findings suggest utility of dose escalation with vedolizumab is uncertain but may benefit early responders, though long-term durability remains uncertain. The VERDICT RCT is currently investigating optimal treatment targets in moderate-to-severe UC by comparing symptomatic, endoscopic, and histologic remission[111]. Treatment escalation follows a vedolizumab-based algorithm, incorporating dose intensification as needed until the target is achieved. This trial will provide valuable insights into whether vedolizumab dose intensification improves the likelihood of reaching these treatment targets.
Strategies for managing LOR to ustekinumab
Role of TDM with ustekinumab: The exposure-efficacy relationship for ustekinumab has been explored in both UC and CD, with higher drug concentrations correlating with improved clinical and endoscopic outcomes[292]. In the UNITI trials for CD, demonstrated that higher ustekinumab levels at week 8 were associated with increased clinical remission rates, with optimal thresholds of 3.3 μg/mL at week 8 and 0.8-1.4 μg/mL during maintenance[188]. A similar trend was observed in the UNIFI trials for UC, where remission was associated with levels of 3.7 μg/mL at week 8 and 1.3 μg/mL during maintenance[145]. The STARDUST trial, which compared a treat-to-target approach vs standard care in CD, found that patients with higher ustekinumab levels were more likely to achieve normalization of CRP and fecal calprotectin, though a relationship with levels and clinical remission was not observed[103,354]. Immunogenicity remains low, with ADA formation occurring in < 5% of patients, and combination therapy with immunomodulators does not appear to significantly impact drug levels[355,356]. The role of routine TDM to guide dose adjustments at present remains unclear for ustekinumab and not significantly appear to impact clinical decision-making or correlate with short-term outcomes in CD[357].
Role for dose optimization of ustekinumab: The STARDUST trial evaluated ustekinumab dose intensification using a treat-to-target approach based on endoscopic and biomarker assessments in patients with moderately active CD[103]. After standard IV induction, all patients received SC ustekinumab 90 mg every 8 weeks, but those in the treat-to-target arm had dose escalation to 90 mg every 4 weeks at week 16 if they had persistent ulcers or elevated inflammatory markers. In the standard of care arm, escalation occurred only for clinical relapse. By week 48, more treat-to-target patients underwent intensification, but endoscopic remission rates were similar, suggesting that proactive escalation may aid mucosal healing but does not consistently achieve deep remission. Observational studies support ustekinumab dose intensification for CD patients with inadequate response to standard dosing. Dose intensification - via interval shortening or IV re-induction - was effective in over 50% of patients at week 16[358-360]. Shortening the dose interval to every 4 weeks improved HBI, CRP, and fecal calprotectin, with 28% achieving clinical remission. IV re-induction led to response in 64% at week 8 and 53% at week 16. While these findings support the role of dose intensification in managing refractory CD, the randomized POWER trial failed to meet its primary endpoint, suggesting that IV re-induction may provide some benefit but is not universally effective[361]. A systematic review and meta-analysis of 15 cohort studies including 925 CD patients found that ustekinumab dose escalation - either through reinduction or interval shortening - was effective in 55% of cases[362]. More recently, however, the REScUE study, a randomized placebo-controlled trial in CD, found that in patients with secondary LOR, IV re-induction followed by every 4 weeks maintenance was not superior to every 8 weeks maintenance in achieving steroid-free remission at week 48 (17% vs 16%, P = 0.96), though endoscopic and biomarker responses were numerically higher in the intensified group. These findings suggest that while some patients may benefit, routine every 4 weeks escalation after IV re-induction does not provide a consistent advantage over standard dosing[363].
Statement 134: TDM for vedolizumab is not routinely recommended, though higher drug levels correlate with improved outcomes. Immunogenicity is low, and combination therapy with immunomodulators does not significantly impact drug levels (evidence level: 3b; strength of recommendation: Conditional; consensus agreement: 100%).
Statement 135: An additional week 10 dose may be considered for delayed responders to vedolizumab in CD, though its benefit in UC remains uncertain. Dose intensification of vedolizumab to once every 4 weeks can restore response in some secondary non-responders but is not effective for primary non-response (evidence level: 1b; strength of recommendation: Conditional; consensus agreement: 100%).
Statement 136: TDM for ustekinumab is not routinely recommended, as no clear exposure-efficacy targets exist, and immunogenicity is low and combination therapy with immunomodulators does not significantly impact drug levels (evidence level: 3b; strength of recommendation: Conditional; consensus agreement: 100%).
Statement 137: Dose intensification with ustekinumab, including interval shortening or IV reinduction, may be considered for patients with secondary LOR in CD, as observational data suggest clinical benefit in select cases. However, randomized trials have not consistently demonstrated superiority of IV reinduction followed by every 4 weeks maintenance over standard dosing (evidence level: 2a; strength of recommendation: Conditional; consensus agreement: 100%).
Strategies for managing LOR to risankizumab
Role of TDM with risankizumab: There is limited data to support TDM for risankizumab in CD and UC. Exposure-response analyses from FORTIFY indicate that higher serum drug concentrations correlate with improved clinical and endoscopic outcomes, though this effect plateaus at induction doses above 600 mg and maintenance doses exceeding 360 mg in CD[191,364]. While modelling suggests that increased serum levels may lead to marginal clinical benefits beyond these thresholds, no definitive TDM targets have been established[364]. Unlike anti-TNFs, immunogenicity appears to have minimal impact on risankizumab exposure, with anti-drug antibodies formation occurring in approximately 1%-3% of patients.
Role for dose optimization of risankizumab: Extended induction with risankizumab improved outcomes in CD and UC patients who did not respond to the initial 12-week induction in their respective phase 3 clinical trials. In CD, 62.3%-76.2% achieved clinical response and 18.0%-32.5% achieved endoscopic response by week 24, with sustained benefits at week 52 (56.7%-69.7% maintained clinical response, and 40.0%-42.4% achieved endoscopic remission)[365]. Similarly, in UC, 50.0%-57.1% achieved clinical response and 8.8%-15.7% achieved remission by week 24, with continued response (45.3%-46.4%) and remission (17.9%-22.8%) at week 52[366]. Extended induction was well tolerated in both cases, with no new safety concerns.
Rescue therapy with risankizumab has been explored as potentially an effective strategy for patients experiencing inadequate response during maintenance therapy[367]. In the FORTIFY trial, patients with CD experiencing LOR (either on active treatment or on placebo withdrawal group) received a single ‘rescue’ IV 1200 mg dose followed by 360 mg subcutaneously every 8 weeks[368]. Among those requiring rescue, 52.5%-75.0% achieved clinical response, while 20.0%-36.4% attained clinical remission or endoscopic response by week 52. Dose intensification of risankizumab has also been explored as a strategy to recapture response in patients with CD who experience a loss of efficacy on standard maintenance dosing. A retrospective study from Mass General Brigham reported that among 22 patients with prior LOR to standard maintenance dosing, escalation to every 4 weeks or 6 weeks led to a 64% clinical response rate, with 45% achieving steroid-free remission[369]. HBI scores improved significantly, while reductions in CRP and fecal calprotectin were not statistically significant. A further study found that among 12 intensified patients, 50% improved and 25% remained stable, with persistent inflammation or symptoms driving escalation after a median of three injections on standard dosing[370]. Both studies highlighted access challenges due to insurance barriers. A smaller United Arab Emirates study showed that intensification to every 4 weeks restored response in 4 of 6 patients with secondary LOR[371]. Rescue data and dose intensification outcomes for UC with risankizumab however have as yet not been reported.
