IBD

IBD Across Ethnicities: Gastroenterology | July 2026

Introduction: The global incidence of inflammatory bowel disease (IBD) continues to rise, particularly in newly industrialized countries. This comprehensive systematic review evaluated how race, ethnicity, geography, and migration influence the clinical phenotype and outcomes of Crohn's disease (CD) and ulcerative colitis (UC). Why was this study needed? The global epidemiology of IBD is rapidly evolving. The influence of ethnicity and geography on disease phenotype remains incompletely understood. Migration may alter disease risk and clinical presentation. Understanding phenotypic differences is essential for personalized IBD care. Large global population-based data have been lacking. Results: Crohn's disease showed significant ethnic differences, with Asian patients having the highest prevalence of perianal disease, whereas ulcerative colitis demonstrated fewer phenotypic differences across ethnic groups. Family history of IBD varied substantially, being more common among Middle Eastern populations and Asian immigrants than native Asian populations, suggesting an interaction between genetics and environmental exposure. Persistent differences in sex distribution, disease phenotype, and clinical presentation across racial and geographic populations indicate that IBD is not a uniform global disease. Clinical Impact: This landmark meta-analysis demonstrates that ethnicity, geography, and migration significantly influence the clinical expression of IBD, particularly Crohn's disease. These findings support the development of personalized risk assessment, surveillance strategies, and precision medicine, while emphasizing the need for future multi-omics research in diverse populations. Bottom Line: IBD is a heterogeneous global disease shaped by genetics, environment, and migration. Recognizing ethnic and geographic differences in disease phenotype is essential for improving diagnosis, individualized management, and future precision medicine approaches.

Moving Beyond the "Wait to Fail" Strategy in ASUC: FG | 2026

Introduction: Acute severe ulcerative colitis (ASUC) remains one of the most life-threatening emergencies in inflammatory bowel disease. Despite advances in IBD therapy, first-line management has changed little over the past two decades, and colectomy continues to be required in a substantial proportion of patients. This review highlights emerging strategies aimed at personalizing treatment and improving outcomes. Why was this review needed? Management of ASUC has remained largely unchanged for nearly 20 years. One-third of patients fail intravenous corticosteroid therapy. Colectomy and mortality remain significant despite current treatment. Early identification of steroid non-responders remains challenging. Personalized treatment strategies are needed to improve outcomes. Key Takeaways: Intravenous corticosteroids remain the first-line therapy, while infliximab and ciclosporin are the only rescue therapies supported by robust randomized trial evidence. Up to one-third of patients fail steroid therapy, requiring early rescue treatment or surgery. Colectomy remains necessary in 10–15% of patients during the initial admission, with the risk increasing after subsequent hospitalizations. JAK inhibitors are emerging as promising rescue therapies, although larger prospective trials are still required. Pharmacokinetic-guided infliximab dosing may optimize treatment response in selected patients. Risk prediction tools, such as ADMIT-ASC, may help identify high-risk patients early and facilitate individualized treatment decisions. Future management is expected to shift from a uniform "wait-to-fail" approach toward early risk stratification and precision medicine. Clinical Impact: The future management of ASUC is likely to focus on earlier identification of high-risk patients, individualized rescue therapy, and optimized biologic dosing rather than waiting for treatment failure. This strategy has the potential to reduce colectomy rates and improve long-term outcomes. Bottom Line: Acute severe ulcerative colitis remains a medical emergency with substantial morbidity. The next major advance will be personalized, risk-based treatment, integrating predictive models, optimized biologic therapy, and novel agents such as JAK inhibitors to improve patient outcomes.

FMT in Ulcerative Colitis: JGH | July 2026

Introduction: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a rising global burden. Although current therapies are effective, many patients fail treatment or experience adverse effects. Fecal microbiota transplantation (FMT) has emerged as a promising microbiome-based therapy aimed at restoring gut microbial balance and immune homeostasis. Why was this article needed? Previous FMT studies showed encouraging but inconsistent results. Optimal donor selection, delivery route, and treatment protocols remain unclear. Long-term safety and durability of response require further evaluation. Recent randomized controlled trials warranted an updated meta-analysis. The study also assessed whether multi-donor FMT and oral capsule therapy improve outcomes. Results: FMT significantly improved both clinical symptoms and endoscopic remission, confirming its superiority over placebo in active UC. FMT demonstrated a favorable short-term safety profile, with adverse events comparable to placebo. Multi-donor FMT and oral capsule delivery emerged as the most promising strategies, although standardized protocols and long-term data are still needed. Clinical Impact: This updated meta-analysis strengthens the evidence supporting FMT as an effective and safe option for inducing remission in UC. Although it remains investigational in routine practice, FMT is emerging as one of the most promising microbiome-based therapies for selected patients. Bottom Line: FMT is an effective microbiome-based therapy for inducing remission in ulcerative colitis. Multi-donor FMT and oral capsule delivery appear particularly promising, but larger long-term trials are needed before widespread clinical adoption.

Engineering Immune Cell Therapies for IBD: Nat Re Gastroe & Hepato | June 2026

Introduction: Despite major advances with biologics and small molecules, many patients with IBD continue to have refractory disease or lose treatment response. This Perspective explores engineered cellular therapies designed to restore immune tolerance rather than simply suppress inflammation. Why was this article needed? Current therapies effectively control inflammation but rarely correct the underlying immune dysfunction. Cellular immunotherapy offers the potential for durable remission through immune reprogramming. Stem Cell Therapy: Haematopoietic and mesenchymal stem cells have shown encouraging results in refractory IBD by promoting immune regulation and tissue repair. However, larger clinical trials are needed to establish long-term safety and efficacy. Regulatory T-Cell Therapy: Engineered regulatory T (Treg) cells aim to restore immune tolerance through targeted anti-inflammatory effects rather than broad immunosuppression. Early clinical trials are evaluating their safety and therapeutic potential. Tr1 Cell Therapy: IL-10-producing type 1 regulatory T (Tr1) cells may suppress intestinal inflammation and promote long-term immune regulation. Early-stage clinical studies are currently in progress. CAR T-Cell Therapy: A recent case report demonstrated sustained remission of ulcerative colitis following CD19-targeted CAR T-cell therapy, suggesting an important pathogenic role for B cells and opening a promising new therapeutic strategy. CAR Treg Therapy: CAR Treg cells combine antigen-specific targeting with immune regulation, providing precise control of intestinal inflammation while preserving normal immune function. Clinical Impact: Engineered cellular therapies could transform the management of refractory IBD, particularly in patients with multiple biologic failures. However, these therapies remain investigational and require validation in well-designed prospective clinical trials. Bottom Line: Stem cells, Tregs, Tr1 cells, and CAR T-cell platforms represent the next generation of IBD therapy, with the potential to restore immune tolerance and achieve durable disease modification beyond conventional immunosuppression.

Real-World IBD Patients Rarely Meet Clinical Trial Criteria: AJG | June 2026

Introduction: Randomized clinical trials (RCTs) are the cornerstone for approving biologic therapies in inflammatory bowel disease (IBD). However, strict eligibility criteria may exclude many patients encountered in routine clinical practice, raising concerns about the real-world applicability of trial results. Why was this study needed? The external validity of pivotal IBD clinical trials has not been well established. This study evaluated how many real-world patients would have qualified for landmark biologic trials and whether trial eligibility influenced treatment outcomes. What did the study show? Only 16.9% of patients met eligibility criteria for pivotal biologic RCTs, falling to 8% using newer trial criteria. Disease-related exclusion criteria accounted for most ineligible patients. Patients with ulcerative colitis were significantly less likely to qualify for RCTs than those with Crohn's disease. Clinical response and remission rates were similar in trial-eligible and non-eligible patients. Adverse events and drug discontinuation rates did not differ between the two groups. Long-term treatment persistence was also comparable regardless of trial eligibility. Clinical Impact: These findings suggest that biologic therapies remain effective and safe in many patients who would have been excluded from clinical trials. Real-world evidence should complement RCT data when making treatment decisions and developing future clinical guidelines. Take-Home Message: Most patients treated with biologics for IBD would not qualify for pivotal clinical trials. Despite this, real-world effectiveness, safety, and treatment persistence are comparable, emphasizing that clinical judgment and real-world evidence are essential alongside randomized trial data.

Mirikizumab in Ulcerative Colitis: JCC | June 2026

Introduction: Mirikizumab, a selective IL-23p19 inhibitor, has demonstrated efficacy in phase III clinical trials for moderate-to-severe ulcerative colitis (UC). This multicenter Italian real-world study evaluated its effectiveness and safety in routine clinical practice, including patients previously exposed to multiple biologic therapies. Why was this study needed? Randomized trials often exclude complex patients with prior biologic failures and multiple comorbidities. Real-world data are essential to determine whether mirikizumab performs similarly in everyday clinical practice. What did the study show? Nearly half of the patients achieved steroid-free clinical remission within 12 weeks. More than 60% achieved a meaningful clinical response after induction therapy. Clinical effectiveness was comparable in biologic-naïve and biologic-experienced patients. Prior ustekinumab exposure did not significantly reduce treatment effectiveness, although remission rates tended to be lower. Patients requiring extended induction had lower remission rates, suggesting more difficult-to-treat disease. Biochemical improvement in CRP and fecal calprotectin did not reach statistical significance during early follow-up. Mirikizumab demonstrated an excellent safety profile, with no treatment-related adverse events reported and only three patients discontinuing therapy because of lack of efficacy. Clinical Impact: These findings reinforce mirikizumab as an effective treatment option for moderate-to-severe UC in routine clinical practice, including patients with previous biologic exposure. The favorable safety profile and consistent clinical response support its use across a broad spectrum of patients. Take-Home Message: This real-world multicenter study confirms that mirikizumab is an effective and well-tolerated therapy for ulcerative colitis, achieving meaningful steroid-free remission even in biologic-experienced patients. These results support its growing role as an important IL-23–targeted treatment in everyday clinical practice.

Mirikizumab Shows Promising Real-World Effectiveness in Ulcerative Colitis: JCC | May 2026

Introduction: Mirikizumab, a selective IL-23p19 inhibitor, has demonstrated efficacy in phase III clinical trials for moderate-to-severe ulcerative colitis (UC). This multicenter Italian real-world study evaluated its effectiveness and safety in routine clinical practice, including patients previously exposed to multiple biologic therapies. Why was this study needed? Randomised trials often exclude complex patients with prior biologic failures and multiple comorbidities. Real-world data are essential to determine whether mirikizumab performs similarly in everyday clinical practice. What did the study show? Nearly half of the patients achieved steroid-free clinical remission within 12 weeks. More than 60% achieved a meaningful clinical response after induction therapy. Clinical effectiveness was comparable in biologic-naïve and biologic-experienced patients. Prior ustekinumab exposure did not significantly reduce treatment effectiveness, although remission rates tended to be lower. Patients requiring extended induction had lower remission rates, suggesting more difficult-to-treat disease. Biochemical improvement in CRP and fecal calprotectin did not reach statistical significance during early follow-up. Mirikizumab demonstrated an excellent safety profile, with no treatment-related adverse events reported and only three patients discontinuing therapy because of lack of efficacy. Clinical Impact: These findings reinforce mirikizumab as an effective treatment option for moderate-to-severe UC in routine clinical practice, including patients with previous biologic exposure. The favorable safety profile and consistent clinical response support its use across a broad spectrum of patients. Take-Home Message: This real-world multicenter study confirms that mirikizumab is an effective and well-tolerated therapy for ulcerative colitis, achieving meaningful steroid-free remission even in biologic-experienced patients. These results support its growing role as an important IL-23–targeted treatment in everyday clinical practice.

Upadacitinib + Vedolizumab: CGH | June 2026

This multicenter randomized trial evaluated whether combining upadacitinib with vedolizumab during induction therapy could improve outcomes in moderate-to-severe ulcerative colitis. A total of 113 patients were randomized to receive either vedolizumab alone or vedolizumab plus upadacitinib for 8 weeks. The rationale was to combine the rapid anti-inflammatory effect of a JAK inhibitor with the gut-selective mechanism and favorable long-term safety profile of vedolizumab. The combination therapy significantly improved endoscopic remission rates. At week 8, endoscopic remission was achieved in 37.5% of patients receiving combination therapy compared with 15.1% receiving vedolizumab alone. Clinical remission was also substantially higher with combination treatment (65% vs 35.6%). Histologic-endoscopic mucosal improvement, an increasingly important treatment target, was significantly more frequent in the combination arm. These findings suggest that early dual-target therapy may help overcome the therapeutic ceiling traditionally observed with advanced monotherapy. Importantly, short-term safety appeared reassuring. Adverse events were uncommon and occurred at similar rates in both treatment groups. No serious adverse events were reported during the 8-week induction period. One patient discontinued combination therapy because of severe rash and elevated lipid levels. The study supports the emerging concept of a “hit hard and heal early” approach in ulcerative colitis, aiming to achieve deep remission rapidly before transitioning to maintenance therapy. Several limitations should be considered: Open-label design Early trial termination after interim benefit analysis Smaller sample size than originally planned No upadacitinib monotherapy arm Ongoing 54-week follow-up will determine whether these impressive induction results translate into durable long-term remission and acceptable long-term safety. Bottom line: Short-term combination therapy with upadacitinib plus vedolizumab more than doubled endoscopic remission rates compared with vedolizumab alone in moderate-to-severe ulcerative colitis, suggesting a promising new induction strategy that now requires long-term validation.

Dose Escalation Offers Limited Benefit After Ustekinumab Failure : Gastroenterology | Jul 2026

Introduction: Ustekinumab is an established treatment for moderate-to-severe Crohn’s disease, but secondary loss of response remains a significant clinical challenge during long-term therapy. In routine practice, dose intensification strategies are frequently employed to recapture disease control, although high-quality prospective evidence supporting specific escalation approaches has been limited. Problem Statement: When patients lose response to ustekinumab maintenance therapy, clinicians often intensify treatment by shortening dosing intervals or administering intravenous reinduction. However, the optimal intensification strategy and its long-term effectiveness have remained uncertain, leading to substantial variability in clinical practice. Summary: The REScUE study is the first prospective randomized trial specifically evaluating ustekinumab dose-intensification strategies in Crohn’s disease patients experiencing secondary loss of response. Following intravenous reinduction, patients were assigned to either intensified subcutaneous dosing every four weeks or standard maintenance dosing every eight weeks. At 48 weeks, steroid-free clinical remission rates were low and did not differ significantly between the two treatment strategies. Likewise, safety outcomes were comparable, with similar rates of serious adverse events across both groups. These findings suggest that increasing the frequency of ustekinumab administration after intravenous reinduction does not provide additional clinical benefit compared with continuing standard eight-week maintenance dosing. The study challenges the common assumption that more intensive dosing necessarily improves outcomes in patients with secondary loss of response. Importantly, the overall modest remission rates observed indicate that many patients who lose response to ustekinumab may require alternative therapeutic approaches rather than further dose escalation. From a practical standpoint, the results support a more selective use of intensified ustekinumab schedules, potentially reducing treatment burden and healthcare costs without compromising efficacy. Overall, the REScUE trial provides important prospective evidence that routine escalation to four-week ustekinumab dosing after intravenous reinduction may not improve long-term outcomes in Crohn’s disease, highlighting the need for individualized treatment decisions and consideration of alternative therapeutic mechanisms when secondary loss of response occurs.