Statement 138: TDM for risankizumab is not recommended in view of very low anti-drug antibody rates and the absence of defined exposure-efficacy targets (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 139: Extended induction with risankizumab with a further three IV induction doses may be considered for non-responders at week 12 in CD and UC. In CD, a single IV rescue dose of 1200 mg or dose intensification to 4 weekly subcutaneous maintenance injections may be considered for secondary LOR. There is currently insufficient evidence to recommend dose intensification for UC (evidence level: 2a; strength of recommendation: Conditional; consensus agreement: 82%).
Strategies for managing LOR to mirikizumab
Role of TDM with mirikizumab: TDM for mirikizumab in IBD remains exploratory, with data from phase 3 trials for UC (LUCENT) and CD (VIVID) suggesting low immunogenicity and minimal impact of anti-drug antibodies on efficacy[150,193,372]. In LUCENT, 23.6% of patients developed anti-drug antibodies over 52 weeks, but only 2% had high-titter anti-drug antibodies linked to reduced drug levels and response. A post-hoc analysis of phase 2 and 3 data from the UC trials initially suggested an exposure-response relationship, but this was later attributed to confounding factors, indicating that fixed dosing is appropriate without the need for routine dose adjustments[373]. Similarly, in CD, 12.6% of mirikizumab-treated patients developed treatment-emergent anti-drug antibodies, the majority with low titre (< 1:160). High-titre ADAs (≥ 1:160) were not associated with reduced efficacy, as clinical remission and endoscopic improvement rates at week 52 were comparable between anti-drug antibodies-positive and anti-drug antibodies-negative groups. While further studies may refine its role, current evidence does not strongly support TDM for mirikizumab.
Role for dose optimization of mirikizumab: Extended induction with mirikizumab has been explored in UC as an alternative strategy for patients with a delayed response. In the LUCENT trial, 53.7% of patients who did not achieve a clinical response by week 12 responded after an additional 12 weeks of induction, with 72.2% achieving clinical response and 43.1% achieving endoscopic remission by week 52[374]. Long-term follow-up at week 152 showed that 50.0% to 72.2% of those in clinical remission at week 52 remained in corticosteroid-free remission, while 38.6% to 57.4% of those who had achieved clinical response at week 52 sustained remission[375]. Currently, there are no reported data on dose intensification strategies for mirikizumab in UC or CD.
Statement 140: Routine TDM for mirikizumab is not recommended due to its low immunogenicity and minimal impact of anti-drug antibodies on efficacy. Fixed dosing is appropriate based on current evidence (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 141: Extended induction with mirikizumab may be considered for UC patients with a delayed response, as an additional 12 weeks of induction has shown benefit. However, there is currently insufficient evidence to recommend dose intensification strategies for mirikizumab in UC or CD (evidence level: 2a; strength of recommendation: Conditional; consensus agreement: 100%).
Strategies for managing LOR to guselkumab
Role of TDM with guselkumab: The available data on guselkumab suggest that the incidence of anti-drug antibodies and neutralizing antibodies is low in the phase 3 UC RCT (QUASAR)[152]. Among patients who did develop anti-drug antibodies, the titres were generally low and did not impact serum drug concentrations, efficacy, or safety. The full publication for the phase 3 CD RCT (GALAXI-IV induction), and the subcutaneous induction trials ASTRO and GRAVITI has not yet been published, but these are likely to yield further information about the pharmacokinetic profile of guselkumab. The role for TDM with guselkumab at present remains limited.
Role of dose optimization of guselkumab: Dose intensification with guselkumab has not yet been formally studied, but clinical trial data suggest potential benefits, particularly in CD. The QUASAR trial in UC and the GALAXI 2 and 3 trials in CD evaluated maintenance dosing at 100 mg every 8 weeks and 200 mg every 4 weeks. In UC, clinical remission at week 44 was only slightly higher with 200 mg every 4 weeks (50%) vs 100 mg every 8 weeks (45%), with similar trends in endoscopic improvement (48% vs 45%) and corticosteroid-free remission (30% vs 26%), suggesting minimal additional benefit from higher dosing[152]. In CD, the differences were more pronounced, with clinical remission at week 48 reaching 66.1% for 200 mg every 4 weeks vs 60.0% for 100 mg every 8 weeks, alongside higher endoscopic response and deep remission rates with every 4 weeks dosing[195]. In the GRAVITI study evaluating subcutaneous guselkumab for CD, at week 48, clinical remission was achieved in 60.0% of patients receiving 100 mg every 8 weeks and 66.1% of patients receiving 200 mg every 4 weeks, compared to 17.1% in the placebo group (P < 0.001 for both comparisons)[196]. Endoscopic response rates at week 48 were also significantly higher, with 44.3% of patients achieving response with 100 mg every 8 weeks and 51.3% with 200 mg every 4 weeks, vs 6.8% with placebo (P < 0.001 for both comparisons). However, whether patients losing response or experiencing inadequate response to 100 mg every 8 weeks would benefit from dose intensification to 200 mg every 4 weeks remains unclear. The guselkumab trials compared guselkumab naive patients assigned to each regimen from the outset, rather than assessing whether patients failing 100 mg every 8 weeks could recapture response through escalation. While higher doses showed better outcomes in CD, these trials do not establish dose intensification as a real-world rescue strategy in patients with inadequate outcomes on 100 mg every 8 weeks dosing. Based on a possible dose exposure efficacy relationship, escalation to 200 mg every 4 weeks may however be considered on a case-by-case basis.
Statement 142: TDM for guselkumab is not currently recommended due to the low incidence of anti-drug antibodies and neutralizing antibodies, with no significant impact on drug levels, efficacy, or safety (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 143: There is currently insufficient evidence to recommend extended induction with guselkumab for post-induction primary non-response or inadequate response. The role of dose intensification following LOR with guselkumab remains undefined, but based on clinical trial data, escalation to 200 mg every 4 weeks may be considered in patients on 100 mg every 8 weeks on an individual basis in CD (evidence level: 2a; strength of recommendation: Conditional; consensus agreement: 91%).
Strategies for managing LOR to JAK inhibitors-tofacitinib and upadacitinib
Role for TDM with JAK inhibitors: TDM is not required for JAK inhibitors, including tofacitinib and upadacitinib, due to their predictable pharmacokinetics and lack of immunogenicity. Tofacitinib exhibits rapid absorption with peak plasma concentrations occurring approximately one-hour post-dose and follows a one-compartment pharmacokinetic model with dose-proportional exposure, maintaining stable plasma levels during both induction and maintenance therapy. Population pharmacokinetic analysis indicates minimal impact of patient-specific factors on drug clearance, supporting fixed dosing[376]. Similarly, upadacitinib’s pharmacokinetic analysis in UC and CD shows that plasma exposure associated with the 45 mg daily induction dose maximizes efficacy, and maintenance with 30 mg daily provides additional benefit, particularly in sustaining remission and endoscopic improvement[377,378]. As both drugs exhibit predictable dose-response relationships, routine TDM is not necessary.
Role for dose optimisation for tofacitinib: Extended induction of tofacitinib in UC has been explored as a strategy for patients who do not achieve a clinical response after the standard 8-week induction period with 10 mg twice a day. Data from the OCTAVE open study demonstrated that an additional 8 weeks of induction therapy with tofacitinib 10 mg twice a day resulted in a clinical response in 52.2% of patients who had not responded at week 8, bringing the total proportion of responders to 74.6% after 16 weeks of induction therapy[155,379,380]. A comparable safety profile to 8 weeks’ induction therapy was observed. Real-world studies have corroborated these findings, indicating that up to half of non-responders may still achieve a clinical response with extended induction[381,382]. However, product labelling for tofacitinib does not currently recommend induction therapy beyond 16 weeks, necessitating careful patient selection for extended induction. For patients who experience LOR to tofacitinib maintenance therapy, dose escalation from 5 mg twice a day to 10 mg twice a day has been shown to recapture response in a significant proportion of cases[383]. In the OCTAVE open study, among patients who experienced treatment failure after being randomized to tofacitinib 5 mg twice a day, dose escalation to 10 mg twice a day recaptured clinical response in 57.9% of patients at month 2 and 64.9% at month 12[383]. Similarly, patients who experienced a flare after dose reduction to 5 mg twice a day, were able to regain response following dose escalation, with 73.2% achieving remission at month 3. Dose escalation with tofacitinib to 10 mg twice a day therefore can be effective for patients losing response to tofacitinib, especially those with prior TNF exposure, but must be weighed against risks such as VTE and herpes zoster.
Role for dose optimization for upadacitinib: The study on extended induction with upadacitinib in UC demonstrated that patients who failed to respond after 8 weeks of 45 mg once daily could benefit from an additional 8 weeks, with 59.1% achieving clinical response by week 16[384]. At week 52 of maintenance, remission rates were higher with 30 mg once daily (43.6%) than 15 mg once daily (26.5%), with greater endoscopic improvement in the 30 mg group. Patients with a partial response by week 8 (based on reduction in full Mayo score > 0.7 points) were twice as likely to respond by week 16, suggesting early improvement predicts success with extended induction. While efficacy was lower than in standard 8-week responders, extended induction remains a viable option for refractory patients. Safety data showed an increased incidence of herpes zoster with prolonged 45 mg exposure, but no new safety signals emerged. In CD, patients who did not respond to the standard 12-week induction with upadacitinib 45 mg once daily demonstrated delayed response with extended induction, albeit with a lower dose at 30 mg once daily, for an additional 12 weeks[385]. By week 24, 52.7% achieved symptom-based clinical response, 35.9% had a CDAI response, and 13.2% showed endoscopic improvement. At week 52, efficacy was generally sustained, with 23.5% in CDAI remission and 11.8% achieving endoscopic remission. The safety profile remained consistent with prior upadacitinib studies, with Crohn’s worsening being the most common adverse event and isolated cases of arterial thrombosis and non-melanoma skin cancer.
The U-ACTIVATE study assessed the efficacy and safety of upadacitinib retreatment in patients with UC who lost response following treatment withdrawal[386]. This phase 3 open-label extension included patients from the U-ACHIEVE and U-ACCOMPLISH trials who had initially achieved a clinical response after 8 weeks of induction with upadacitinib 45 mg once daily but were subsequently randomized to placebo during maintenance. Of the patients assigned to placebo, 50.2% lost response and entered the U-ACTIVATE long-term extension study. Patients more likely to experience LOR post-withdrawal included those with prior inadequate response or intolerance to at least one biologic (57.1% vs 46.8%) and those requiring corticosteroids at baseline (42.0% vs 33.3%). Patients who lost response were restarted on upadacitinib 15 mg once daily, with outcomes assessed at week 4. Among the 108 evaluable patients, 69.4% achieved clinical response, and 36.1% reached clinical remission. For those with inadequate response to 15 mg once daily, dose escalation to 30 mg once daily was permitted between weeks 2 and 36, with outcomes assessed at week 48. Among the 38 patients who required escalation, 96.8% achieved clinical response, and 71.0% achieved remission. Exposure-adjusted event rates were similar in patients who underwent dose escalation compared to all. The CELEST study, a phase 2 trial evaluating upadacitinib in CD, demonstrated that dose escalation from 12 mg twice a day to 24 mg twice a day (immediate release formulation) in patients with inadequate response improved clinical and endoscopic outcomes[387]. In the CELEST open-label extension study, 23 patients (21.5%) initially on upadacitinib 15 mg once daily required dose escalation to 30 mg once daily after experiencing LOR[388]. At month 30, 55% of these dose-escalated patients achieved clinical remission, while 65% maintained an enhanced clinical response. Endoscopic response was observed in 40% at month 24, though this was lower than the rates seen in the non-escalated groups. Safety concerns included higher rates of infections, serious adverse events, and herpes zoster in the 30 mg once daily group compared to 15 mg once daily, reinforcing the need to balance efficacy benefits against potential risks with dose intensification. Real-world data on upadacitinib dose intensification in UC and CD are limited, with emerging reports showing some success in recapturing response through re-escalation to 30 mg once daily or reinduction with 45 mg once daily[389-392]. While dose intensification may benefit select patients, it must be balanced against safety concerns, including risks of VTE, herpes zoster, and potential malignancy with prolonged higher dosing. Further studies are needed to define its long-term efficacy and safety.
Statement 144: TDM is not recommended for JAK inhibitors, including tofacitinib and upadacitinib, due to their predictable pharmacokinetics, dose-proportional exposure, and lack of immunogenicity (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 145: Extended induction with tofacitinib (10 mg twice a day for up to 16 weeks) may be considered in UC patients who do not respond after 8 weeks; however, it should be used selectively due to a lack of long-term safety data. Dose escalation from 5 mg twice a day to 10 mg twice a day can recapture response in some patients but must be weighed against potential risks, including VTE and herpes zoster (evidence level: 2a; strength of recommendation: Conditional; consensus agreement: 91%).
Statement 146: Extended induction with upadacitinib (16 weeks in UC, 24 weeks in CD) may be considered for delayed responders, while dose intensification to 30 mg once daily can recapture response in some patients. However, safety concerns, including VTE, herpes zoster, and malignancy, should be carefully considered before dose intensification. (evidence level: 2a; strength of recommendation: Conditional; consensus agreement: 91%).
Strategies for managing LOR to S1PR modulators-ozanimod and etrasimod
Role of therapeutic drug monitoring: The pharmacokinetics of both ozanimod and etrasimod are linear, dose-proportional, and subject to low to moderate intersubject variability[393,394]. TDM is not needed for these S1PR modulators due to its predictable pharmacokinetics and lack of immunogenicity.
Role of dose optimization: Etrasimod has a shorter half-life and fewer drug-drug and food interactions as compared to the ozanimod and in addition, no dosing titration is required. Extended induction was only reported with ozanimod in the True North and open-label extension which showed some benefit however the data on duration of extended treatment and durability of response is unclear[395]. There are currently no studies evaluating management of LOR with S1PR modulators.
Statement 147: TDM is not recommended for S1PR modulators due to predictable pharmacokinetics and lack of immunogenicity. There is insufficient evidence to recommend extended induction or dose optimization strategies for managing LOR (evidence level: 3b; strength of recommendation: Conditional; consensus agreement: 100%).
Discontinuation of advanced therapies in sustained remission
The decision to discontinue or de-escalate advanced therapy in patients who have achieved sustained, deep remission is a significant clinical consideration, balancing the desire to reduce treatment exposure against the risk of disease relapse. While most evidence pertains to anti-TNF agents, the principles and emerging data for other therapies are critical for shared decision-making.
Discontinuation of anti-TNF therapy: Discontinuation of infliximab or concomitant immunomodulators in patients with CD who achieve sustained remission is a common consideration due to concerns about long-term immunosuppression, safety risks, cost, and patient preference. However, the risk of disease relapse must be carefully weighed. A meta-analysis of 10 RCTs demonstrated that stopping biologic therapy significantly increased relapse risk in CD, while withdrawing an immunomodulator from combination therapy had no major impact on relapse rates[396]. The HAYABUSA trial further underscored this risk with biologics, finding in patients with UC in remission that discontinuing infliximab led to significantly lower remission rates at 48 weeks (54.3%) compared to continuing infliximab (80.4%), although most patients who relapsed responded effectively to infliximab re-treatment[397]. The SPARE trial, a multicentre RCT, further compared the withdrawal of infliximab vs immunomodulator in patients in stable corticosteroid free clinical remission on combination therapy for at least 6 months[398]. At two years, relapse rates were highest in the infliximab withdrawal group (35%) compared to those who continued combination therapy (12%) or withdrew immunomodulators (9%). Additionally, in the EXIT study, clinical remission rates at one year were similar between those who stopped anti-TNF therapy and those who continued it (76% vs 84%), but patients in the withdrawal group showed higher rates of endoscopic inflammation and elevated fecal calprotectin reinforcing the importance of biomarker monitoring when considering therapy withdrawal[399]. A retrospective cohort study that discontinuation of immunomodulators did not increase short-term LOR to infliximab over 1-2 years but was associated with a twofold increase in anti-drug antibodies formation and declining infliximab trough levels[400]. These findings emphasize that while stopping immunomodulator therapy may be feasible, regular TDM should be implemented to ensure infliximab levels remain within the therapeutic range and to detect early immunogenicity.