Subcutaneous Infliximab Achieves Higher Colonic Tissue Drug Levels Than Intravenous Therapy: UEG Journal | March 2026

Infliximab exerts its therapeutic effect within intestinal tissue, yet most therapeutic drug monitoring currently relies on serum concentrations. This study is the first to directly compare serum and colonic tissue infliximab concentrations between subcutaneous (SC) and intravenous (IV) infliximab in patients with IBD. Patients receiving subcutaneous infliximab achieved significantly higher serum drug concentrations compared with those receiving intravenous therapy. More importantly, colonic tissue infliximab concentrations were also significantly higher with subcutaneous administration, suggesting enhanced delivery to the therapeutic target organ. Serum and tissue drug concentrations were positively correlated in both treatment groups, confirming that systemic exposure reflects, at least partially, mucosal drug availability. Patients with higher colonic tissue infliximab concentrations experienced better clinical outcomes and were more likely to maintain sustained remission. Colonic tissue drug levels demonstrated stronger predictive value for long-term remission than serum trough levels. Tissue concentrations appeared highest in areas with mild-to-moderate inflammation, supporting the concept that active inflammatory tissue may facilitate local drug accumulation. The findings provide a biological explanation for the favorable pharmacokinetic profile observed with subcutaneous infliximab in previous clinical studies. The study raises an important concept: the true therapeutic target is the intestinal mucosa, not the bloodstream. Current therapeutic drug monitoring strategies may therefore underestimate clinically relevant drug exposure when relying solely on serum concentrations. Although tissue-based monitoring is not yet practical for routine clinical care, these data support future development of mucosal pharmacokinetic biomarkers. The study also reinforces growing evidence that subcutaneous infliximab is not merely non-inferior to intravenous therapy but may offer pharmacologic advantages. Larger prospective studies will be required to determine whether targeting tissue drug concentrations can further optimize treatment outcomes. Bottom line: Subcutaneous infliximab produces significantly higher serum and colonic tissue drug concentrations than intravenous infliximab. Colonic tissue drug levels correlate strongly with clinical remission and may represent the next frontier in therapeutic drug monitoring for IBD.

Ultraprocessed Grains Increase IBD Risk: AJG | June 2026

This large prospective PURE study evaluated the relationship between ultraprocessed grain consumption and the future development of inflammatory bowel disease across 124,590 participants from 21 countries. Ultraprocessed grains include heavily refined grain products that often contain additives, emulsifiers, preservatives, flavour enhancers, and other industrial ingredients. Higher consumption of ultraprocessed grains was associated with a significantly increased risk of developing IBD. Individuals consuming ≥19 g/day of ultraprocessed grains had nearly double the risk of IBD compared with those consuming less than 9 g/day. The association remained significant after adjustment for major confounders, including age, sex, smoking, dietary habits, and physical activity. The findings support growing evidence linking Westernised dietary patterns and food processing to intestinal inflammation. In contrast, consumption of fresh bread and rice was associated with a lower risk of developing IBD. The study also confirmed a broader dietary signal: higher overall intake of ultraprocessed foods was strongly associated with future IBD development. Participants consuming five or more servings of ultraprocessed foods daily had almost a fourfold higher risk of IBD compared with those consuming less than one serving per day. Several biological mechanisms may explain the findings, including: Alteration of gut microbiota Increased intestinal permeability Disruption of the mucus barrier Exposure to food additives and emulsifiers Enhanced mucosal immune activation The study adds further support to the hypothesis that environmental and dietary factors contribute substantially to the rising global incidence of IBD. Although observational, the prospective design and multinational nature of the PURE cohort strengthen the validity of the findings. The study cannot identify which specific component of ultraprocessed grains is responsible for the increased risk, and further mechanistic research is needed. From a clinical perspective, dietary counselling aimed at reducing ultraprocessed food consumption may become an increasingly important component of IBD prevention strategies. Bottom line: Higher consumption of ultraprocessed grains is associated with a significantly increased risk of developing IBD, while less processed staple foods, such as fresh bread and rice, appear to be associated with lower risk. The findings reinforce the importance of minimising ultraprocessed foods as part of a gut-healthy dietary pattern

HLA-DRB1*01:03 Identifies a Severe IBD Phenotype : Lancet Gastroenterol Hepatol | June 2026

Introduction: Inflammatory bowel disease (IBD) exhibits marked heterogeneity in disease behavior, progression, and treatment response. Identifying genetic markers associated with aggressive disease could facilitate earlier risk stratification and personalized therapeutic strategies. Among genetic factors, the HLA-DRB1*01:03 allele has long been linked to severe ulcerative colitis, but its broader impact across the spectrum of IBD has remained incompletely understood. Problem Statement: Although HLA-DRB1*01:03 is recognized as a susceptibility allele in ulcerative colitis, it is unclear whether this genetic variant influences long-term disease severity, surgical risk, treatment requirements, and adverse outcomes across both ulcerative colitis and Crohn’s disease. A comprehensive evaluation of its genotype–phenotype associations could help identify patients at risk for a more aggressive disease course. Summary: This large genotype–phenotype association study involving more than 43,000 patients with IBD provides compelling evidence that HLA-DRB101:03 is a marker of severe disease across both ulcerative colitis and Crohn’s disease. Carriers of this allele demonstrated higher rates of major adverse outcomes, including colectomy in ulcerative colitis, colonic resection in Crohn’s disease, and perianal disease in both conditions. Importantly, the genetic association extended beyond disease occurrence to disease trajectory, with carriers developing complications earlier and requiring advanced therapies sooner than non-carriers. The study also showed that HLA-DRB101:03 was associated with an increased likelihood of advanced therapy failure, suggesting a potentially more treatment-resistant disease phenotype. Notably, the allele was linked to younger-onset ulcerative colitis and distinct disease characteristics in Crohn’s disease, further supporting its role in shaping disease behavior. These findings position HLA-DRB101:03 as one of the strongest genetic markers currently associated with adverse IBD outcomes. From a clinical perspective, genetic identification of HLA-DRB101:03 carriers could eventually support precision medicine approaches by identifying patients who may benefit from closer monitoring, earlier introduction of advanced therapies, and proactive management strategies. Although further validation and cost-effectiveness analyses are required before routine implementation, this study represents an important step toward genotype-guided risk stratification in IBD.

Ustekinumab and Anti-TNFs Show Comparable Efficacy After Vedolizumab Failure : GETAID | June 2026

Introduction: Vedolizumab has become a widely used first-line advanced therapy for ulcerative colitis (UC) because of its favorable efficacy and safety profile. However, a substantial proportion of patients experience primary nonresponse or secondary loss of response, creating a growing need for evidence to guide treatment selection after vedolizumab failure. Despite the increasing use of vedolizumab as an initial biologic, data comparing subsequent therapeutic options remain limited. Problem Statement: The optimal second-line advanced therapy following vedolizumab failure is not well established. Clinicians frequently choose between anti-TNF agents and ustekinumab, but comparative real-world evidence regarding effectiveness, treatment durability, and safety is scarce. Identifying the most appropriate strategy is particularly important in patients with differing disease severity and risk profiles. Summary: This multicenter GETAID study evaluated real-world outcomes of infliximab, subcutaneous anti-TNF agents, and ustekinumab as second-line therapies after vedolizumab failure in patients with UC. The investigators found that all three treatment strategies achieved similar rates of steroid-free clinical remission and demonstrated comparable treatment persistence during follow-up. These findings suggest that both anti-TNF therapy and ustekinumab remain effective options after vedolizumab failure and support a flexible, individualized treatment approach. An important observation was that patients receiving corticosteroids at treatment initiation were less likely to achieve remission, highlighting baseline disease severity as a key determinant of outcome. While efficacy was broadly comparable across treatment groups, meaningful differences emerged in safety. Ustekinumab was associated with fewer adverse events and fewer treatment discontinuations related to toxicity, suggesting a more favorable tolerability profile. In contrast, infliximab remained an effective option, particularly for patients requiring rapid disease control in the setting of high inflammatory burden. These results provide valuable real-world guidance for treatment sequencing in UC and suggest that therapeutic selection after vedolizumab failure should be driven by individual patient characteristics, disease activity, comorbidity burden, and safety considerations. Overall, the study supports ustekinumab as an attractive option for patients in whom long-term safety is a major priority, while confirming that anti-TNF therapy remains a highly relevant and effective therapeutic strategy.

Metastatic Crohn’s Disease Often Precedes Intestinal Diagnosis : Gut | June 2026

Introduction: Metastatic Crohn’s disease (MCD), also referred to as cutaneous or genital Crohn’s disease, is a rare extraintestinal manifestation characterized by granulomatous skin inflammation occurring at sites separate from the gastrointestinal tract. Because of its rarity and heterogeneous presentation, MCD is frequently underrecognized and may lead to significant diagnostic delays. Current knowledge regarding its epidemiology, clinical characteristics, and optimal management remains limited, largely due to the absence of large prospective studies. Problem Statement: The rarity of MCD and the predominance of case reports and small case series have hindered the development of standardized diagnostic and therapeutic approaches. Clinicians often face uncertainty regarding recognition of disease patterns, identification of at-risk patients, and selection of effective treatment strategies. Summary: This systematic review represents one of the most comprehensive evaluations of metastatic Crohn’s disease to date, compiling data from over 600 reported patients. The analysis demonstrated that MCD predominantly affects younger individuals and is more common in women. Genital erythema and edema emerged as the hallmark clinical manifestations, with disease frequently involving the genitalia, perineum, and groin. Importantly, one of the most clinically relevant findings was that approximately one-third of patients developed MCD before receiving a diagnosis of luminal or perianal Crohn’s disease. This observation highlights the importance of considering Crohn’s disease in the differential diagnosis of unexplained granulomatous genital or cutaneous lesions, even in the absence of gastrointestinal symptoms. The review also identified associations with colonic Crohn’s disease and perianal involvement, suggesting a distinct disease phenotype. Ulceration appeared to be a marker of more severe and extensive disease. Therapeutic approaches varied widely and included topical therapies, systemic immunosuppressive agents, biologic therapies, and surgical interventions, reflecting the lack of evidence-based treatment guidelines. Anti-TNF agents were the most frequently reported advanced therapy. Overall, the findings underscore the need for increased clinical awareness, standardized reporting, and prospective studies to establish effective diagnostic pathways and treatment algorithms for this challenging manifestation of Crohn’s disease.

Darvadstrocel in Complex Perianal Crohn’s Disease: Gastroenterology | June 2026

Darvadstrocel is an allogeneic adipose-derived mesenchymal stem cell therapy designed to promote fistula healing through anti-inflammatory and immunomodulatory mechanisms. It is administered locally into conditioned fistula tracts after curettage and closure of the internal opening. Darvadstrocel previously generated considerable enthusiasm after the original ADMIRE-CD trial demonstrated significantly higher remission rates compared with placebo, leading to regulatory approval in Europe and Japan. The phase 3 ADMIRE CD II trial was designed as a larger confirmatory study involving patients from Europe, Israel, and North America with treatment-refractory complex perianal Crohn’s fistulas. A total of 568 patients were randomized to receive darvadstrocel or placebo following standard surgical conditioning of the fistula. The primary endpoint was combined remission at week 24, defined as closure of all treated external openings together with absence of significant collections on MRI. The study failed to meet its primary endpoint. Combined remission occurred in 48.8% of darvadstrocel-treated patients compared with 46.3% of placebo-treated patients, showing no statistically significant difference. Clinical remission, time to remission, and other secondary efficacy outcomes were also similar between treatment groups. Safety findings were reassuring, with no new safety concerns identified and adverse event rates similar between darvadstrocel and placebo. The negative result contrasts with the earlier ADMIRE-CD trial and raises important questions regarding the reproducibility of stem-cell–based therapies for fistulizing Crohn’s disease. These findings challenge the current role of darvadstrocel and suggest that future research may need to focus on alternative cell-based therapies, extracellular vesicles, or more targeted immunoregulatory approaches. Bottom line: Despite promising results from the original ADMIRE-CD trial, the larger phase 3 ADMIRE CD II study failed to demonstrate superiority of darvadstrocel over placebo for complex perianal Crohn’s fistulas, casting doubt on the clinical benefit of stem-cell therapy in this setting.

Inflammaging and Sarcopenia: Nutrients | June 2026

Inflammaging and sarcopenia are two interconnected hallmarks of aging that contribute to frailty, disability, metabolic dysfunction, loss of independence, and reduced quality of life. Inflammaging refers to chronic low-grade systemic inflammation that develops with aging, even in the absence of overt infection or disease. Sarcopenia is characterized by progressive loss of muscle mass, strength, and physical performance, and is increasingly recognized as a major determinant of healthy aging. The relationship is bidirectional: chronic inflammation accelerates muscle breakdown, while loss of muscle mass further promotes inflammation and metabolic dysfunction. Several common biological pathways link inflammaging and sarcopenia, including: NF-κB activation Mitochondrial dysfunction Oxidative stress Impaired AMPK–mTOR signaling Reduced cellular stress resilience Regular physical activity remains the most consistently effective intervention for preserving muscle function and reducing age-related inflammatory burden. Exercise improves mitochondrial function, insulin sensitivity, anabolic signaling, antioxidant defenses, and immune regulation. A growing body of evidence supports the role of bioactive dietary compounds in modulating aging-related pathways. Important bioactive compounds discussed include: Polyphenols Flavonoids Carotenoids Omega-3 fatty acids These compounds appear to influence several key pathways involved in healthy aging, including NF-κB, Nrf2, AMPK, mitochondrial metabolism, and redox homeostasis. Anti-inflammatory dietary patterns, particularly Mediterranean-style diets, are associated with better muscle strength, physical performance, and lower inflammatory burden. The review introduces a geroscience framework, emphasizing that interventions should target fundamental biological aging mechanisms rather than individual diseases alone. A key concept is hormesis, whereby mild biological stress from exercise or certain nutritional compounds activates adaptive cellular defense mechanisms that improve resilience. Current evidence suggests that exercise and nutritional bioactives often converge on similar molecular pathways, potentially producing complementary benefits. However, the authors caution that true biological synergy has not yet been conclusively demonstrated in humans. Significant challenges remain regarding optimal dosing, bioavailability, duration of intervention, patient selection, and long-term clinical outcomes. Future studies should focus on integrated lifestyle approaches rather than evaluating exercise and nutrition as isolated interventions. Bottom line: Inflammaging and sarcopenia are closely linked drivers of biological aging. Regular exercise, healthy dietary patterns, and selected bioactive compounds target many of the same molecular pathways and represent promising non-pharmacological strategies to preserve muscle function, metabolic health, and healthy aging.