Given the findings from the SPARE trial, thiopurine withdrawal can be considered in adult patients with CD who have been in steroid-free clinical remission for more than six months, provided they meet certain criteria. Ideally candidates should have sustained deep remission, including clinical, biochemical (normal CRP, fecal calprotectin), and endoscopic remission, and stable infliximab trough levels above 10 μg/mL with no detectable anti-drug antibodies. Additionally, HLA-DQA1*05-negative patients, who have a lower risk of anti-drug antibodies formation, may be better candidates for immunomodulator withdrawal. Regardless of the approach, close post-withdrawal monitoring with biomarker assessments (CRP, fecal calprotectin) and scheduled TDM is critical to identifying early signs of relapse or declining infliximab levels.
Discontinuation of other biologics and small molecules: Evidence for the de-escalation or discontinuation of biologics other than anti-TNFs and small molecules is sparse, though recent studies are providing more clarity[401]. For vedolizumab, the risk of relapse after discontinuation appears high. The retrospective GETAID-Vedo-STOP study found that 64% of IBD patients relapsed within a median of one year after stopping vedolizumab[402]. Similarly, the prospective POLONEZ study showed that among UC patients in remission who discontinued therapy, 37% relapsed within 26 weeks[403]. The retrospective REVEUS study, which included both UC and CD patients stopping either vedolizumab or ustekinumab, reported relapse rates of approximately 20% at 12 months, 42% at 24 months, and 52% at 48 months[404]. The REVEUS study also highlighted that patients with UC were more likely to relapse early than those with CD, but importantly, that retreatment with the same biologic was successful in over 80% of patients who flared. There is currently no published evidence regarding discontinuation for the newer anti-IL-23 agents (risankizumab, mirikizumab, guselkumab). For small molecules, no formal withdrawal studies in patients in remission exist apart from limited case series that report high rates of relapse[405,406]. Given this lack of evidence, any decision to de-escalate or discontinue non-anti-TNF biologics or small molecules must be highly individualized, undertaken with caution, and involve a thorough discussion with the patient about the potential for relapse and the limited data on successfully recapturing response.
Statement 148: Stopping infliximab may significantly increase relapse risk in CD and UC. Discontinuation should only be considered in carefully selected patients with sustained deep remission, with close monitoring for early signs of disease recurrence (evidence level: 1a; strength of recommendation: Conditional; consensus agreement: 100%).
Statement 149: Thiopurine withdrawal may be considered in patients with CD in sustained steroid-free clinical remission on combination therapy with infliximab for at least 6 months, particularly in those with stable infliximab trough levels and low immunogenicity risk. Post-withdrawal monitoring with biomarkers and scheduled TDM is essential to detect early relapse (evidence level: 1b; strength of recommendation: Conditional; consensus agreement: 100%).
Statement 150: There is currently insufficient evidence to recommend the routine discontinuation of non-anti-TNF biologics or small molecules in patients in remission. The limited data available suggest a significant risk of relapse upon withdrawal. Therefore, any decision to stop therapy must be individualized, balancing the risks of long-term drug exposure against the consequences of a disease flare, and made with caution (evidence level: 4; strength of recommendation: Conditional; consensus agreement: 100%).
SPECIAL CONSIDERATIONS IN IBD
This section of the guideline reviews the current clinical evidence guiding the positioning of therapies for special populations in IBD, including ASUC, CD-related strictures, perianal fistulizing disease, intra-abdominal abscesses, postoperative CD, and IBD in pregnancy and postpartum. The recommendations incorporate comparative efficacy data, risk stratification, and evolving treatment paradigms to optimize management strategies in these complex scenarios.
ASUC
ASUC is distinct from moderate-to-severe UC in that it is associated with higher morbidity and a significant risk of colectomy[58,407]. Despite advances in therapy, approximately 30%-40% of patients with ASUC require surgery during their first hospitalization or subsequent flares[408]. The rapid progression of inflammation in ASUC makes early recognition and timely intervention critical in avoiding complications such as toxic megacolon, perforation, or life-threatening sepsis.
Classification of ASUC: ASUC is defined by the presence of at least six bloody stools per day combined with one or more markers of systemic toxicity, including tachycardia (pulse > 90 beats per minute), fever (> 37.8 °C), anaemia (haemoglobin < 10.5 g/dL), and elevated inflammatory markers (CRP > 30 mg/L or ESR > 30 mm/hour)[57]. These criteria have remained the gold standard for defining ASUC although additional scoring indices such as the Lichtiger index have been developed to refine risk stratification[409].
Initial assessment and general medical: The initial assessment of ASUC includes routine blood tests and stool studies to rule out infections like Clostridioides difficile, which increases morbidity and colectomy risk. Abdominal X-ray is essential to detect toxic megacolon (> 6 cm dilation). Flexible sigmoidoscopy with biopsy helps evaluate disease activity and screen for cytomegalovirus infection based on specific criteria which may worsen outcomes in steroid-refractory UC[199]. IV ganciclovir is used for severe cytomegalovirus-associated disease, with immunosuppressive therapy continuing unless disseminated cytomegalovirus occurs. Endoscopic scoring systems such as UCEIS and Mayo score help predict the need for rescue therapy or colectomy. Screening for latent tuberculosis and hepatitis B and hepatitis C is recommended before initiating advanced therapies as part of a rescue strategy in the event of steroid non-response.
Initial management and response assessment: Patients with ASUC should be admitted under a gastroenterology team, with early involvement of a colorectal surgeon upon admission to facilitate timely surgical decision-making if needed. Comprehensive management includes thromboprophylaxis due to the increased VTE risk in IBD, nutritional assessment with enteral support for malnourished patients, and fluid and electrolyte correction[58,410]. Routine parenteral nutrition and total bowel rest are not recommended, as enteral nutrition is safer and more effective. IV corticosteroids remain the cornerstone of initial therapy for ASUC, dramatically reducing mortality rates from 22%-75% in the pre-steroid era to < 1% in the present day. The pivotal Truelove and Witts’s study in 1955 demonstrated that IV hydrocortisone significantly improved outcomes in severe UC patients compared to placebo[57]. The recommended corticosteroid regimen consists of IV methylprednisolone (60 mg/day) or hydrocortisone (100 mg every 6 hours) for 3-5 days. Studies have consistently shown no additional benefit from higher doses[411,412]. A meta-analysis evaluating dose escalation in ASUC found that methylprednisolone doses > 60 mg/day did not improve clinical outcomes and were associated with a higher risk of adverse effects, including hyperglycaemia, secondary infections, and psychiatric complications[412,413].
Response assessment is crucial, with the Travis criteria being the most widely used ASUC risk stratification tool[59]. On day 3 of corticosteroids, patients with > 8 stools/day or ≥ 3 stools/day with CRP > 45 mg/L have an 85% risk of colectomy, warranting early escalation to rescue therapy or surgery. Patients showing improvement can continue IV corticosteroids for 5-7 days, followed by oral prednisolone (40 mg/day) with a gradual 5 mg/week taper. However, non-responders must promptly be considered for salvage therapy (infliximab or cyclosporine). Steroid responders, however, are conventionally transitioned to azathioprine for maintenance. However, the ACTIVE trial found that in ASUC patients responding to steroids, combination therapy with infliximab and azathioprine was more effective than azathioprine alone, with treatment failure at 52 weeks occurring in 81.5% of the azathioprine group vs 53.3% in the infliximab plus azathioprine group (P = 0.03)[99]. These findings suggest that early infliximab plus azathioprine may improve long-term outcomes in ASUC responders.
Salvage therapy for steroid-refractory ASUC: Approximately 30%-40% of ASUC patients fail to respond to IV corticosteroids and require second-line rescue therapy, with infliximab and cyclosporine being the most established options. An RCT of infliximab for ASUC showed that a single 5 mg/kg dose of infliximab reduced 3-month colectomy rates by 50%, leading to its widespread use, particularly in anti-TNF-naive patients[414]. The standard infliximab induction regimen (5 mg/kg IV at weeks 0, 2, and 6) is followed by maintenance dosing every 8 weeks, with thiopurine co-therapy improving drug persistence and reducing anti-drug antibody formation. An RCT exploring cyclosporine for ASUC reported an 82% response rate with IV cyclosporine (4 mg/kg/day) compared to placebo, with later studies confirming similar efficacy at lower doses (2 mg/kg/day), reducing toxicity[409]. However, cyclosporine requires transition to thiopurine or vedolizumab for long-term remission and is limited by risks of nephrotoxicity, hypertension, and opportunistic infections. Direct comparisons between infliximab and cyclosporine in steroid-refractory ASUC have been evaluated in two landmark RCTs. The CYSIF trial (2012) found no significant difference in treatment failure rates (54% for infliximab vs 60% for cyclosporine), suggesting both therapies are viable options[415]. Similarly, the CONSTRUCT trial (2016, United Kingdom) demonstrated comparable colectomy-free survival at 12 months-36 months, though infliximab was associated with higher treatment costs[416]. While both therapies remain viable second-line options, the decision between infliximab and cyclosporine should be individualized based on prior therapy exposure, clinician expertise, and potential toxicity concerns[410].
The PREDICT-UC RCT evaluated accelerated infliximab dosing in steroid-refractory ASUC[321]. Among 138 patients, high-dose infliximab (10 mg/kg) was compared to standard-dose infliximab (5 mg/kg), with standard dosing further split into accelerated (0, 7, 21 days) and conventional (0, 14, 42 days) regimens. At day 7, clinical response rates were similar (65% vs 61%, P = 0.62), with no significant difference in 12-month colectomy-free survival (7%, 22%, and 15%, P = 0.13) or infliximab rescue success (83%, 81%, and 80%, P = 0.93). A post hoc analysis suggested a possible benefit in hypoalbuminemic patients (albumin < 25 g/L) and those with CRP > 50, but results were not statistically significant. These findings indicate that standard infliximab dosing remains appropriate, though select subgroups may benefit from dose optimization. Given the rapid advancements in ASUC treatment, JAK inhibitors, specifically tofacitinib and upadacitinib, are emerging as effective rescue therapies for steroid-refractory ASUC, offering oral administration, rapid onset, and colectomy-free survival rates of approximately 80%[417]. The TACOS trial demonstrated superior response with tofacitinib (10 mg, three times daily) plus steroids vs steroids alone (83% vs 59%, P = 0.007)[418]. Upadacitinib has shown promising results in ASUC, with the largest observational study including 25 patients, 9 of whom were anti-TNF naive[419]. Upadacitinib was administered at 45 mg daily or at a high-intensity, off-label dose of 30 mg twice daily alongside corticosteroids, reporting a 76% colectomy-free rate and rapid symptom improvement within 24 hours. A network meta-analyses in rescue therapies for ASUC, that did not include upadacitinib in the analysis suggest superior induction efficacy of tofacitinib over infliximab, both JAK inhibitors appear to offer similar colectomy-free survival ASUC[420]. A recent review of 30 studies (373 patients) on tofacitinib and 10 studies (74 patients) on upadacitinib in ASUC reported a weighted mean colectomy-free survival rate of 82% and 79%, respectively[417]. Current data do not reveal any new safety concerns when JAK inhibitors are used in ASUC, though follow-up periods remain short, and long-term safety data are needed to fully assess risks. JAK inhibitors may be considered on a case-by-case basis as rescue therapy for ASUC in patients with prior exposure and mechanistic LOR to infliximab. Their role as first-line therapy at present remains undefined, however, multiple studies are currently ongoing to further explore the role of JAK inhibitors in ASUC. The TRIUMPH study is evaluating tofacitinib as second-line therapy, while the SMART study (NCT05867329) is assessing upadacitinib as a first-line alternative to IV steroids[421]. The TOCASU trial (NCT05112263) is directly comparing tofacitinib vs cyclosporine in ASUC. Current guidelines advise against sequential therapy (for example JAK inhibitors or cyclosporine after infliximab failure or vice versa) due to high complication risks and worse surgical outcomes from delayed colectomy[58,200]. Studies report remission rates of 33%-60%, but adverse events occur in up to 23%, including serious infections and mortality[422-424]. A systematic review of 314 patients found short term clinical remission in 38.9%, with colectomy rates of 28.3% at 3 months and 42.3% at 12 months[424]. Given these risks, sequential therapy should be avoided, except in specialized centers with close monitoring and thorough patient counselling.
Surgical management in ASUC: Current guidelines recommend colectomy for patients who fail to respond within 7 days of rescue therapy, have developed complications such as a toxic megacolon or are not candidates for medical treatment. However, with advancing treatment options and the use of IUS to objectively assess improvement or worsening of mucosal disease, daily reassessment is essential for timely decision-making especially in view of varying response times[200,410,425]. A multidisciplinary approach ensures accurate risk evaluation, close monitoring, and a balanced discussion on surgical timing and benefits. In emergency cases, a subtotal colectomy with ileostomy is the preferred approach, avoiding pelvic dissection to reduce complications and maintain future restorative options. For patients opting for ileal pouch-anal anastomosis (IPAA), pouch creation is typically performed three to six months later, though it carries potential complication such as a greater risk of pouchitis, leakage, and potential fertility concerns[426].
Statement 151: IV corticosteroids remain the cornerstone of initial therapy for ASUC, with early response assessment using Travis criteria at day 3 to identify patients requiring rescue therapy (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 152: Rescue therapy with infliximab or cyclosporine is recommended for steroid-refractory ASUC, with the choice guided by prior therapy exposure, clinician expertise, and potential toxicity concerns. Sequential rescue therapy (e.g., cyclosporine or JAK inhibitors after infliximab failure) should generally be avoided due to high complication risks (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 91%).
Statement 153: Early involvement of a colorectal surgeon is essential for patients with ASUC, with colectomy recommended for those failing to respond within 7 days of rescue therapy, developing complications (e.g., toxic megacolon, perforation), or being unsuitable for medical therapy (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 154: JAK inhibitors may be considered as rescue therapy for steroid-refractory ASUC in selected patients, though their role as first-line rescue therapy remains under investigation (evidence level: 1b; strength of recommendation: Conditional; consensus agreement: 100%).
Management of CD related strictures
CD-associated strictures result from a complex interplay of chronic inflammation, fibrosis, and muscular hypertrophy, leading to luminal narrowing and obstructive symptoms[427,428]. While strictures can be classified as inflammatory or fibrotic, most exhibit a mixed pathology. Diagnosis requires a combination of endoscopic assessment and cross-sectional imaging (MRE/CTE) and IUS, to determine stricture morphology, length, and the presence of pre-stenotic dilation. All IBD strictures should be biopsied to exclude malignancy. In UC, colonic strictures are considered malignant until proven otherwise, and Crohn’s strictures, especially new or rapidly progressing ones, also require biopsy[429,430].