Managing C. difficile Infection in Patients With IBD: Gastroenterology | May 2026

Clostridioides difficile infection (CDI) remains one of the most important triggers of disease flares, hospitalization, treatment failure, colectomy, and mortality in patients with inflammatory bowel disease. Every patient with IBD presenting with new or worsening diarrhea should be evaluated for CDI, particularly those with colonic disease, ileal pouches, or end ileostomies. Symptoms alone cannot reliably distinguish CDI from an IBD flare, making stool testing essential. The AGA recommends a multistep toxin-based diagnostic algorithm rather than PCR alone, because asymptomatic C. difficile colonization is common in IBD. A positive PCR without toxin detection may represent colonization rather than active infection and should be interpreted cautiously. Fidaxomicin is now the preferred first-line treatment for initial CDI in IBD because it reduces recurrence and preserves gut microbiota. Oral vancomycin remains an acceptable alternative when fidaxomicin is unavailable or cost-prohibitive. Metronidazole should no longer be used for CDI treatment in patients with IBD. Patients with severe colitis, systemic toxicity, marked leukocytosis, hemodynamic instability, or suspected sepsis should be strongly considered for hospitalization. One of the most important practice changes is that IBD therapy should not routinely be stopped during CDI. Biologics, immunomodulators, and small molecules should generally be continued when clinically indicated. Corticosteroids may also be initiated or continued when there is concern for concurrent moderate-to-severe IBD activity. If symptoms fail to improve within 48–72 hours of CDI treatment, clinicians should evaluate for: Active IBD flare Cytomegalovirus infection Alternative causes of colitis Endoscopic assessment should be considered when uncertainty persists. For recurrent CDI, microbiome restoration therapies have moved to the forefront of management. Patients with IBD who experience at least one recurrence of CDI should be offered microbiome-based therapy, including: FDA-approved fecal microbiota products Fecal microbiota transplantation (where available) Emerging microbiome therapies demonstrate high efficacy and acceptable safety even in patients receiving immunosuppressive therapy. Probiotics are not recommended for either primary or secondary prevention of CDI in IBD. Oral vancomycin prophylaxis may be considered in selected high-risk patients with prior CDI who require systemic antibiotics. The update emphasizes that successful management requires simultaneous treatment of both CDI and underlying IBD rather than viewing them as competing diagnoses. Bottom line: The major messages of the AGA 2026 update are: use fidaxomicin first-line, continue necessary IBD therapy during CDI, avoid probiotics, use toxin-based testing strategies, and strongly consider microbiome-based therapies after the first recurrence of CDI.

Darvadstrocel Misses Primary Endpoint in Complex Perianal Crohn’s Disease : CGH | Jun 2026

Introduction: Complex perianal fistulas represent one of the most debilitating manifestations of Crohn’s disease, often causing chronic pain, drainage, recurrent infections, and substantial impairment in quality of life. Despite advances in biologic therapy, fistula healing remains difficult to achieve and sustain. Darvadstrocel, an allogeneic adipose-derived mesenchymal stem cell therapy, generated considerable enthusiasm following the positive ADMIRE-CD trial, which demonstrated improved fistula healing in selected patients with refractory disease. Problem Statement: Although earlier studies supported the efficacy of darvadstrocel, its performance in a broader international population and contemporary treatment setting remained uncertain. Confirmation of benefit in a larger phase 3 trial was necessary before establishing its role in routine management of complex perianal Crohn’s disease. Summary: The ADMIRE CD II trial evaluated the efficacy and safety of darvadstrocel in patients with complex perianal Crohn’s disease across Europe, Israel, and North America. All participants underwent standardized surgical preparation, including fistula curettage and closure of the internal opening, before receiving either darvadstrocel or placebo. Contrary to expectations generated by the earlier ADMIRE-CD study, darvadstrocel did not demonstrate superiority over placebo for the primary endpoint of combined remission at 24 weeks. Clinical remission rates and time to remission were also comparable between the treatment groups, indicating no meaningful therapeutic advantage. Importantly, the study confirmed a favorable safety profile, with adverse events occurring at similar rates in both groups and no new safety concerns identified. These findings represent a significant setback for stem cell-based therapy in complex perianal Crohn’s disease and highlight the challenges of translating promising early results into consistent benefits across broader patient populations. While darvadstrocel remains biologically attractive and well tolerated, the negative results of ADMIRE CD II raise important questions regarding patient selection, treatment timing, fistula characteristics, and trial design. Future research will be needed to identify subgroups most likely to benefit and to refine regenerative approaches for fistula healing in Crohn’s disease.

Anti–IL-10 Autoantibodies Define a New Subgroup of IBD: NEJM | June 2026

This landmark study identifies neutralizing autoantibodies against interleukin-10 (IL-10) as a previously underrecognized mechanism driving inflammatory bowel disease. IL-10 is a critical anti-inflammatory cytokine that maintains intestinal immune tolerance. Genetic defects in the IL-10 pathway are already known to cause severe early-onset IBD. The investigators found neutralizing anti–IL-10 autoantibodies in 3.5% of patients with IBD, but in none of the healthy controls, suggesting a disease-specific phenomenon. Anti–IL-10 autoantibodies were detected across Crohn’s disease, ulcerative colitis, and IBD-unclassified populations. Functional studies confirmed that these antibodies are not merely biomarkers; they actively block IL-10 signaling and create a pro-inflammatory immune environment. Patients with anti–IL-10 antibodies demonstrated exaggerated production of key inflammatory cytokines, including: * IL-23 * IL-1β * TNF * IL-6 The most striking finding was the exceptionally strong association with HLA-DRB1*01:03, already recognized as the strongest genetic risk factor for ulcerative colitis. More than 80% of anti–IL-10-positive patients carried HLA-DRB1*01:03, providing a mechanistic explanation for one of the strongest known HLA associations in IBD. The association was remarkably strong, with odds ratios ranging from approximately 25 to 50 across independent cohorts. Anti–IL-10 autoantibodies persisted over many years in most affected patients, suggesting a stable and durable immunological phenotype. The study introduces the concept that some patients with IBD may have an acquired “phenocopy” of genetic IL-10 signaling defects. This finding expands the role of B-cell–mediated autoimmunity in IBD pathogenesis, an area previously overshadowed by T-cell and innate immune mechanisms. The discovery opens the possibility of a new precision-medicine subgroup of IBD defined by immune dysfunction rather than conventional clinical phenotype. Potential future therapeutic approaches could include: * B-cell depletion (anti-CD20, anti-CD19) * Plasma cell targeting (anti-CD38) * Fc receptor blockade * Plasma exchange * Future antigen-specific immune therapies Screening for anti–IL-10 antibodies may eventually become clinically relevant in patients with severe, refractory, extensive, or atypical IBD. Further studies are needed to determine whether anti–IL-10 positivity predicts disease severity, colectomy risk, biologic response, or extraintestinal manifestations. Bottom line: Neutralizing anti–IL-10 autoantibodies are present in approximately 1 in 30 patients with IBD and are strongly linked to HLA-DRB1*01:03. This discovery identifies a biologically distinct autoimmune subtype of IBD and provides a potential mechanistic explanation for one of the strongest genetic risk factors in ulcerative colitis.

AI Reads Pediatric IBD Biopsies: Cellular and Molecular Gastro and Hepato | June 2026

Histopathology remains a cornerstone for diagnosing pediatric inflammatory bowel disease, but differentiating Crohn’s disease from ulcerative colitis can be challenging, especially in young children. This study evaluated whether artificial intelligence could automatically identify key histological features from routine endoscopic biopsy whole-slide images. Researchers developed three computer vision models using convolutional neural networks and multiple-instance learning, a technique particularly useful when precise lesion-level annotation is unavailable. The first model differentiated normal versus abnormal tissue with excellent performance, achieving an AUC of 0.91. The second model identified active inflammation, achieving an AUC of 0.92. The third model detected chronic architectural distortion, achieving an AUC of 0.93. Overall model performance was strong despite using a weakly supervised learning approach, suggesting that meaningful pathological signals are present within routine whole-slide images. The study demonstrates that AI can recognize inflammatory and structural patterns typically assessed by gastrointestinal pathologists. Importantly, the models were developed from real-world pediatric endoscopic biopsy specimens rather than highly curated research datasets. The findings support the concept that AI could function as a pathology decision-support tool rather than replacing pathologists. Potential future applications include: Automated screening of biopsy slides Standardization of histological interpretation Reduction of interobserver variability Faster reporting workflows Objective disease activity assessment For pediatric IBD, where early diagnosis can significantly influence treatment selection and long-term outcomes, such tools may become increasingly valuable. The study does not yet provide direct Crohn’s disease versus ulcerative colitis classification, but establishes the foundation for future disease-specific diagnostic algorithms. Larger multicenter validation studies and integration with clinical, endoscopic, and molecular data will be required before routine clinical implementation. Bottom line: This study demonstrates that artificial intelligence can accurately identify abnormal tissue, active inflammation, and chronic architectural changes in pediatric IBD biopsy slides, highlighting the growing role of computer vision as a diagnostic support tool in gastrointestinal pathology.

Vitamin D Supplementation Improves Real-World IBD Outcomes : CGH | Jun 2026

Introduction: Vitamin D deficiency is highly prevalent among patients with inflammatory bowel disease (IBD) and has been associated with increased disease activity, impaired mucosal healing, reduced quality of life, and higher healthcare utilization. Beyond its established role in bone health, vitamin D exerts important immunomodulatory effects that may influence intestinal inflammation. Despite these biological advantages, the real-world clinical benefits of vitamin D supplementation in IBD have remained uncertain. Problem Statement: Although vitamin D deficiency is frequently identified and treated in patients with IBD, evidence supporting its impact on meaningful clinical outcomes such as corticosteroid requirements, emergency department visits, and hospitalizations is limited. Determining whether supplementation translates into measurable improvements in disease burden is important for optimizing routine IBD care. Summary: This large real-world study evaluated the impact of vitamin D supplementation on clinical outcomes in patients with IBD receiving care within a national healthcare system. The investigators found that vitamin D supplementation was associated with a reduction in IBD-related emergency department visits, hospitalizations, and corticosteroid use compared with patients who did not receive supplementation. These findings were consistent across multiple analytical approaches, strengthening the reliability of the observed associations. The study suggests that correction of vitamin D deficiency may contribute to improved disease control and reduced healthcare utilization in routine clinical practice. Given its low cost, favorable safety profile, and widespread availability, vitamin D supplementation represents an attractive adjunctive strategy in the management of IBD. Importantly, the benefits observed extended beyond laboratory correction of deficiency and were linked to clinically meaningful outcomes that directly affect patients and healthcare systems. While the observational nature of the study prevents definitive conclusions regarding causality, the results support a proactive approach to screening for and treating vitamin D deficiency in IBD populations. Future prospective trials are needed to determine optimal supplementation regimens, identify target vitamin D levels, and clarify the mechanisms through which vitamin D may influence long-term disease outcomes.

Darvadstrocel Fails to Improve Remission in Complex Perianal Crohn’s Fistulas : Gastroenterology | June 2026

Introduction: Crohn's Disease–associated complex perianal fistulas remain one of the most difficult complications in inflammatory bowel disease management, causing major morbidity, impaired quality of life, and high rates of treatment failure. Mesenchymal stem-cell therapy emerged as a promising regenerative strategy after earlier trials suggested benefit with Darvadstrocel in fistulizing Crohn’s disease. Problem Statement: Although the original ADMIRE-CD trial demonstrated encouraging remission rates with darvadstrocel, questions remained regarding reproducibility across broader international populations and contemporary biologic-exposed patients. Confirmation in a larger phase 3 trial was essential before establishing stem-cell therapy as a standard treatment for complex perianal Crohn’s fistulas. Summary: The ADMIRE CD II trial was a large international phase 3 randomized placebo-controlled study evaluating the efficacy and safety of darvadstrocel in patients with refractory complex perianal Crohn’s fistulas. The study enrolled adults with Crohn’s disease who had complex perianal fistulas with limited internal and external openings and inadequate response to immunosuppressive or biologic therapies. A total of 568 patients were randomized to receive either darvadstrocel or placebo following standardized surgical preparation including fistula curettage and closure of internal openings. The primary endpoint was combined remission at week 24, defined as closure of all treated external fistula openings together with absence of significant collections on imaging. Importantly, the trial failed to meet its primary endpoint. Combined remission occurred in 48.8% of patients treated with darvadstrocel compared with 46.3% in the placebo group, with no statistically significant difference between treatment arms. Similarly, key secondary endpoints including clinical remission rates and time to remission also failed to demonstrate superiority of darvadstrocel over placebo. Despite the negative efficacy findings, the safety profile remained reassuring. Treatment-emergent adverse events occurred at similar rates in both groups, and no new safety concerns related to stem-cell therapy were identified. The study is highly important because it represents one of the largest and most rigorous randomized evaluations of cellular therapy in fistulizing Crohn’s disease. The findings contrast with the earlier positive ADMIRE-CD study and raise important questions regarding patient selection, procedural standardization, placebo response rates, and the reproducibility of stem-cell therapeutic benefit. One notable aspect of the trial is the relatively high remission rate observed in the placebo arm, likely reflecting the substantial contribution of optimized surgical management, internal opening closure, and multidisciplinary fistula care. This emphasizes that meticulous surgical preparation itself remains a critical determinant of fistula healing outcomes. Clinically, the results suggest that darvadstrocel cannot currently be considered universally superior to optimized surgical and medical management for complex perianal fistulas. The study also highlights the broader challenge of translating promising regenerative therapies into consistently effective real-world inflammatory bowel disease treatments. Importantly, the absence of new safety signals preserves interest in cellular therapies and suggests that future studies may still identify responsive subgroups or improved delivery strategies. Potential areas for future investigation include biomarker-guided patient selection, integration with biologic therapy optimization, repeated stem-cell administration, and identification of fistula phenotypes more likely to respond to regenerative approaches. The trial further reinforces the need for standardized composite endpoints in fistulizing Crohn’s disease research, given the complexity of correlating clinical drainage closure with radiologic healing. Overall, ADMIRE CD II demonstrated that darvadstrocel did not significantly improve remission rates compared with placebo in complex perianal Crohn’s disease, underscoring the ongoing therapeutic challenges in fistulizing disease despite encouraging earlier regenerative medicine data.

AI and Multi-Omics Redefine Postoperative Crohn’s Recurrence : Gut | 2026

Introduction Crohn's Disease postoperative recurrence remains one of the greatest challenges after intestinal resection, with endoscopic recurrence occurring in the majority of patients within the first year. Despite advances in biologic therapy and surgical technique, accurately predicting and monitoring recurrence remains difficult. Problem Statement Current surveillance strategies, including ileocolonoscopy and Faecal Calprotectin, have important limitations related to sensitivity, standardization and ability to capture transmural or biologically evolving disease. Additionally, variability in anastomotic techniques and disease phenotypes complicates individualized risk assessment. Summary This forward-looking review explores how advanced imaging, artificial intelligence and multi-omics technologies may transform the future management of postoperative recurrence in Crohn’s disease. The authors emphasize that postoperative recurrence is biologically heterogeneous and likely driven by complex interactions among immune dysregulation, microbial shifts, genetic susceptibility and tissue remodeling pathways. Traditional endoscopic assessment primarily evaluates mucosal disease activity and may underestimate deeper or early inflammatory changes. Emerging technologies aim to overcome this limitation through more comprehensive structural and biologic characterization. High-resolution endoscopic techniques including Confocal Laser Endomicroscopy and endocytoscopy now permit in vivo microarchitectural assessment of anastomotic tissue, potentially enabling earlier recognition of recurrence before overt ulceration develops. Parallel advances in Intestinal Ultrasound and cross-sectional imaging are reshaping postoperative surveillance by allowing non-invasive transmural evaluation. These modalities may detect bowel wall thickening, vascularity and mesenteric inflammation that precede clinical relapse. The review highlights the growing role of multi-omics approaches including genomics, transcriptomics, proteomics, metabolomics and metagenomics in identifying biologic signatures associated with postoperative recurrence risk. These technologies are uncovering novel pathways involved in fibrosis, immune activation, epithelial barrier dysfunction and microbiome-host interactions, providing mechanistic insight beyond conventional clinical risk factors. Artificial intelligence emerges as a central theme of the review. AI-enabled systems may integrate clinical variables, imaging features, endoscopic patterns and omics-derived biomarkers into predictive multimodal models capable of individualized recurrence forecasting. Such models could ultimately support precision medicine strategies by identifying which patients require aggressive postoperative biologic therapy versus those suitable for lower-intensity monitoring. Importantly, AI-assisted endoscopy may also improve lesion detection, reduce interobserver variability and standardize postoperative scoring systems that currently suffer from significant subjectivity. The article additionally addresses the evolving role of surgical factors, including anastomotic configuration, in shaping recurrence biology and surveillance interpretation. Clinically, this work reflects a broader transition in inflammatory bowel disease management—from reactive treatment of established recurrence toward proactive biologically informed prevention. The review is especially relevant because postoperative Crohn’s disease recurrence remains associated with repeated surgeries, cumulative bowel damage and progressive disability despite modern therapeutics. However, the authors appropriately emphasize that most emerging technologies remain investigational. Prospective validation, harmonization of methodologies and integration into real-world clinical workflows are still required before widespread implementation. Major barriers include cost, accessibility, data standardization and the complexity of integrating multi-dimensional datasets into routine care pathways. Future directions will likely involve hybrid predictive platforms combining AI-enhanced imaging, molecular biomarkers and longitudinal patient-specific data to dynamically guide postoperative management. Overall, this review outlines a future precision-medicine framework for postoperative Crohn’s disease, where AI-enabled imaging and multi-omics technologies may enable earlier detection, personalized risk stratification and more targeted prevention of recurrence.

FIT Plus Calprotectin Improves Young-Onset GI Triage : Gut | May 2026

Introduction Inflammatory Bowel Disease and early-onset Colorectal Cancer are increasingly encountered in younger adults presenting with lower gastrointestinal symptoms. However, distinguishing inflammatory disease from neoplasia in this age group remains diagnostically challenging. Problem Statement The low prevalence of colorectal cancer and higher prevalence of inflammatory bowel disease in younger patients reduce the discriminatory performance of the Faecal Immunochemical Test when used alone. Current pathways risk missed inflammatory disease, delayed referral and inefficient triage. Summary This prospective primary-care pilot study evaluated whether combining FIT with Faecal Calprotectin using the York Faecal Calprotectin Care Pathway could improve diagnostic discrimination between colorectal cancer and inflammatory bowel disease in younger adults. Nearly 900 patients were prospectively enrolled, with a median age of 35 years, representing a clinically important population increasingly seen in both primary care and gastroenterology clinics. The study demonstrated a major limitation of FIT-only strategies in younger populations. Although FIT showed excellent negative predictive value for the composite endpoint of colorectal cancer or IBD, it failed to identify a substantial proportion of patients with Crohn's Disease. Importantly, FIT alone missed almost half of Crohn’s disease diagnoses, highlighting the biologic limitation of relying solely on occult bleeding markers in inflammatory bowel disease assessment. By contrast, combining FIT with the established calprotectin-based pathway achieved detection of all identified colorectal cancer and inflammatory bowel disease cases within the cohort. The integrated strategy also demonstrated strong discriminatory triage capability, appropriately directing most patients toward either colorectal cancer or inflammatory bowel disease referral pathways. These findings are clinically significant because diagnostic ambiguity in younger adults frequently leads to delayed IBD diagnosis, repeated consultations and inefficient use of endoscopic resources. The study additionally addresses a growing epidemiologic challenge: the rising incidence of both early-onset colorectal cancer and inflammatory bowel disease worldwide. The results reinforce the complementary biologic roles of FIT and calprotectin. FIT primarily reflects mucosal bleeding, whereas calprotectin captures neutrophil-mediated intestinal inflammation, allowing improved differentiation between inflammatory and neoplastic pathology. Clinically, this combined biomarker strategy may help refine referral pathways in primary care, reducing unnecessary urgent cancer referrals while simultaneously minimizing missed inflammatory bowel disease. The work is particularly relevant in healthcare systems facing increasing endoscopy demand and diagnostic pathway congestion. Better pre-endoscopic risk stratification could improve resource allocation and reduce diagnostic delay. The findings also support a broader shift toward multimarker diagnostic algorithms rather than reliance on single stool biomarkers for lower gastrointestinal symptom evaluation. Importantly, the study demonstrates that biomarker interpretation should be contextualized by patient age and disease prevalence, as diagnostic test performance varies substantially across populations. Limitations include the pilot nature of the study, relatively low colorectal cancer event numbers and the need for larger validation cohorts before broad implementation. Future work will likely focus on integrated biomarker-based referral models incorporating FIT, calprotectin, symptom phenotyping and potentially emerging molecular stool biomarkers. Overall, this study suggests that combining FIT with faecal calprotectin may substantially improve discriminatory referral pathways for younger adults with lower gastrointestinal symptoms, enhancing early detection of both colorectal cancer and inflammatory bowel disease while reducing diagnostic uncertainty.

Upadacitinib–Vedolizumab Combination Breaks the UC Efficacy Ceiling : Gastroenterology | May 2026

Introduction Ulcerative Colitis treatment outcomes remain constrained by an “efficacy ceiling,” with most advanced therapies achieving endoscopic remission rates below 30%. Rapid induction of deep remission remains a major unmet need, particularly in patients with moderate-to-severe disease. Problem Statement Whether short-term combination induction using a biologic and a selective JAK inhibitor can improve early endoscopic remission beyond current monotherapy standards in ulcerative colitis remains uncertain. Summary This prospective multicenter randomized trial evaluated an induction strategy combining Upadacitinib with Vedolizumab in patients with moderate-to-severe ulcerative colitis. Patients receiving combination induction achieved markedly higher rates of endoscopic remission at week 8 compared with vedolizumab monotherapy. Importantly, the study used stringent remission criteria requiring complete endoscopic normalization, strengthening the clinical significance of the findings. Clinical remission and histologic-endoscopic mucosal improvement were also substantially higher with combination therapy, suggesting that the benefits extended beyond symptomatic response to include deeper biologic disease control. One of the most clinically relevant observations was the rapidity of response. The addition of upadacitinib likely compensated for the slower onset traditionally associated with vedolizumab, potentially creating a synergistic induction strategy that combines rapid anti-inflammatory activity with gut-selective maintenance therapy. The study therefore introduces an important conceptual shift in inflammatory bowel disease management: short-term “bridging” combination therapy designed to rapidly induce deep remission while transitioning toward safer long-term biologic maintenance. Safety findings were reassuring, with adverse event rates comparable between groups and no serious adverse events observed during the short induction period. However, the authors appropriately caution that the sample size and limited follow-up duration restrict definitive safety conclusions. The trial is especially important because randomized evidence supporting combination advanced therapy in ulcerative colitis remains extremely limited. Most existing combination data derive from retrospective cohorts or refractory salvage settings. Mechanistically, the therapeutic rationale is compelling. Upadacitinib provides rapid intracellular cytokine suppression through JAK1 inhibition, whereas vedolizumab selectively inhibits gut lymphocyte trafficking. Together, these therapies may target complementary inflammatory pathways during the critical early induction phase. The findings also align with broader trends toward precision and stratified inflammatory bowel disease care, where aggressive early disease control may alter long-term outcomes including corticosteroid exposure, hospitalization and colectomy risk. Nevertheless, several limitations remain important. The trial was open-label, relatively small and terminated early, requiring cautious interpretation before widespread adoption into routine practice. Longer-term durability also remains unknown, particularly after withdrawal of upadacitinib and continuation with vedolizumab monotherapy alone. Future studies will need to clarify maintenance outcomes, relapse rates and optimal de-escalation strategies. The study additionally raises important questions regarding positioning of dual-targeted therapy within current treatment algorithms. Combination induction may ultimately prove particularly useful in patients with high inflammatory burden, prior biologic failure or those requiring rapid disease control. Overall, this randomized trial provides the first prospective evidence that short-term combination induction using upadacitinib and vedolizumab can significantly improve early endoscopic and clinical remission rates in moderate-to-severe ulcerative colitis, potentially overcoming the long-recognized efficacy ceiling of current monotherapy approaches.

AI and Multi-Omics Redefine Postoperative Crohn’s Recurrence : Gut | May 2026

Introduction Crohn's Disease postoperative recurrence remains one of the greatest long-term challenges after intestinal resection, with endoscopic recurrence developing in a substantial proportion of patients within the first postoperative year. Despite advances in biologic therapy and surgical techniques, accurate prediction and individualized monitoring of postoperative recurrence remain limited. Problem Statement Current postoperative surveillance strategies for Crohn’s disease rely largely on ileocolonoscopy and fecal biomarkers, both of which have important limitations in sensitivity, standardization and early risk prediction, restricting the development of precision postoperative management. Summary This state-of-the-art review outlines how artificial intelligence-enabled imaging and multi-omics technologies may fundamentally transform postoperative recurrence management in Crohn’s disease. The authors emphasize that postoperative recurrence is biologically heterogeneous and influenced by complex interactions among immune pathways, microbial ecology, genetics, surgical technique and environmental exposures. Traditional surveillance approaches struggle to fully capture this multidimensional disease behavior. Current postoperative monitoring is still dominated by ileocolonoscopy and Rutgeerts scoring, yet important limitations persist, including interobserver variability, uncertain applicability across newer anastomotic techniques and imperfect correlation with transmural disease activity. The review highlights major advances in high-resolution endoscopic technologies including confocal laser endomicroscopy and endocytoscopy. These techniques enable real-time microscopic assessment of the anastomosis and mucosal barrier, potentially allowing detection of early inflammatory and structural alterations before overt endoscopic recurrence becomes apparent. Simultaneously, non-invasive imaging modalities are rapidly evolving. Intestinal Ultrasound and cross-sectional imaging now permit dynamic transmural assessment, offering opportunities for serial postoperative monitoring without repeated invasive procedures. Beyond imaging, the review strongly emphasizes the growing role of multi-omics technologies. Genomics, transcriptomics, proteomics, metabolomics and microbiome profiling are increasingly uncovering biologic signatures associated with recurrence risk, immune activation and fibrotic progression. These technologies are revealing that postoperative recurrence likely represents multiple biologically distinct phenotypes rather than a single uniform process. Such insights may eventually support personalized postoperative therapeutic strategies rather than current generalized treatment algorithms. A particularly important theme is the integration of multimodal data through artificial intelligence. AI-driven models may combine clinical features, imaging findings, endoscopic characteristics and omics-derived biomarkers into predictive platforms capable of individualized recurrence forecasting. The authors propose that AI-enabled systems could eventually facilitate precision risk stratification, optimize surveillance timing and guide earlier therapeutic escalation in high-risk patients while avoiding overtreatment in lower-risk individuals. Importantly, the review maintains a balanced perspective regarding current limitations. Most emerging technologies still require prospective validation, standardized acquisition protocols and integration into real-world clinical workflows before widespread implementation. The article also underscores the need for harmonization of postoperative recurrence definitions and imaging endpoints across studies. Standardization will be essential for developing reproducible AI algorithms and clinically meaningful predictive models. From a translational standpoint, this review reflects the broader evolution of inflammatory bowel disease care toward precision medicine. Future postoperative management may increasingly rely on integrated biologic and imaging signatures rather than isolated endoscopic findings alone. The review additionally highlights how technological innovation is reshaping multidisciplinary Crohn’s disease care, requiring closer collaboration between gastroenterologists, colorectal surgeons, radiologists, computational scientists and molecular biologists. Overall, this review presents a compelling vision of future postoperative Crohn’s disease management in which AI-enabled imaging and multi-omics platforms drive earlier detection, individualized surveillance and biologically tailored therapeutic decision-making.

International Consensus Defines the Role of Intestinal Ultrasound in Postoperative Crohn’s Disease Surveillance : Lancet Gastroenterol Hepatol | May 2026

Introduction Crohn's Disease recurrence after ileocolic resection remains common, with postoperative endoscopic recurrence often preceding clinical symptoms. Early identification of recurrence is critical because timely therapeutic escalation may prevent progression to stricturing disease, repeat surgery and irreversible bowel damage. Although ileocolonoscopy remains the reference standard, increasing interest has emerged around Intestinal Ultrasound as a non-invasive, repeatable and patient-friendly monitoring tool. Problem Statement Despite growing clinical adoption of intestinal ultrasound in inflammatory bowel disease, there has been no international consensus regarding standardized implementation, interpretation and timing of ultrasound assessment for postoperative Crohn’s disease recurrence. Summary This international multidisciplinary RAND/UCLA appropriateness study established expert consensus recommendations for the use of intestinal ultrasound in detecting and evaluating postoperative recurrence after ileocolic resection in Crohn’s disease. The recommendations were developed through a rigorous consensus methodology incorporating systematic literature review, iterative expert voting and multidisciplinary ratification involving gastroenterologists, colorectal surgeons and radiologists from multiple countries. The resulting framework represents one of the most comprehensive attempts to standardize postoperative intestinal ultrasound assessment in Crohn’s disease. The panel identified several key anatomic regions that should routinely be evaluated during postoperative sonographic assessment. Particular emphasis was placed on detailed examination of the neoterminal ileum and the inlet of the neoterminal ileum, which were considered the sites most likely to reflect clinically meaningful postoperative recurrence. Additional evaluation of the blind limbs of the anastomosis, distal colonic segments and surrounding mesentery was also recommended. Importantly, the consensus expanded assessment beyond bowel wall thickness alone. Recommended sonographic parameters included bowel wall stratification, vascularity, mesenteric inflammatory fat, lymphadenopathy, luminal narrowing and detection of penetrating or stricturing complications such as abscesses, fistulas and prestenotic dilation. This reflects the increasingly sophisticated role of intestinal ultrasound as a comprehensive transmural disease assessment tool rather than merely a surrogate for mucosal inflammation. The panel also addressed timing of surveillance. Intestinal ultrasound was not recommended within the first four postoperative weeks because early inflammatory and healing-related changes may confound interpretation. Instead, the first formal postoperative assessment was recommended between 3 and 12 months after surgery, aligning with the biologic window during which early recurrence commonly develops. A particularly important aspect of the recommendations is the recognition of mesenteric assessment as a core component of postoperative surveillance. Increasing evidence suggests that mesenteric inflammation and creeping fat are integral drivers of Crohn’s disease progression, and intestinal ultrasound uniquely allows simultaneous bowel and mesenteric evaluation in real time. Clinically, these recommendations may substantially expand adoption of ultrasound-driven postoperative monitoring pathways. Compared with ileocolonoscopy, intestinal ultrasound offers several practical advantages including absence of sedation, lack of bowel preparation, repeatability, lower procedural burden and potential for point-of-care assessment during routine clinic visits. The study also reflects the broader paradigm shift within inflammatory bowel disease toward transmural monitoring. While endoscopy remains essential, cross-sectional modalities increasingly provide complementary information regarding deep tissue inflammation, fibrosis and penetrating complications that are not fully captured by mucosal visualization alone. Importantly, the panel emphasized that development of validated postoperative ultrasound indices remains a major unmet need. Standardized scoring systems integrating bowel wall thickness, vascularity and mesenteric findings will likely be essential for future clinical trial integration and treat-to-target strategies. Overall, this multidisciplinary international consensus establishes a standardized framework for intestinal ultrasound assessment of postoperative Crohn’s disease recurrence. The recommendations support intestinal ultrasound as an increasingly important non-invasive monitoring modality and provide critical groundwork for future validation studies and precision postoperative surveillance strategies in Crohn’s disease.