Medical therapy remains the first-line approach for inflammatory strictures, with anti-TNF agents (adalimumab, infliximab) being the most studied[426]. The CREOLE study demonstrated that 64% of CD patients with symptomatic small bowel strictures achieved treatment success with adalimumab at 24 weeks, with nearly half maintaining prolonged success at 4 years[431]. Additionally, over 50% of patients avoided bowel resection within four years. The STRIDENT trial demonstrated that 79% of CD patients with symptomatic strictures receiving intensive adalimumab plus thiopurine therapy improved at 12 months, compared to 64% on standard adalimumab[432]. However, evidence for the efficacy of newer agents such as ustekinumab, risankizumab, and upadacitinib remains limited. Endoscopic balloon dilation (EBD) is an option for fibrotic strictures < 5 cm without deep ulceration or penetrating complications, with systematic reviews showing a 52% rate of repeat dilation within 12 months and a 30% likelihood of surgical resection[34,423,433,434]. In cases where EBD fails, endoscopic stricturotomy or self-expanding metal stents may be considered, though the evidence for these approaches are still evolving[34,428,435,436]. Surgical intervention is required for strictures refractory to medical and endoscopic therapy, particularly those with penetrating complications (fistulae, abscesses) or significant pre-stenotic dilation. The choice between ileocolic resection and stricturoplasty depends on disease location, bowel preservation, and prior surgeries[437]. The BACARDI risk model identified pre-stenotic dilation, CRP > 11 mg/L, Montreal B3 phenotype, prior/current anti-TNF exposure, and NOD2 risk allele presence as independent predictors for surgery where patients would benefit from early resection rather than prolonged ineffective medical therapy[438]. Despite advances in medical and endoscopic therapy, nearly half of patients with strictures require surgery within five years. A multidisciplinary approach integrating gastroenterologists, surgeons, radiologists, and IBD specialists remains essential to optimising stricture management.
Statement 155: Medical therapy remains the first-line approach for inflammatory CD-associated strictures, with anti-TNF agents such as infliximab, particularly in combination with thiopurines, demonstrating the strongest evidence for treatment success (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 156: EBD should be considered for fibrotic strictures < 5 cm without deep ulceration or penetrating complications, with repeat dilations required in over half of cases within 12 months (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 91%).
Statement 157: Surgical intervention is indicated for strictures refractory to medical or endoscopic therapy, particularly in the presence of penetrating complications or significant pre-stenotic dilation, with the choice between resection and stricturoplasty guided by bowel preservation principles (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Management of perianal fistulizing CD
Perianal fistulizing CD is a debilitating phenotype of CD, affecting up to 25% of patients and leading to significant morbidity, including pain, fecal incontinence, recurrent infections, and increased healthcare utilization[439,440]. The primary goal of treatment is to achieve fistula healing while maintaining sphincter integrity, thereby improving the patient’s QoL. Medical management remains the cornerstone of therapy, with biologic agents playing a critical role. However, before initiating biologic therapy, adequate sepsis control is essential. Short term antibiotics, particularly ciprofloxacin and metronidazole, are often used as first-line therapy to reduce bacterial load and control infection in active fistulizing disease[441]. An RCT demonstrated that the combination of ciprofloxacin with infliximab significantly improved fistula response rates compared to infliximab alone[442,443]. In addition, examination under anaesthesia with drainage of abscesses and seton placement is recommended prior to starting biologics to prevent secondary infection, although recent data for benefits of seton placement is conflicting[436,444,445]. Failure to control perianal sepsis before biologic initiation increases the risk of treatment failure, abscess recurrence, and hospitalization.
Anti-TNF agents such as infliximab and adalimumab have the strongest evidence for efficacy, demonstrating significantly higher rates of fistula closure compared to placebo in RCTs[446]. The ACCENT II trial showed that infliximab led to fistula closure in 36% of patients at one year, compared to 19% with placebo[176]. The optimal trough level for infliximab in perianal fistulizing CD is suggested to be ≥ 15 μg/mL, with higher levels correlating with improved rates of fistula healing[292]. Adalimumab has also demonstrated efficacy, though some studies suggest that higher drug concentrations > 12 μg/mL are needed to maintain fistula closure. Upadacitinib, an oral JAK inhibitor, has shown efficacy in perianal fistulizing CD. A post hoc analysis of three phase 3 trials (U-EXCEL, U-EXCEED, U-ENDURE) found that upadacitinib 45 mg led to fistula drainage resolution in 44.7% vs 5.6% with placebo (P = 0.003) and closure of external openings in 22.1% vs 4.8% (P = 0.013) at induction[447]. During maintenance, upadacitinib 15 mg and 30 mg maintained higher fistula closure rates than placebo. Alternative biologic therapies, such as vedolizumab and anti-IL agents, have shown promise, albeit with lower rates of fistula closure compared to anti-TNF agents[446,448]. Mesenchymal stem cell therapy has emerged as a novel approach, with randomized trials demonstrating a significant benefit in fistula healing, particularly in refractory cases, although clinical trial outcomes have been conflicting due to various reasons[449-453]. Hyperbaric oxygen therapy and exclusive enteral nutrition have also been explored as adjunctive options, but robust evidence supporting their routine use is lacking[440,454].
Combined anti-TNF with surgical intervention remains essential for optimizing outcomes, particularly in complex fistulas[440,455]. The use of setons to maintain drainage and prevent abscess formation is standard practice, with studies suggesting that seton placement combined with anti-TNF therapy leads to superior healing rates compared to either modality alone. However, prolonged seton use may delay definitive closure, and its role in long-term outcomes remains debated[456]. Other surgical techniques include fistulotomy, advancement flaps, ligature of the intersphincteric fistula tract, and stem cell-based therapies, which have shown promise in select patients[457]. A systematic review and meta-analysis found that while combining medical and surgical therapy does not significantly improve fistula closure rates compared to anti-TNF therapy alone, it does yield better outcomes than surgery alone[458]. Fecal diversion, using a loop ileostomy or colostomy, is a surgical option for severe or refractory perianal CD[459]. While it improves symptoms in many patients, nearly half may require permanent diversion due to persistent rectal inflammation or strictures. The management of perianal fistulizing CD necessitates a multidisciplinary approach integrating gastroenterologists, colorectal surgeons, and radiologists. Early initiation of biologic therapy, aggressive infection control, and individualized surgical strategies are key to otimizing outcomes.
Statement 158: Infliximab in combination with azathioprine is the preferred first-line biologic therapy for perianal fistulizing CD (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 159: Before initiating biologic therapy, adequate perianal sepsis control through examination under anaesthesia, abscess drainage, and seton placement is recommended to reduce the risk of treatment failure and recurrent infections (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 160: Combination therapy with infliximab and surgical interventions, including seton placement, is associated with superior outcomes in complex fistulizing CD compared to either modality alone (evidence level: 2a; strength of recommendation: Strong; consensus agreement: 100%).
Statement 161: Upadacitinib may be considered as a preferred second-line option over other agents for perianal fistulizing CD in patients with failure or intolerance to anti-TNF therapy (evidence level: 2b; strength of recommendation: Weak; consensus agreement: 100%).
Management of intra-abdominal abscess in CD
Penetrating CD complicated by intra-abdominal abscesses can occur in 10% to 30% of patients[460]. Management of intra-abdominal abscesses requires a multifaceted approach involving antimicrobial therapy, drainage procedures, surgical intervention and long-term disease control with advanced therapies[208]. These decisions are individualized based on abscess size, location, associated fistulas or strictures, and overall disease severity. Initial management involves IV broad-spectrum antibiotics targeting gram-negative bacilli, anaerobes, and gram-positive organisms[461]. Empirical options include piperacillin-tazobactam, carbapenems, or a third-generation cephalosporin with metronidazole. Antibiotics alone are rarely curative, and duration depends on drainage efficacy - typically 3-7 days if drainage is successful, but longer if incomplete. Supportive care, including IV fluids, bowel rest, and nutritional optimization, is crucial, especially for malnourished patients will may benefit from exclusive enteral nutrition or total parenteral nutrition if exclusive enteral nutrition is not tolerated[462]. Corticosteroids should be avoided due to their association with increased septic complications and poor surgical outcomes. Immunosuppressive therapies, including advanced therapies, should generally be withheld until abdominal sepsis is controlled[463].