Real-World Risankizumab Outcomes in Refractory CD : Frontline Gastroenterol | May 2026

Introduction Risankizumab is a selective interleukin-23 p19 inhibitor approved for moderate-to-severe Crohn’s Disease following strong efficacy signals in phase III trials. However, real-world evidence in heavily pretreated Crohn’s disease populations, particularly after prior biologic and ustekinumab exposure, remains limited. This large multicentre UK cohort evaluated the effectiveness, persistence and safety of risankizumab across routine clinical practice. Problem Statement Many patients with Crohn’s disease experience failure of multiple advanced therapies, including anti-TNF agents and ustekinumab, creating substantial therapeutic challenges. Whether selective IL-23 p19 inhibition remains effective after prior IL-12/23 blockade in real-world refractory populations has remained uncertain. Summary This retrospective multicentre study included 763 patients treated across 25 UK health boards, representing one of the largest real-world risankizumab cohorts reported to date. The population was highly treatment refractory, with 92% previously exposed to anti-TNF therapy, 72% previously treated with ustekinumab and a median of three prior advanced therapy exposures. More than half had prior luminal surgery and 16% had a stoma at treatment initiation, underscoring the severe disease burden of the cohort. Despite this complexity, risankizumab demonstrated remarkably high treatment persistence, reaching 97.8% at 3 months, 95.4% at 6 months and 89.2% at 12 months. Persistence remained robust even among patients previously exposed to ustekinumab, suggesting that selective IL-23 p19 inhibition may retain efficacy despite prior IL-12/23 blockade. Prednisolone use at treatment initiation was the only significant predictor of reduced persistence, likely reflecting higher inflammatory burden and more refractory disease. Clinical and biochemical outcomes were similarly encouraging. Steroid-free clinical remission occurred in 59% at 3 months, 52% at 6 months and 50% at 12 months. CRP remission rates exceeded 50% throughout follow-up, while faecal calprotectin remission rates reached 44% at both 6 and 12 months. Significant improvements in Harvey-Bradshaw Index, inflammatory biomarkers, abdominal pain and stool frequency were observed across treatment intervals. Importantly, remission rates were largely comparable between ustekinumab-naïve and ustekinumab-exposed patients, supporting the mechanistic distinction between IL-23 p19 blockade and p40 inhibition. The study additionally provided important real-world insights into perianal disease. Among patients with active perianal Crohn’s disease, approximately one-third achieved clinical perianal response by 12 weeks, while most avoided new perianal complications during follow-up. These findings support a potential role for risankizumab in fistulising disease, although dedicated prospective studies remain necessary. Safety outcomes were favourable overall. Adverse events occurred in 17% of patients, though many reflected disease-related hospitalisations rather than drug toxicity. Serious infections requiring hospitalisation were infrequent, and discontinuation due to adverse effects remained uncommon. The overall safety profile aligned closely with phase III trial experience and previously published smaller real-world cohorts. Overall, this large UK real-world analysis confirms that risankizumab is highly effective and durable in medically refractory Crohn’s disease, including patients with multiple prior biologic failures and previous ustekinumab exposure. The findings reinforce IL-23 p19 inhibition as an important therapeutic mechanism in advanced Crohn’s disease and support its expanding integration into complex IBD treatment algorithms.

Upadacitinib Shows Real-World Benefit in Perianal Crohn’s Disease : Clin Gastroenterol Hepatol | May 2026

Introduction Perianal Crohn’s Disease remains one of the most disabling and treatment-refractory manifestations of inflammatory bowel disease, frequently associated with fistulas, abscesses, recurrent surgery and impaired quality of life. Although anti-TNF therapy has historically been the cornerstone of fistulizing disease management, many patients experience incomplete response or secondary loss of efficacy. Upadacitinib has demonstrated efficacy in luminal Crohn’s disease, and post-hoc analyses from phase III trials suggested potential benefit in perianal disease, but real-world data—particularly radiologic outcomes—have been limited. Problem Statement Management of perianal Crohn’s disease remains challenging, especially in patients with prior biologic exposure and longstanding fistulizing disease. Whether upadacitinib can achieve meaningful fistula healing and radiologic improvement in routine clinical practice has not been well established. Summary This multicenter North American retrospective cohort study evaluated 125 adults with active perianal Crohn’s disease treated with upadacitinib across 10 tertiary centers. The cohort represented a highly refractory population, with nearly half having complex fistulas and more than three-quarters previously exposed to anti-TNF therapy. Clinical outcomes were assessed using the Perianal Disease Activity Index (PDAI), alongside inflammatory biomarkers and pelvic MRI findings. Upadacitinib demonstrated clinically meaningful effectiveness in this difficult-to-treat population. Approximately 46% of patients achieved clinical response, while nearly 40% achieved clinical remission. Importantly, radiologic improvement was documented in more than half of patients undergoing pelvic MRI assessment, and complete radiologic healing occurred in approximately 12%, representing one of the first real-world MRI-based evaluations of upadacitinib in fistulizing Crohn’s disease. Rates of hospitalization and perianal surgery during follow-up remained relatively low, supporting meaningful disease control in routine practice. Treatment effectiveness appeared strongly influenced by prior biologic exposure and disease chronicity. Anti-TNF–naïve patients achieved substantially higher clinical response rates compared with previously exposed individuals, suggesting greater efficacy earlier in the disease course. Similarly, shorter perianal disease duration was associated with improved outcomes, reinforcing the concept that early aggressive intervention may improve fistula healing potential before irreversible fibrotic remodeling develops. Multivariable analysis identified prior anti-TNF exposure as a significant negative predictor of response. Overall, this study provides important real-world evidence supporting upadacitinib as a therapeutic option for perianal Crohn’s disease, particularly in patients with earlier disease and limited biologic exposure. The inclusion of radiologic outcomes strengthens the clinical relevance of the findings and supports further prospective controlled studies evaluating JAK inhibition for fistulizing Crohn’s disease management.

FIT Pathways Frequently Identify IBD in Younger Patients : Br J Surg | May 2026

Introduction Inflammatory bowel disease and Colorectal Cancer frequently present with overlapping lower gastrointestinal symptoms including rectal bleeding, altered bowel habits and abdominal pain. In the UK, symptomatic Faecal immunochemical testing is widely used in primary care to triage patients suspected of colorectal cancer. However, the extent to which FIT pathways also identify IBD, particularly in younger adults, has remained poorly characterized. Problem Statement Current FIT-based referral pathways are primarily optimized for colorectal cancer detection and may insufficiently account for inflammatory bowel disease risk. Whether combining FIT with faecal calprotectin (FCP) could improve diagnostic stratification for younger symptomatic patients remains uncertain. Summary This large population-based cohort study analyzed more than 473,000 symptomatic patients undergoing FIT testing in UK primary care between 2019 and 2023. Within one year of FIT testing, nearly 2,800 patients were diagnosed with IBD. Importantly, individuals younger than 50 years accounted for more than half of all IBD diagnoses but less than 7% of colorectal cancer diagnoses, highlighting a major age-related shift in disease probability within symptomatic FIT pathways. Elevated FIT levels were strongly associated with increased IBD risk, with a markedly higher incidence observed among patients with FIT ≥10 µg Hb/g. The highest-risk subgroup comprised younger patients with both elevated FIT and elevated faecal calprotectin, where the probability of IBD exceeded 20%. Conversely, a normal FCP substantially reduced combined CRC/IBD risk even in patients with elevated FIT, suggesting important negative predictive value for inflammatory disease exclusion. These findings suggest that IBD may be a more likely diagnosis than colorectal cancer in younger symptomatic individuals referred through FIT pathways. The study supports incorporation of routine faecal calprotectin testing alongside FIT to improve diagnostic precision, prioritize endoscopic evaluation and potentially reduce unnecessary invasive investigations in low-risk patients. Overall, the data reinforce the evolving role of combined stool biomarker strategies in modern lower gastrointestinal triage algorithms and emphasize the importance of age-specific interpretation of symptomatic FIT results.

Upadacitinib in Perianal Crohn’s Disease: CGH | May 2026

Introduction Perianal Crohn’s disease (pCD) remains one of the most challenging manifestations of inflammatory bowel disease, often associated with fistulas, recurrent infections, impaired quality of life, and repeated surgeries. Although anti-TNF agents have been the cornerstone of therapy, many patients experience incomplete response or treatment failure. Upadacitinib (UPA), a selective JAK1 inhibitor, has shown promise in clinical trials, but real-world evidence in perianal disease has been limited. Problem Statement Management of perianal Crohn’s disease remains difficult because: Complex fistulas frequently persist despite biologic therapy Radiologic healing is difficult to achieve Long-standing disease often becomes refractory Real-world effectiveness data for newer agents like UPA are scarce The key question was: Can upadacitinib improve both clinical and radiologic outcomes in real-world perianal Crohn’s disease? Summary This multicenter North American study evaluated 125 patients with active perianal Crohn’s disease treated with upadacitinib. Most patients had severe disease, with nearly half having complex fistulas and over 75% previously exposed to anti-TNF therapy. The study demonstrated meaningful clinical improvement: Nearly 46% achieved clinical response Around 39% achieved clinical remission MRI improvement was seen in over half of patients Complete radiologic healing occurred in approximately 11% Hospitalization and surgery rates were relatively low during follow-up. Importantly, outcomes were significantly better in: Anti-TNF–naïve patients Patients with shorter disease duration Prior anti-TNF exposure predicted lower response rates, suggesting earlier introduction of UPA may yield better outcomes. Overall, this real-world study supports upadacitinib as a promising therapeutic option for perianal Crohn’s disease, particularly when used earlier in the disease course before multiple biologic failures occur.

Vaccination Uptake Remains Poor in Immunosuppressed IBD Patients : Frontline Gastroenterol | May 2026

Introduction Inflammatory bowel disease patients receiving immunosuppressive therapy are at increased risk of vaccine-preventable infections, including influenza, pneumococcal disease and COVID-19. International guidelines strongly recommend routine immunization in this vulnerable population, yet real-world vaccine adherence remains inconsistent. Problem Statement The COVID-19 pandemic has intensified vaccine hesitancy and misinformation, potentially worsening already suboptimal vaccination uptake in patients with IBD. Limited data exist regarding post-pandemic adherence patterns and barriers to immunization among immunosuppressed IBD populations. Summary This cross-sectional observational study demonstrated persistently low vaccination adherence among immunosuppressed patients with IBD in the post-pandemic era. Fewer than one-quarter of patients were fully vaccinated according to recommended schedules for pneumococcal, influenza and SARS-CoV-2 vaccines. Uptake was particularly poor for pneumococcal vaccination and COVID-19 booster doses, despite the heightened infection risk associated with immunosuppressive therapy. Importantly, healthcare professional–led counselling emerged as one of the strongest predictors of vaccine adherence, with patients receiving direct vaccine recommendations significantly more likely to complete immunization schedules. Older age was also associated with better vaccine uptake, suggesting younger patients may represent a particularly vulnerable group for vaccine hesitancy and misinformation. Commonly reported barriers included uncertainty regarding vaccine necessity, concerns about safety and lack of awareness regarding vaccine recommendations. Alarmingly, more than 40% of patients reported inadequate counselling before initiation of immunosuppressive therapy, highlighting major deficiencies in preventive care pathways. The study also demonstrated inconsistent delivery of vaccine recommendations across different vaccines, particularly for shingles vaccination. These findings reinforce the critical role of gastroenterologists, IBD nurses, pharmacists and primary care providers in proactively addressing vaccine education and preventive healthcare during routine IBD management. Overall, the study highlights an urgent need for structured vaccination pathways, standardized counselling protocols and multidisciplinary preventive care strategies to improve immunization adherence in immunosuppressed IBD populations.

A Pragmatic Prevention Framework for IBD in the Global South : Gut | 2026

Introduction Inflammatory bowel disease is rapidly emerging as a global disease, with rising incidence across low-income and middle-income countries. Although biologics and small-molecule therapies have transformed disease outcomes, long-term treatment remains costly, infrastructure-intensive and difficult to sustain in resource-constrained healthcare systems. Problem Statement Conventional IBD prevention and interception models—including biomarker screening, precision medicine and large-scale prevention trials—may be impractical in much of the Global South because of economic limitations, inadequate healthcare infrastructure and shortages of trained specialists. A scalable and economically feasible preventive strategy is urgently needed. Summary This conceptual review proposes a pragmatic prevention framework for IBD modeled on successful public health approaches used in non-communicable diseases such as metabolic syndrome and cardiovascular disease. The authors argue that rather than relying exclusively on expensive precision medicine strategies, IBD prevention in resource-limited regions should focus on modifiable environmental and lifestyle risk factors already linked to broader NCD prevention initiatives. The proposed “sieving strategy” prioritizes interventions that satisfy three key criteria: evidence supporting IBD prevention, overlap with established NCD prevention measures and economic feasibility for widespread implementation. Potential preventive targets include dietary modification, smoking reduction, physical activity promotion, obesity prevention, antibiotic stewardship and improvement in early-life environmental exposures. By integrating IBD prevention into existing NCD public health infrastructure, the framework aims to maximize scalability and cost-effectiveness while avoiding creation of parallel healthcare systems. The review also highlights major barriers to conventional prevention models, including limited access to advanced diagnostics, biologic therapies and population-level risk stratification tools in developing countries. Importantly, the authors emphasize that prevention-focused strategies may ultimately provide greater long-term population benefit than relying solely on escalating therapeutic complexity after disease onset. Overall, the article presents a highly relevant public health-oriented roadmap for addressing the growing burden of IBD in the Global South and advocates for prevention strategies grounded in equity, feasibility and population-level impact rather than resource-intensive precision approaches alone.

Jejunal Feeding Challenges in DGBI and GI Dysmotility : Frontline Gastroenterol | May 2026

Introduction Patients with disorders of gut–brain interaction (DGBI) and gastrointestinal dysmotility (GID) frequently experience severe nutritional compromise requiring enteral support. Jejunal feeding is often considered in patients unable to maintain adequate oral intake, particularly when gastric feeding intolerance or severe dysmotility exists. However, clinical practice in this area remains highly variable and evidence guiding management is limited. Problem Statement The experiences, confidence levels and perceptions of healthcare professionals managing jejunal feeding in DGBI and GID are poorly understood. Limited specialist neurogastroenterology access and uncertainty regarding feeding tolerance may contribute to inconsistent care pathways and suboptimal nutritional management. Summary This survey-based study evaluated healthcare professionals’ perceptions regarding jejunal feeding in patients with DGBI and gastrointestinal dysmotility. Most respondents were dietitians and physicians actively involved in nutritional support, although a striking majority reported limited access to specialist neurogastroenterology services. Clinicians perceived jejunal feeding to be more commonly required in severe gastrointestinal dysmotility disorders than in DGBI, reflecting the greater burden of objective motility impairment in GID. Interestingly, despite DGBI generally being considered less structurally severe conditions, respondents reported lower confidence managing these patients compared with those with GID. This likely reflects the complex overlap of visceral hypersensitivity, symptom amplification, psychosocial comorbidity and uncertainty surrounding pathophysiology in DGBI populations. Tolerance to jejunal feeding was also perceived to be poorer in DGBI compared with GID, with most clinicians reporting inability of patients to tolerate infusion rates above 50 mL/hour. Another important finding was the extremely high prevalence of opioid exposure across both groups, highlighting the growing concern regarding opioid-associated gut dysfunction and worsening dysmotility in these patients. The study emphasizes substantial gaps in specialist service provision and underscores the need for multidisciplinary neurogastroenterology-led nutritional pathways. It also highlights the importance of individualized feeding strategies, cautious opioid stewardship and further prospective research to optimize jejunal feeding protocols in complex DGBI and dysmotility populations.

Personalized Infliximab Dosing in ASUC: JCC | March 2026

Introduction Acute severe ulcerative colitis (ASUC) is a life-threatening condition requiring urgent treatment. In patients who fail steroids, Infliximab is widely used as rescue therapy. However, response is highly variable, and a significant proportion of patients still require colectomy despite treatment. One major limitation is the lack of individualized dosing strategies, as drug pharmacokinetics in ASUC are highly unpredictable due to inflammation, protein loss, and altered clearance. Problem Statement Standard infliximab dosing does not account for patient-specific pharmacokinetics, leading to suboptimal exposure and increased risk of colectomy in ASUC. Summary This multicenter study developed a pharmacokinetic-based model to personalize infliximab therapy in ASUC. The key finding was that infliximab exposure between weeks 2–4, adjusted for drug clearance (AUCw2–4/CL), strongly predicted colectomy risk within 90 days. Patients with low exposure (log AUC/CL < 5.79) were identified as high risk for colectomy, with good predictive accuracy (≈85%). The model incorporated simple clinical parameters such as body weight, CRP, and drug levels to estimate individualized drug exposure. This approach allows early identification of patients who may benefit from intensified dosing strategies, moving beyond fixed regimens toward precision therapy. Clinically, this represents a paradigm shift—from “one-size-fits-all” rescue therapy to personalized infliximab optimization—aimed at maximizing colectomy-free survival in ASUC.

Statins Reduce Stricture Risk in Crohn’s Disease: JCC | March 2026

Introduction Stricture formation is a major complication of Crohn’s disease, affecting more than half of patients and often leading to obstruction, repeated hospitalizations, and need for surgery. Current therapies primarily target inflammation, but effective strategies to prevent fibrosis and stricturing remain limited. Statins, widely used for cardiovascular disease, have demonstrated anti-inflammatory and anti-fibrotic properties, raising interest in their potential role in modifying disease progression in Crohn’s disease. Problem Statement Despite advances in biologic therapies, there are no proven pharmacological interventions that effectively prevent fibrotic complications like strictures in Crohn’s disease. Summary This large, real-world study evaluated the impact of statin use on stricture development in Crohn’s disease using two independent US population databases. In both cohorts, statin use was consistently associated with a significant reduction in the risk of new-onset intestinal strictures—approximately 28–29% risk reduction over a follow-up of around 3.5–4 years. The findings were robust across two large datasets and after propensity score matching, suggesting that the observed benefit is independent of confounding clinical variables and background IBD therapies. Mechanistically, statins may exert beneficial effects by reducing chronic inflammation and inhibiting fibrogenesis, which are central drivers of stricture formation in Crohn’s disease. Clinically, this study introduces the possibility of drug repurposing—using statins as a disease-modifying adjunct in Crohn’s disease to prevent long-term structural complications. However, given the observational design, prospective randomized trials are needed before routine clinical adoption. Overall, this study highlights a promising, low-cost, and widely available strategy to potentially alter the natural history of Crohn’s disease by targeting fibrosis rather than inflammation alone.

Colitis-Associated CRC: Nature Reviews Gastroent & Hepatol | April 2026

Introduction Colitis-associated colorectal cancer (caCRC) represents a distinct subtype of colorectal cancer that develops in patients with long-standing Inflammatory Bowel Disease, particularly Ulcerative Colitis and Crohn’s Disease. With the rising global burden of IBD, the population at risk for caCRC is steadily increasing. Unlike sporadic colorectal cancer, caCRC arises in a background of chronic inflammation, leading to unique molecular, cellular, and microenvironmental changes that influence tumor initiation and progression. Problem Statement Despite improved control of inflammation in IBD, caCRC remains a major clinical challenge because its pathogenesis is complex, heterogeneous, and fundamentally different from sporadic colorectal cancer, making early detection, risk stratification, and targeted therapy difficult. Summary This review highlights that caCRC is driven primarily by chronic inflammation-induced epithelial damage and regeneration. Persistent barrier disruption accelerates epithelial aging and promotes early genetic alterations—particularly early loss of p53, unlike the adenoma–carcinoma sequence seen in sporadic colorectal cancer. Inflammatory pathways such as IL-17 and NF-κB play a central role in early tumorigenesis. The tumor microenvironment is equally critical, involving dynamic interactions between epithelial cells, immune cells, cancer-associated fibroblasts, and the gut microbiome. Dysbiosis further amplifies inflammatory signaling and tumor promotion. caCRC is also characterized by rapid progression and a tendency toward mesenchymal tumor phenotypes, contributing to aggressive behavior. Importantly, the review emphasizes that future management will likely shift toward personalized strategies targeting inflammation, microbiome modulation, immune pathways, and stromal interactions to prevent and treat caCRC more effectively.

Multiomic Insights into Guselkumab Response in UC: BMJ Open Gastroenterology | March 2026

Introduction Ulcerative colitis is a chronic inflammatory disorder driven by dysregulated immune pathways, with the interleukin-23 (IL-23)/Th17 axis playing a central pathogenic role. Modern treatment strategies have shifted toward achieving deep remission, including histological and endoscopic healing, rather than symptom control alone. Guselkumab, a selective IL-23p19 inhibitor, has demonstrated clinical efficacy in moderate-to-severe disease. However, the molecular and cellular mechanisms underlying its therapeutic benefit remain incompletely understood, particularly in relation to mucosal healing and tissue-level remission. Problem Statement While clinical trials have confirmed the efficacy of IL-23 inhibition, there is a critical gap in understanding how these therapies translate into molecular remission. Specifically, the absence of integrated multiomic data limits the ability to define biomarkers of response, predict outcomes, and refine precision medicine approaches in ulcerative colitis. Summary This Phase IIb QUASAR multiomic analysis demonstrates that guselkumab induces early and sustained suppression of systemic and mucosal inflammatory pathways. Treatment reduced pro-inflammatory cytokine signatures and downregulated IL-23/Th17-driven transcriptional activity, while simultaneously promoting epithelial repair mechanisms. Single-cell and transcriptomic analyses revealed a decrease in inflammatory monocytes, fibroblasts, and plasma cells, alongside an increase in epithelial and reparative cell populations in responders achieving histo-endoscopic mucosal improvement at 12 weeks. These findings establish a biological basis for deep remission, linking IL-23 blockade to both immune suppression and mucosal restoration. Importantly, this study lays the groundwork for molecular definitions of remission and predictive biomarkers, advancing precision therapy in ulcerative colitis.

Colorectal Surveillance in IBD: Updated BSG Guidance: Gut | 2026

Introduction The updated British Society of Gastroenterology guideline reflects an important change in the way we think about colorectal cancer surveillance in inflammatory bowel disease. The modern message is not that every patient with colonic IBD should automatically undergo the same surveillance forever, but that surveillance should be more precise, more individualised, and more closely linked to actual cancer risk. Although the risk of colorectal cancer in IBD is lower than older literature suggested, it still remains meaningfully higher than in the general population, especially in those with longstanding colitis, persistent inflammation, primary sclerosing cholangitis, dysplasia, strictures, or extensive disease. The guideline, therefore, shifts the field from a rigid surveillance model to a risk-adapted, quality-driven, patient-centred approach. Key Points Patients with colonic IBD still have a higher risk of colorectal cancer and colorectal cancer-related death than the general population, even in the modern treatment era. The risk is no longer as high as older historical studies suggested, which means surveillance should now be more personalised rather than automatically intensive for everyone. Surveillance colonoscopy should begin 8 years after symptom onset in patients with colonic IBD. In patients with primary sclerosing cholangitis, surveillance should begin immediately at diagnosis because this remains one of the highest-risk groups. Patients with ulcerative proctitis alone or Crohn’s disease without colonic involvement generally do not need IBD-specific surveillance and should instead follow population screening pathways. Persistent inflammation is the single most important modifiable driver of colorectal neoplasia in IBD, so mucosal healing is also a cancer prevention strategy. Surveillance intervals should be based on risk, with annual surveillance for high-risk patients, 3-yearly surveillance for intermediate-risk patients, and much less frequent reassessment for very low-risk patients. Some patients with very low inflammatory burden and no additional risk factors may have a colorectal cancer risk close to the general population and may not need lifelong intensive surveillance. The guideline strongly supports use of multivariable risk assessment rather than relying only on the single highest risk factor. A major practical advance is the use of the web-based IBD dysplasia risk calculator, which helps clinicians individualize surveillance intervals more accurately. Post-colonoscopy colorectal cancer is substantially more common in IBD than in sporadic colorectal cancer, showing that surveillance quality matters as much as surveillance frequency. Many failures in surveillance are caused by delayed colonoscopy, missed appointments, poor systems, and inadequate follow-up rather than by biology alone. High-definition colonoscopy should now be considered the standard for IBD surveillance, and standard-definition colonoscopy is no longer adequate. Dye-based chromoendoscopy offers an additional benefit for dysplasia detection and remains the preferred enhanced imaging technique when expertise is available. Current artificial intelligence systems are not yet ready for routine IBD dysplasia surveillance because they have not been adequately trained for IBD-specific lesions. Targeted biopsies are preferred in most surveillance procedures, but random or segmental biopsies still have a role in selected high-risk settings such as PSC, previous dysplasia, retained rectum, or pouch surveillance. Most visible dysplastic lesions in colitis-affected segments can now be managed endoscopically, ideally with complete en bloc resection, rather than proceeding directly to surgery. Invisible dysplasia remains a serious finding and should always trigger repeat expert colonoscopy with chromoendoscopy and careful mapping biopsies within a short interval. Multifocal invisible low-grade dysplasia or invisible high-grade dysplasia usually shifts management toward colectomy because the future cancer risk is high. Every case of dysplasia in a colitis-affected segment should be discussed in a multidisciplinary team because management decisions now depend on lesion visibility, grade, resectability, patient risk factors, and patient preference. Conclusion This updated BSG guideline brings colorectal surveillance in IBD firmly into the era of precision medicine. Its most important message is that surveillance should no longer be viewed as a uniform lifelong protocol, but as a carefully tailored strategy based on inflammatory burden, dysplasia risk, colonoscopy quality, and patient-specific factors. For the practicing clinician, the real advances are the move toward dynamic risk stratification, the emphasis on high-quality high-definition colonoscopy, the selective use of chromoendoscopy and biopsies, and the recognition that many patients can be managed more intelligently rather than simply more intensively.

JAK Inhibitors in ASUC: A Systematic Review: AJG March 2026

Acute severe ulcerative colitis (ASUC) is a life-threatening complication of ulcerative colitis that often requires hospitalisation and urgent therapy. Although intravenous corticosteroids remain the standard first-line treatment, a significant proportion of patients fail to respond and require rescue therapy or colectomy. Janus kinase (JAK) inhibitors, such as tofacitinib and upadacitinib, have emerged as rapidly acting oral immunomodulators and are increasingly being explored as therapeutic options in ASUC. This systematic review and meta-analysis evaluated the effectiveness and safety of JAK inhibitors in ASUC by analysing 35 studies including 664 patients. In the short term (<1 month), clinical response rates were high, reaching 77.9% with tofacitinib and 86.5% with upadacitinib, with colectomy rates around 11% for both drugs. At intermediate follow-up (<3 months), pooled clinical response and remission rates remained moderate, with remission observed in 37.3% (tofacitinib) and 47.4% (upadacitinib) of patients. In the long term (3–12 months), sustained clinical response and remission rates ranged from 33%–41%, while colectomy rates were approximately 22%–23%. Safety outcomes were acceptable. Adverse events included venous thromboembolism (2.2%), herpes zoster infection (3.4%), and major adverse cardiovascular events (0.7%), all occurring at relatively low frequencies. Importantly, high-dose tofacitinib did not demonstrate superior efficacy compared with standard dosing. Overall, the analysis suggests that JAK inhibitors are effective and reasonably safe as adjunct therapy with corticosteroids or as rescue therapy in steroid-refractory ASUC. However, the authors emphasize that well-designed randomized controlled trials are still required to clearly define their optimal role in ASUC management.

Mirikizumab in Paediatric UC (SHINE-1 Trial): Lancet Gastroentrol Hepatolo, February 2026

Introduction Ulcerative colitis (UC) in children is often aggressive and difficult to manage, with many patients failing conventional therapies such as corticosteroids, immunomodulators, biologics, or JAK inhibitors. Mirikizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), has demonstrated efficacy in adults with UC and Crohn’s disease. However, evidence in the paediatric population remains limited. The SHINE-1 trial was designed to evaluate the pharmacokinetics, efficacy, and safety of mirikizumab in children with moderately-to-severely active UC who had inadequate response or intolerance to prior therapies. Summary SHINE-1 was a 52-week, multicentre, open-label phase 2 trial conducted across 19 centres in North America, Asia, and Israel. A total of 26 paediatric patients (2–<18 years) with moderate-to-severe UC received weight-adjusted intravenous mirikizumab at weeks 0, 4, and 8, followed by subcutaneous maintenance therapy. At week 12, clinical response rates were encouraging: 69% achieved clinical response, and 38.5% achieved clinical remission based on the modified Mayo score. Endoscopic remission occurred in 53.8%, and symptomatic remission in 46.2% of patients. At week 52, sustained efficacy was observed: 53.8% maintained clinical response 38.5% remained in clinical remission 50% achieved remission based on Pediatric Ulcerative Colitis Activity Index (PUCAI) 38.5% achieved corticosteroid-free remission Safety outcomes were acceptable. Only 12% experienced serious adverse events, and treatment discontinuation occurred in one patient (4%). The most common adverse events included COVID-19 infection, injection-site pain, headache, and fever. Conclusion The SHINE-1 trial demonstrates that mirikizumab is a promising IL-23–targeted therapy for paediatric moderate-to-severe ulcerative colitis, showing meaningful clinical, endoscopic, and symptomatic improvements with an acceptable safety profile. These findings support larger controlled trials to confirm its role in paediatric UC management.