The optimal approach to abscess drainage is influenced by abscess size, location, and the presence of associated fistulas or strictures. Percutaneous drainage is the preferred initial strategy when feasible and has been associated with a high success rate in retrospective studies[464]. A large cohort study from the Mayo clinic demonstrated that percutaneous drainage and surgery (bowel resection) had comparable abscess recurrence rates (31.2% vs 20.3%), and percutaneous drainage allowed for early initiation of biologic therapy while avoiding the need for a stoma[465]. However, meta-analyses suggest that up to 70.7% of patients initially treated with percutaneous drainage ultimately require surgery, particularly in cases of large, multiloculated, or fistulizing abscesses[464]. The success of percutaneous drainage is influenced by several factors, including abscess size (< 6 cm), absence of complex fistulas, fibrostenotic disease or pre-stenotic dilatation and the ability to achieve adequate drainage[463,466]. When percutaneous drainage is unfavorable, fails or is not technically feasible, surgical intervention becomes necessary.
The timing of surgery for intra-abdominal abscesses in CD is critical. In unstable patients with uncontrolled sepsis, emergent surgery for source control is required. For those who stabilize with antibiotics and percutaneous drainage, elective surgery can be deferred by a few weeks to optimize nutritional status and facilitate a bowel-sparing resection[200,208]. Studies indicate that delaying surgery after initial percutaneous drainage improves perioperative outcomes, reduces the need for fecal diversion, and lowers postoperative complications[467]. When surgery is necessary, the decision between segmental resection with primary anastomosis or staged surgery with a diverting stoma depends on disease extent, bowel wall integrity, and active peritonitis. A diverting stoma is often warranted in malnourished patients or those on prolonged immunosuppression due to the increased risk of anastomotic leak. Following abscess resolution and sepsis control, long-term disease control with biologic therapy is critical to prevent recurrence and disease progression.
Statement 162: Percutaneous drainage is generally preferred to surgical drainage for intra-abdominal abscesses in CD when feasible, as it may enable earlier biologic therapy and avoid immediate surgery. However, select patients may respond to antibiotics alone, particularly for smaller or less complex abscesses. Surgery should be considered if drainage is not feasible, unsuccessful, or if sepsis persists (evidence level: 2b; strength of recommendation: Strong; consensus agreement: 100%).
Management of post-operative CD
Post-operative recurrence remains a significant clinical challenge in the management of CD. Among patients who undergo ileocecal resection, endoscopic recurrence occurs in 40% within the first-year post-surgery[468]. The primary goal of post-operative management is to prevent endoscopic recurrence, as this precedes clinical recurrence and future surgical interventions. Effective risk stratification is crucial in guiding post-operative treatment decisions. Several well-defined risk factors have been consistently associated with a higher likelihood of post-operative recurrence. These include smoking, a history of prior resection/s, penetrating (B3) or perianal disease, younger age (< 30), and histologic markers such as granuloma or myenteric plexitis in resection specimen[469,470]. Patients who exhibit these risk factors are at the greatest risk for early disease recurrence and should be considered for immediate post-operative biologic therapy. ECCO guidelines recommend prophylactic therapy after intestinal resection only in high-risk patients, based on risk stratification[469]. In contrast, AGA guidelines advocate for early prophylactic treatment in all patients with surgically induced remission of CD, which has been supported by recent observational studies[470-472].
Infliximab remains the most extensively studied biologic for the prevention of post-operative recurrence. The PREVENT trial demonstrated that infliximab significantly reduced endoscopic recurrence rates (22.4% vs 51.3% in placebo, P < 0.001) at 76 weeks post-surgery[473]. However, while there was a trend toward lower clinical recurrence, the difference did not reach statistical significance (12.9% vs 20.0%, P = 0.097). Another RCT compared adalimumab, azathioprine, and mesalamine, finding that adalimumab resulted in the lowest recurrence rates (6.3% vs 64.7% with azathioprine and 83.3% with mesalamine)[474]. The REPREVIO trial randomized patients within 4 weeks of ileocolonic resection to receive either vedolizumab (300 mg IV) or placebo every 8 weeks[475]. At week 26, vedolizumab was shown to significantly reduced endoscopic recurrence, with 77.8% probability of a lower modified Rutgeerts score compared to placebo (P < 0.0001). Severe recurrence (i2b or higher) was less frequent with vedolizumab (23.3%) compared to placebo (62.2%, P = 0.0004). There are currently no RCT data for other advanced therapies in prevention on post-operative recurrence. A recent network meta-analysis compared the efficacy of anti-TNFs, vedolizumab, ustekinumab, and immunomodulators across RCTs and observational studies found that anti-TNFs were the most effective in preventing clinical recurrence, while vedolizumab ranked highest for preventing endoscopic recurrence[476]. These findings reinforce that anti-TNFs remain the preferred first-line therapy, with vedolizumab as a reasonable alternative in select cases. Alternative advanced therapies such as those within the IL class or upadacitinib may however be considered on an individualised basis.
In patients not commenced on early prophylactic therapy, endoscopic assessment remains the gold standard for evaluating post-operative recurrence and guiding therapy. The Rutgeerts score, provides a structured grading system based on the severity of mucosal lesions at the neoterminal ileum, helping determine the need for treatment escalation[76]. It categorizes post-operative disease activity into five levels, with i0 (no lesions) and i1 (≤ 5 aphthous ulcers) considered low risk, while i2 (≥ 5 aphthous ulcers or lesions at the anastomosis), i3 (diffuse inflammation with larger ulcers), and i4 (severe inflammation with stricturing/nodular lesions) indicating progressive risk of recurrence. The modified Rutgeerts score refines risk assessment by distinguishing i2a (isolated anastomotic lesions) from i2b (≥ 5 ulcers or larger lesions extending into the neoterminal ileum). i2a lesions are generally benign, while i2b lesions carry a higher risk of clinical recurrence. The POCER trial reinforced the importance of early endoscopic assessment within 6-12 months post-surgery to identify patients at risk of progressive disease[104,477]. Patients with i2b or higher lesions should undergo immediate therapy escalation, whereas i0-i1 patients may not require active treatment beyond surveillance.
Statement 163: Post-operative prophylactic therapy should be considered in high-risk patients for prevention of early disease recurrence (e.g., smokers, prior resections, penetrating or perianal disease, younger age, histologic risk factors) to prevent early disease recurrence, with anti-TNFs being the preferred first-line option and vedolizumab as an alternative in select cases (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 91%).
Statement 164: Anti-IL therapies (anti-IL-12/IL-23 and anti-IL-23) and JAK may be considered on a case-by-case basis for post operative recurrence prevention (evidence level: 5; strength of recommendation: Conditional; consensus agreement: 100%).
Statement 165: Early post-operative endoscopic assessment (within 6-12 months) using the modified Rutgeerts score is recommended to guide therapy escalation, with i2b or higher lesions warranting immediate treatment intensification (evidence level: 1b; strength of recommendation: Strong; consensus agreement: 100%).
Management of IBD in pregnancy and post-partum
IBD frequently affects individuals during their reproductive years, making preconception counselling, pregnancy management, and postpartum care essential aspects of IBD care[478,479].