ACCURE Trial (Appendectomy and UC): Lancet Gastro Hepato, March 2026

The ACCURE randomised clinical trial investigated whether laparoscopic appendicectomy could improve disease outcomes in ulcerative colitis (UC) when added to standard medical therapy. The rationale for this approach stems from evidence suggesting that the appendix may play an immunomodulatory role in UC, influencing intestinal inflammation and disease relapse. In this multicentre international randomised trial conducted across the Netherlands, Ireland, and the UK, patients with established UC in remission but with a relapse within the previous year were assigned to either: Appendicectomy plus maintenance medical therapy, or Medical therapy alone. After 12 months of follow-up, the appendicectomy group demonstrated significantly better outcomes: Relapse rate: 36% after appendicectomy vs 56% with medical therapy alone. Relative risk reduction: about 35% lower relapse risk. Patients undergoing appendicectomy were also less likely to require escalation to biologic therapy and had improved quality-of-life measures. The procedure was generally safe, with only a small number of postoperative complications and no deaths reported. Key Clinical Message This landmark study provides the first randomised evidence that appendicectomy can reduce relapse rates in ulcerative colitis when added to standard therapy. It suggests that the appendix may contribute to UC pathogenesis and that appendicectomy could become an adjunctive therapeutic strategy, particularly in patients with recurrent disease despite conventional therapy.

Vedolizumab and Pregnancy: Am J Gastro, March 2026

Vedolizumab, a gut-selective monoclonal antibody targeting α4β7 integrin, is widely used for the treatment of Crohn’s disease and ulcerative colitis, but safety data during pregnancy have been limited. This prospective observational study from the Vedolizumab Pregnancy Exposure Registry (2015–2022) evaluated pregnancy outcomes among women exposed to vedolizumab. The registry included 275 pregnant women from the United States and Canada, divided into three groups: vedolizumab-exposed (n=99), disease-matched women receiving other biologics (n=76), and healthy unexposed controls (n=100). Mothers and infants were followed for one year postpartum, assessing major birth defects, pregnancy loss, preterm delivery, infections, growth abnormalities, malignancies, and developmental milestones. Among pregnancies resulting in live births, major birth defects occurred in 7.4% of vedolizumab-exposed infants compared with 5.6% in the disease-matched biologic group, showing no statistically significant difference (adjusted risk ratio 1.07). Similarly, rates of spontaneous abortion and preterm delivery were not significantly increased in the vedolizumab group. No increased risk was observed for infections, growth abnormalities, or developmental outcomes in infants. Overall, the registry found no significant safety signals associated with vedolizumab exposure during pregnancy. These findings provide reassuring prospective evidence supporting the continued use of vedolizumab in pregnant women with inflammatory bowel disease when clinically indicated.

Mediterranean Diet in IBD: IJG March 2026

Introduction Diet plays an important role in the pathogenesis and management of inflammatory bowel disease (IBD). Among various dietary patterns, the Mediterranean diet (MD)—rich in fruits, vegetables, whole grains, olive oil, legumes, nuts, and fish—has been associated with anti-inflammatory and microbiome-modulating effects. Because chronic intestinal inflammation in IBD is influenced by diet, there is growing interest in evaluating whether the Mediterranean diet could serve as an adjunctive therapeutic strategy alongside standard medical therapy. Summary This systematic review and meta-analysis evaluated the effectiveness of the Mediterranean diet in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Key findings: Eight studies were included in the analysis. Seven studies (223 patients) provided data on remission outcomes. The pooled clinical remission rate with the Mediterranean diet was 62% (95% CI 0.39–0.80). Remission rates were similar between Crohn’s disease and ulcerative colitis: CD: RR 0.67 UC: RR 0.56 When compared with control diets, the Mediterranean diet did not show a statistically significant advantage for inducing remission (OR 0.98). Endoscopic and histological outcomes were not reported in the available studies. Conclusion The Mediterranean diet, when used alongside conventional medical therapy, is associated with a moderate clinical remission rate (~62%) in IBD, with comparable benefits in both CD and UC. However, current evidence is limited by small sample sizes, heterogeneity in study design, and lack of objective outcomes such as endoscopic healing. Further well-designed randomised controlled trials are required to determine the true impact of the Mediterranean diet on mucosal healing, disease activity, and long-term outcomes in IBD.

Microbiome Signature at IBD Onset: Gastroenterology | March 2026

Introduction Most microbiome studies in inflammatory bowel disease (IBD) are confounded by prior treatment, long disease duration, and inconsistent sequencing/bioinformatic methods—making “core” signatures hard to trust. This systematic review tackles a key unmet question: what does the gut microbiome look like at diagnosis, before therapy starts? The authors go a step further than conventional meta-analysis by reprocessing raw 16S sequence datasets through a single unified pipeline mapped to updated taxonomy, aiming to identify reproducible microbial perturbations in treatment-naïve new-onset Crohn’s disease (CD) and ulcerative colitis (UC). Summary Across 36 eligible studies, 18 contributed raw sequencing data for unified reanalysis and 24 contributed to supplementary meta-analysis. The pooled dataset included samples from 1743 individuals (CD, UC, healthy controls, and symptomatic non-IBD controls), with a large proportion of mucosal biopsies. Standard meta-analysis proved unreliable due to extreme methodological heterogeneity, so the central contribution was the unified QIIME2 reprocessing with multivariable modeling (MaAsLin2) adjusting for sample type, age group, geography, and sequencing differences. Key findings were consistent across CD and UC at disease onset: depletion of obligate anaerobes and enrichment of aerobic, facultative anaerobic, and microaerophilic bacteria, alongside a striking enrichment of orally associated genera in the gut. Importantly, fecal and mucosal biopsy communities were clearly distinct, and geography also shaped community structure—reinforcing why harmonised reanalysis is necessary. The authors interpret the pattern as support for the “oxygen hypothesis” in early IBD—where inflamed mucosa increases luminal oxygenation, disadvantaging anaerobes and enabling oxygen-tolerant and oral taxa to expand. Clinically, these core signatures may aid earlier diagnosis and risk prediction, and therapeutically they point toward microbiome-targeted strategies—potentially including interventions that alter luminal oxygen availability—especially relevant at diagnosis and in high-risk groups.

Faecal S100A9- A new IBD Biomarker: Gastroenterology | March 2026

Why Look Beyond Fecal Calprotectin? Fecal calprotectin (FC) is one of the most widely used noninvasive biomarkers in inflammatory bowel disease (IBD). It reflects intestinal inflammation through the detection of the S100A8/S100A9 heterotetramer, released primarily from neutrophils. However, FC measurement traditionally focuses on the tetrameric complex, without distinguishing between different molecular configurations of its subunits. Emerging evidence suggests that S100A8 and S100A9 homodimers may have distinct biological and inflammatory functions. In particular, fecal S100A9 has attracted attention as a potentially more sensitive indicator of disease activity and chronic intestinal inflammation. This study explores whether analysing these specific subunits can improve disease monitoring and uncover new therapeutic targets in IBD. Summary Using advanced proteomic analysis, investigators characterized the structural forms of S100A8 and S100A9 proteins present in stool from patients with inflammatory bowel disease. Besides the classic calprotectin heterotetramer, high levels of S100A8 and S100A9 homodimers were detected in active disease. Importantly, fecal S100A9 levels correlated strongly with clinical and endoscopic activity, even in patients with relatively low fecal calprotectin concentrations, suggesting added diagnostic sensitivity. Functional experiments demonstrated that oral exposure to recombinant S100A8 or S100A9 homodimers, but not the calprotectin tetramer, aggravated intestinal inflammation in mouse models of colitis. Mechanistic studies showed that these homodimers enhance activation of CD4⁺ and CD8⁺ T cells, thereby amplifying inflammatory responses. Conversely, genetic deletion of S100a9 protected mice from experimental colitis, and pharmacologic inhibition of S100A9 significantly reduced chronic intestinal inflammation. Together, these findings suggest that fecal S100A9 dimers represent both a novel biomarker and a potential therapeutic target in IBD, linking biomarker detection directly with pathogenic mechanisms of chronic intestinal inflammation.

A Normal UCEIS Is Zero, not Three: Gastroenterology | March 26

Introduction The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) was developed to standardise the endoscopic assessment of ulcerative colitis activity. It evaluates vascular pattern, bleeding, and erosions/ulcers, generating a score reflecting disease severity. Although initially described with a range of 3–11, subsequent validation rebased the scoring system to 0–8, making a completely normal colonoscopy score 0. Despite this revision, confusion about the correct scoring persists in clinical practice and literature. Summary This commentary highlights ongoing misconceptions regarding the UCEIS scoring system and emphasises the importance of adopting the validated 0–8 scale. The rebasing from 3–11 to 0–8 improved clinical interpretation, so a normal colonoscopy now scores 0 rather than 3. However, surveys among inflammatory bowel disease specialists revealed that over one-third still believe a normal colonoscopy corresponds to a score of 3. Literature review also identified multiple publications, guideline documents, and online calculators continuing to reference the outdated scale. This inconsistency may influence research and clinical decision-making, as UCEIS is increasingly used to guide treatment escalation and predict outcomes, including response to intravenous steroids in acute severe ulcerative colitis. The authors call for universal adoption of the validated scoring system and improved educational resources, including standardised image examples for each descriptor. Establishing a common understanding of UCEIS is essential for reliable communication, accurate disease assessment, and consistency across clinical care and research in ulcerative colitis.

VECTORS Trial - BMJ Open Gastro Feb. 26

The VECTORS trial, a landmark phase 4 randomized controlled trial (RCT), was recently published in *BMJ Open Gastroenterology* on February 26. This trial represents a significant step forward in the treatment of Crohn’s disease (CD) by evaluating transmural healing (TMH) as a novel treatment target. The trial explores the potential benefits of targeting deeper levels of disease control beyond the traditional focus on mucosal healing. ### Key Highlights of the VECTORS Trial: #### Purpose and Rationale: - **Transmural Disease in Crohn's**: CD is a transmural inflammatory disease, meaning it affects the entire bowel wall, not just the mucosal lining. Historically, treatment targets have focused on symptom relief or mucosal healing seen through colonoscopy. However, these targets may not address the deeper, transmural nature of the disease. - **Transmural Healing (TMH)**: The trial aims to evaluate TMH as a treatment goal, hypothesising that it could offer more comprehensive disease control, reduce complications, and improve long-term outcomes. #### Trial Design: - **Phase**: Phase 4, multicenter RCT. - **Participants**: 304 patients with moderately to severely active Crohn’s disease. - **Sites and Countries**: Conducted across 66 sites in 13 countries. - **Novel Monitoring Tool**: The trial uses intestinal ultrasound (IUS), a non-invasive, radiation-free, and repeatable imaging tool to monitor TMH. IUS offers real-time insights into bowel wall inflammation, making it a game-changer for tight disease monitoring. #### Treatment Comparison: The trial compares two treatment strategies: 1. **Corticosteroid-free TMH Remission Group**: - TMH assessed via serial IUS. - Combined with clinical and biomarker remission. 2. **Corticosteroid-free Clinical and Biomarker Remission Group**: - Focuses only on clinical and biomarker remission without TMH as a target. #### Endpoints: - **Primary Endpoint**: Corticosteroid-free endoscopic remission at week 48. - **Key Secondary Endpoint**: CD-related complications through week 96, such as strictures, fistulae, and surgeries. ### Why the VECTORS Trial Matters: 1. **Pushes the Boundaries of Treatment**: By moving beyond mucosal healing to target the entire bowel wall, the trial addresses the full scope of Crohn’s disease pathology. 2. **Validates IUS**: Demonstrates the utility of intestinal ultrasound as a safe, accessible, and radiation-free tool for real-time disease monitoring. 3. **Potential to Reduce Complications**: TMH could help prevent long-term complications like strictures, fistulae, and surgeries, which are common in Crohn's disease. 4. **Influences Clinical Guidelines**: If successful, the trial could lead to updated clinical guidelines emphasising TMH as a formal treatment target. 5. **Builds on Previous Successes**: Builds on the "treat-to-target" approach established by prior trials like CALM, but takes it a step further by targeting deeper disease control. ### Summary of Implications: 1. Current treatment targets, such as mucosal healing, may be insufficient to address the transmural nature of Crohn’s disease. 2. TMH could offer a more comprehensive approach to disease management, potentially improving long-term outcomes for patients. 3. The use of IUS as a monitoring tool is a significant advancement, offering a fast, cost-effective, and non-invasive alternative to traditional imaging methods. 4. The VECTORS trial is the first RCT to rigorously test TMH as a treatment target, and its findings could have substantial real-world implications for both patients and clinicians. In conclusion, the VECTORS trial is a groundbreaking study that could redefine treatment strategies for Crohn’s disease, emphasizing the importance of transmural healing and the role of innovative tools like intestinal ultrasound in achieving better patient outcomes.

Caffeine and IBD - JGH Feb 26

This is the first comprehensive meta-analysis examining the relationship between caffeine intake and inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), synthesising data from 21 studies (13,209 participants). Overall, caffeine intake was not significantly associated with total IBD risk. However, important differences emerged in subgroup analyses. For ulcerative colitis, caffeine—particularly from coffee and tea—was associated with a reduced risk, especially in Asia and Europe. Coffee reduced UC risk by 57%, and tea by 46%. In contrast, in the Americas, caffeine intake was associated with an increased UC risk. For Crohn’s disease, no overall association was observed. However, in smokers, caffeine intake increased CD risk by 80%, whereas in non-smokers, the association was neutral or potentially protective. Education level also influenced findings, suggesting lifestyle and socioeconomic confounding. Age was a critical modifier: in individuals ≤18 years, caffeine was associated with markedly increased IBD risk, whereas in adults, the association was neutral to slightly protective. Clinical implications: The relationship between caffeine and IBD appears context-dependent—varying by age, geography, smoking status, and caffeine source. Blanket recommendations are inappropriate. Instead, clinicians should individualise advice, particularly for adolescents and smokers. Further dose-response and mechanistic studies are needed to clarify causality.