Preconception counselling: The primary determinant of a healthy pregnancy outcome in individuals with IBD is disease activity at conception. Active IBD at the time of conception is associated with significantly increased risks of miscarriage, preterm birth, low birth weight, small-for-gestational-age infants, and other adverse maternal and fetal outcomes[478,480]. Achieving objectively confirmed steroid-free remission for at least three to six months before conception is the cornerstone of IBD management in individuals planning pregnancy[478]. Despite these recommendations, studies have shown that a substantial proportion of individuals with IBD either discontinue or alter their medications due to concerns about fetal exposure, often without consulting their physician, which can lead to disease flares and poor pregnancy outcomes[481]. Preconception counselling should include discussions on the importance of maintaining remission, medication safety, the heritability of IBD, and the impact of prior surgeries on fertility. IPAA surgery is associated with a three to sixfold increase in infertility risk, primarily due to pelvic adhesions and altered tubal motility[482]. Patients considering pregnancy should be counselled about the potential impact of surgery on fertility, and in those requiring colectomy, a laparoscopic approach should be prioritized to mitigate fertility risks. Additionally, male fertility can be impacted by sulfasalazine, which has been shown to reduce sperm count and motility; however, this effect is reversible within three months of discontinuation. Assisted reproductive technologies such as in vitro fertilization are generally successful in individuals with IBD, with comparable pregnancy rates to those in the general population, except in individuals with prior pelvic surgery[483]. Preconception counselling should also involve nutritional optimization, including iron, folic acid, and vitamin B12 supplementation where necessary, as deficiencies are common in IBD due to malabsorption or chronic inflammation[484]. It is also crucial to ensure that patients are up to date on vaccinations, particularly for hepatitis B, HPV, and varicella, as live vaccines are contraindicated during pregnancy[485].
During pregnancy: Once pregnancy is achieved, close disease monitoring is essential to ensure ongoing remission and to detect early signs of disease flares. Pregnancy itself does not inherently alter the course of IBD, but those with active disease at conception are at a significantly higher risk of persistent or worsening inflammation throughout pregnancy[486,487]. Routine monitoring of disease activity should include fecal calprotectin and CRP each trimester, as these biomarkers remain reliable indicators of inflammation during pregnancy[234]. Endoscopy is generally avoided unless there is a strong clinical indication, in which case flexible sigmoidoscopy without sedation is preferred. Radiological assessments such as MRE without gadolinium contrast or IUS are considered safe in pregnancy and should be utilized when necessary for evaluating disease activity or complications[488,489].
A key principle in IBD management during pregnancy is the continuation of maintenance therapy, as disease control is paramount to ensuring optimal maternal and fetal outcomes. Multiple studies have demonstrated that the risks associated with active IBD far outweigh the theoretical risks of medication exposure. 5-ASA are considered safe throughout pregnancy[490]. Thiopurines can also be safely continued if already established before pregnancy; however, initiation of thiopurines during pregnancy is not recommended due to their potential for hepatotoxicity and myelosuppression[491]. The safety of biologic therapies, including anti-TNF agents is well established. These agents can be used throughout pregnancy, with evidence suggesting that they do not increase the risk of congenital anomalies, preterm birth, or low birth weight. Discontinuation of anti-TNFs (and other biologic classes) in the third trimester, previously recommended to reduce neonatal drug exposure, is now largely discouraged, as the benefits of continued disease control outweigh theoretical risks to the fetus[478,479]. As reported by the Pregnancy and Neonatal Outcomes registry, non-anti-TNF biologics, including vedolizumab and ustekinumab, appear to have a similar safety profile, though data remain limited[492]. IL-23 inhibitors such as risankizumab, mirikizumab and guselkumab lack extensive pregnancy data, and their use should be considered on a case-by-case basis[484,493]. In contrast, JAK inhibitors (tofacitinib, upadacitinib) and S1PR modulators (ozanimod) are contraindicated due to potential teratogenicity[235]. Methotrexate is also strictly contraindicated and should be discontinued at least three to six months before conception[494]. Labor and delivery planning in individuals with IBD should be individualized, with vaginal delivery being safe for most patients[495]. However, caesarean section should be considered in cases of active perianal disease or prior IPAA surgery to minimize the risk of fecal incontinence and anastomotic complications[496].
Postpartum care: Postpartum care is particularly important, as individuals with IBD are at increased risk of disease relapse in the months following delivery, especially if medications were altered or discontinued during pregnancy[497]. Resumption of pre-pregnancy therapy should be encouraged immediately after delivery, with close postpartum follow-up to monitor for signs of disease reactivation. For peripartum complicated by infection, temporarily holding biologic therapy can be considered. Breastfeeding should be encouraged, as it provides numerous benefits for both the mother and the infant, and most IBD medications are safe for use during lactation[234,498]. 5-ASA, thiopurines, anti-TNFs, vedolizumab, and ustekinumab have minimal transfer into breast milk and do not pose significant risks to the infant. Conversely, methotrexate, JAK inhibitors, and S1P modulators should be avoided due to potential toxicity[234]. Neonatal outcomes in infants born to individuals with IBD are generally favorable, provided that the disease is well-controlled during pregnancy. However, infants exposed to biologics including anti-TNF therapy in the third trimester may have detectable drug levels at birth, which can persist for several months[499]. As a precaution, the ECCO guidelines recommend that these infants should avoid live vaccines (e.g., bacillus Calmette-Guerin) for the first twelve months of life[478,494]. The oral polio vaccine is contraindicated in this setting; however, the inactivated polio vaccine can be safely administered. Live rotavirus vaccine may be provided on schedule in infants exposed to anti-TNFs in utero as per the updated PIANO global consensus recommendations. Other routine childhood vaccinations should be administered according to the standard immunization schedule.
Statement 166: Preconception counselling should be provided to all individuals with IBD planning pregnancy, emphasizing the importance of achieving sustained steroid-free remission for at least 3-6 months before conception to optimize maternal and fetal outcomes (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 167: Referral to an obstetrician-gynecologist, ideally one with expertise in high-risk pregnancies, and multidisciplinary team co-management are recommended for individuals with IBD during pregnancy (evidence level: 5; strength of recommendation: Strong; consensus agreement: 100%).
Statement 168: Aminosalicylates, thiopurines, anti-TNFs, vedolizumab, ustekinumab and IL-23 inhibitors are considered safe and should generally be continued during pregnancy, as active disease poses greater risks than medication exposure. Methotrexate, JAK inhibitors, and S1PR modulators should be discontinued prior to conception due to teratogenicity (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 91%).
Statement 169: Pregnant individuals with IBD should undergo routine disease monitoring using fecal calprotectin and CRP each trimester. Endoscopy should be reserved for strong clinical indications, while MRE (without gadolinium) and IUS are preferred for imaging when necessary (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 170: Labor and delivery planning should be individualized, with vaginal delivery being safe for most patients. Caesarean section is recommended in cases of active perianal disease or prior IPAA surgery to reduce the risk of complications (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
Statement 171: Breastfeeding should be encouraged in individuals with IBD, as most medications, including 5-ASA, thiopurines, anti-TNFs, vedolizumab, ustekinumab, and IL-23 inhibitors, have minimal transfer into breast milk and do not pose significant risks. Methotrexate, JAK inhibitors, and S1PR modulators should be avoided (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 91%).
Statement 172: Infants exposed to biologics in utero, particularly anti-TNFs, should avoid live vaccines (e.g., bacillus Calmette-Guerin) for the first 12 months of life due to prolonged drug clearance. The 12-month recommendation is based on ECCO guidelines. The oral polio vaccine is contraindicated in this setting; however, the inactivated polio vaccine can be safely administered. Live rotavirus vaccine may be provided on schedule in infants exposed to anti-TNFs in utero. Routine childhood vaccinations with inactivated vaccines should follow the standard immunization schedule (evidence level: 3b; strength of recommendation: Strong; consensus agreement: 100%).