Subcutaneous Guselkumab for Crohn’s: Interpreting GRAVITI Carefully- Gastroenterology Feb.26

Introduction Fully subcutaneous biologic regimens are attractive in Crohn’s disease because they can reduce infusion burden and improve convenience. The GRAVITI trial evaluated a fully subcutaneous induction and maintenance strategy with guselkumab (IL-23p19) and reported improvements in clinical remission and endoscopic response through 48 weeks. The key questions raised for GRAVITI 1) Does the endoscopic endpoint reliably reflect inflammation (vs fibrosis)? The coprimary endoscopic endpoint relied on improvement in SES-CD. The critique highlights a real-world limitation: SES-CD can over-score fibrostenotic segments as “active” disease, potentially inflating perceived response. This concern is most relevant in ileal-predominant Crohn’s, where fibrostenotic disease is common. Clinical implication: If fibrotic strictures are misclassified as inflammatory activity, “endoscopic response” may not always mean the drug is reversing active inflammation. What would strengthen confidence: histologic correlation (where feasible), imaging stratification (e.g., MRE features of fibrosis vs inflammation), or predefined exclusion of fixed fibrotic strictures. 2) Does crossover/rescue design distort placebo vs drug comparisons? A major critique is that a substantial proportion of placebo patients crossed over to active therapy early and were then counted as “nonresponders” for placebo in longer-term analyses. Why clinicians should care: This can make: placebos look artificially low long-term, and Active therapy looks stronger by comparison. What would help: reporting outcomes for rescued participants as a separate analytic group, sensitivity analyses that show how rescue impacts the effect size. 3) Is the SC induction dose “validated,” especially in higher-clearance subgroups? The SC induction regimen appears to have been extrapolated from IV data using assumed bioavailability, rather than derived from dedicated SC dose-ranging. The critique emphasises that: Some patients (e.g., higher BMI) may have altered clearance, and without pharmacokinetic (PK) and exposure–response analyses, it’s hard to know whether the SC dose is optimised. Clinical implication: In real practice, heterogeneous PK could mean variable efficacy—especially in patients who need rapid disease control. What would help: through levels and exposure–response relationships, subgroup analyses by BMI, and explicit discussion of underdosing risk vs safety margin. 4) How does SC guselkumab compare with IV induction (the established route)? Even if SC regimens are convenient, clinicians want to know: Is SC truly noninferior to IV for induction? Are there differences in early control, durability, or safety? The critique argues that cross-trial comparisons are not enough, and head-to-head or noninferiority designs would provide the clarity needed to guide route choice. Additional pragmatic points raised Prior IL-23 exposure: With increasing real-world use of IL-23 agents, the key question is whether guselkumab works after prior IL-23p19 therapy (class effect vs meaningful differences). Durability beyond 48 weeks and “deep remission” outcomes: endoscopic healing, sustained steroid-free remission, and persistence/adherence matter for practice. Health system implications: SC induction reduces infusion-centre burden but shifts monitoring and adherence responsibility—raising the need for cost-effectiveness and implementation studies. Bottom-line takeaway: GRAVITI supports the feasibility of fully subcutaneous guselkumab in Crohn’s disease, but important uncertainties remain about endpoint interpretation (fibrosis vs inflammation), rescue-related bias, PK validation across patient subgroups, and how SC compares directly with IV induction. Clinicians should view the results as promising, not definitive, and await more granular analyses and head-to-head data before changing protocols broadly. One-line GastroAGI takeaway SC guselkumab in Crohn’s looks promising—but GRAVITI’s design leaves key unanswered questions about “true” endoscopic benefit and real-world dosing.

Inpatient IBD Care: Practical Guidance From the AGA- Gastroenterology Feb.26

Introduction Despite major advances in outpatient therapies, hospitalisation for inflammatory bowel disease (IBD) remains common and challenging. Outcomes vary widely, with persistent problems such as: hospital-acquired complications, delays in appropriate surgery, and high 30-day readmission rates. To reduce this variability and improve outcomes, the American Gastroenterological Association (AGA) released this Clinical Practice Update to provide clear, pragmatic Best Practice Advice for the inpatient management of adults with ulcerative colitis (UC) and Crohn’s disease (CD). What this document is (and is not) This is an expert review, not a formal guideline. Recommendations are based on best available evidence plus expert consensus. The focus is on real-world inpatient decision-making, not exhaustive literature grading. Core principles that shape inpatient IBD care 1️⃣ Admit early when risk is high Hospitalization should be considered for patients with: severe disease refractory to outpatient therapy, suspected complications (obstruction, abscess, perforation), or significant malnutrition, anemia, or failure to thrive. The modern inpatient population increasingly includes patients failing multiple advanced therapies, not just classic fulminant presentations. 2️⃣ Start with supportive care—but do it well All hospitalised IBD patients should receive: IV fluids and electrolyte correction, anaemia and nutrition assessment (early dietitian involvement), careful pain control (avoid routine opioids), screening for vitamin and iron deficiency. Supportive care is not ancillary—it directly affects outcomes. 3️⃣ Always rule out infection and complications Symptoms in hospitalised IBD patients are frequently driven by: C. difficile, CMV colitis, or structural complications. Early stool testing, cross-sectional imaging when indicated, and targeted endoscopy are essential to avoid inappropriate escalation of immunosuppression. 4️⃣ Use objective disease assessment CRP is emphasised as a real-time inflammatory marker guiding decisions. Endoscopic evaluation (often flexible sigmoidoscopy) should be performed early when feasible, both to assess severity and to obtain biopsies for CMV. Faecal calprotectin may help, but is often delayed in the inpatient setting. 5️⃣ Prevent what is preventable: VTE prophylaxis Hospitalised IBD patients have a markedly increased risk of venous thromboembolism. 👉 All hospitalised IBD patients without contraindications should receive pharmacologic VTE prophylaxis, even in the presence of active bleeding. Disease-specific highlights Acute Severe Ulcerative Colitis (ASUC) IV corticosteroids remain first-line therapy. Response must be assessed within 72 hours using stool frequency and CRP trends. Nonresponse requires early preparation for rescue therapy (infliximab, cyclosporine, or JAK inhibitors) and early surgical consultation. Continuing IV steroids beyond 7 days without response offers no benefit and increases harm. Crohn’s Disease–Related Complications Obstruction: If inflammatory → trial IV steroids. If fibrotic or complicated → surgery. Intra-abdominal abscess: Drainage (when feasible) + antibiotics first. Immunosuppression only after source control. Perianal disease: Requires a multidisciplinary medical–surgical approach from the outset. 6️⃣ Plan discharge early—and deliberately Safe discharge requires: clinical stability (not necessarily normal labs), a clear steroid taper or induction plan, coordination with outpatient providers, and addressing barriers such as insurance approval, transportation, and infusion scheduling. Poor discharge planning is a major driver of readmissions. Why this update matters This document reinforces a shift in inpatient IBD care: from reactive, prolonged hospitalisations to structured, time-bound decision-making with early reassessment, escalation, or surgery. It emphasises that delays—not disease severity alone—often drive poor outcomes. Bottom-line takeaway: High-quality inpatient IBD care depends on early objective assessment, proactive complication management, timely escalation or surgery, and meticulous discharge planning. This AGA update provides a practical roadmap for achieving that consistently. One-line GastroAGI takeaway: In inpatient IBD care, timing and coordination matter as much as therapy choice.

From Treatment to Prevention in IBD - Gastroenterology Feb.26

Introduction Inflammatory bowel disease (IBD) is no longer a condition confined to Western countries. With globalisation, urbanisation, and changing environmental exposures, IBD incidence is rising worldwide, while prevalence in industrialised nations continues to compound. If current trends persist, IBD prevalence may exceed 1% of the population in several countries within the next decade. This consensus-driven paper argues that even modest reductions in incidence could meaningfully reverse long-term prevalence, and that the time has come to shift the IBD paradigm—from reacting to established disease to predicting and preventing it. Why prevention is now realistic Accumulating evidence shows that Crohn’s disease (CD) has a long preclinical phase, marked by: immune activation, gut barrier dysfunction, microbiome alterations, and circulating biomarkers are detectable years before symptoms. These insights mirror earlier breakthroughs in type 1 diabetes, where defining preclinical stages enabled the first approved preventive therapy. The authors argue that IBD is now at a similar inflexion point. The role of the PROMISE Consortium To accelerate progress, PROMISE integrates: prospective cohorts of asymptomatic first-degree relatives (FDRs), large prediagnostic biobanks, and multiomics platforms (genomics, proteomics, microbiome, immune profiling). The goal is not a single biomarker, but integrated risk models that identify individuals most likely to progress to clinical disease—creating a rational entry point for prevention trials. Key challenges that must be solved The workshop identified several critical gaps: 1) Low positive predictive value (PPV) Even strong biomarkers struggle with PPV because IBD prevalence is low. Defining what level of risk justifies intervention—ethically and clinically—remains unresolved. 2) Lack of a preclinical staging system Unlike type 1 diabetes, IBD lacks clearly defined stages before diagnosis. Without staging, it is difficult to time interventions or define trial endpoints. 3) Biological heterogeneity Preclinical pathways may differ by phenotype (ileal vs colonic CD, complicated vs inflammatory disease), demanding phenotype-specific biomarkers. 4) Limited scalable screening tools Most current biomarkers are research-grade. Clinically deployable, reproducible, noninvasive assays are urgently needed. What patients and families think Importantly, patients and unaffected relatives are not resistant to prevention: Most are willing to undergo risk testing, especially blood- or stool-based. Lifestyle-based interventions (diet, exercise, smoking avoidance) are widely acceptable. Acceptance of drug-based prevention depends on perceived risk and benefit. This underscores the need for risk counselling, shared decision-making, and close partnership with patient advocacy groups. A prevention framework for IBD The authors outline a risk-based prevention strategy: Population-level (primordial prevention): Healthy diet, physical activity, smoking avoidance, and reduced antibiotic exposure. High-risk individuals (primary prevention): Targeted lifestyle and dietary interventions in FDRs or genetically susceptible individuals. Preclinical disease (secondary prevention): Trials testing whether immune- or microbiome-targeted therapies can delay or prevent disease onset. Several dietary, microbial, and biologic interception trials are already underway. Call to action The paper concludes with a strong, unified message: Prediction and prevention of IBD will not happen without global coordination. Priorities include: integrating preclinical cohorts worldwide, standardising biomarker platforms, establishing high-risk clinics, designing ethically sound prevention trials, and embedding patients and families at every stage. Bottom-line takeaway: IBD is no longer a disease we must wait to diagnose. With emerging biomarkers, longitudinal cohorts, and lessons from other immune-mediated diseases, prediction and prevention are now scientifically plausible. What’s needed next is coordinated investment, consensus, and courage to rethink how—and when—we intervene. One-line GastroAGI takeaway: The future of IBD care may begin years before symptoms—if we choose to act.

Nutrition management puzzle in IBD- Front. Med. 2026

### Nutritional Management in IBD: Current Insights 1. **Importance of Nutrition in IBD**: - Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is influenced by genetic, immunological, environmental, and gut microbiota factors. - Nutrition plays a critical role in managing IBD, not only to support remission and reduce inflammation but also to prevent complications like malnutrition, osteoporosis, and sarcopenia. 2. **Challenges in Nutritional Management**: - IBD patients often experience malnutrition due to inflammation, dietary restrictions, medication side effects, and rapid weight loss. - Vitamin and mineral deficiencies, particularly vitamin D, are common and can lead to complications such as impaired immune function and bone health issues. 3. **Dietary Interventions**: - **Low-FODMAP Diet**: Combining a low-FODMAP diet with enteral nutrition has been shown to reduce inflammation (e.g., C-reactive protein levels) and improve nutritional markers like albumin. - **IgG-Elimination Diet (IgG-ED)**: This diet has shown promising results in achieving endoscopic remission in IBD patients. - **Protein Intake**: Adequate protein intake is essential to prevent muscle loss and sarcopenia, which can lower the risk of surgical interventions. - **Vitamin D Supplementation**: Maintaining serum levels of 25-hydroxyvitamin D above 75 nmol/L is crucial. Aerosol forms of vitamin D may require lower doses compared to oral supplementation, offering a practical advantage. 4. **Nutritional Risk and Socioeconomic Factors**: - Malnutrition is prevalent in over one-third of IBD patients, with socioeconomic factors such as lower income contributing to higher disease activity. - Nutritional education, socioeconomic support, and regular monitoring of nutritional status are vital components of IBD management. 5. **Preventive and Therapeutic Role of Nutrition**: - Early implementation of enteral nutrition, anti-inflammatory diets, and personalized nutritional strategies can prevent disease progression and alleviate symptoms. - Addressing sarcopenia through dietary and physical interventions can reduce the risk of surgery in IBD patients. 6. **Tailored Nutrition**: - There is no universal diet for IBD, as different clinical goals (e.g., reducing inflammation, improving nutritional status, achieving remission) require individualised approaches. - Comprehensive and personalised nutritional care should be an integral part of IBD therapy.

The PIONIR Trial - Gut Jan. 2026

The PIONIR (Preventing IBD ONset in Individuals at Risk) trial, as described in the study published in *Gut*, January 2026, focuses on evaluating whether the Tasty&Healthy diet can reduce the risk of developing Crohn’s disease (CD) in first-degree relatives (FDRs) of CD patients. This trial is significant because FDRs are at a higher genetic and environmental risk of developing CD. The study also addresses the challenge of identifying the optimal preclinical stage of CD for enrolling participants in prevention trials. In the pre-PIONIR screening stage, faecal calprotectin, a biomarker of intestinal inflammation, was measured in asymptomatic FDRs aged 6–38 years. Of the 950 individuals approached, 331 (35%) participated in the screening. Persistent elevation of calprotectin (>70 µg/g in at least two tests) was observed in 63 individuals (19% of those screened). Further diagnostic evaluations (via panenteric video capsule-endoscopy or ileocolonoscopy) revealed that 9 individuals (2.7%) had endoscopic findings consistent with presymptomatic CD. Another 33 individuals (17.9% of those screened) were categorized as having "potential pre-CD" based on non-specific mucosal changes or histological inflammation. The study demonstrated that calprotectin levels >225 µg/g were highly predictive of presymptomatic CD, with an area under the receiver operating characteristic curve of 0.97, sensitivity of 89%, and specificity of 94%. Additionally, the findings underscored the variability in single calprotectin measurements, with 22% of cases normalizing upon repeat testing. In conclusion, the PIONIR trial highlights the utility of faecal calprotectin as a tool for identifying at-risk individuals and emphasizes the importance of early detection in designing preventive strategies for CD. The findings pave the way for future prevention trials targeting high-risk populations.

Biological and chronic pouchitis (AP&T) - Jan,2026

I am unable to provide information from the future (e.g., January 2026) as my training data only includes content up to October 2023. However, I can provide you with detailed insights into the role of biologics in chronic pouchitis based on current knowledge and the provided context. ### Chronic Pouchitis Overview: Chronic pouchitis is a persistent inflammation of the ileal pouch created during ileal pouch-anal anastomosis (IPAA) surgery, typically performed in patients with ulcerative colitis (UC) who require colectomy. While pouchitis is a common complication after IPAA, chronic pouchitis refers to cases that are resistant to conventional treatment, such as antibiotics, and require long-term management strategies. Chronic pouchitis can significantly impair a patient's quality of life and poses a therapeutic challenge due to its refractory nature. ### Role of Biologics in Chronic Pouchitis: Biological therapies have emerged as a critical option for managing chronic pouchitis, especially in cases where conventional therapies fail. Biologics target specific components of the immune system to reduce inflammation and improve symptoms. The two biologics discussed in the study you provided are **ustekinumab** and **vedolizumab**, both of which have distinct mechanisms of action. 1. **Ustekinumab**: - **Mechanism of Action**: Ustekinumab is a monoclonal antibody that targets interleukin (IL)-12 and IL-23, key cytokines involved in the inflammatory pathways of autoimmune diseases, including inflammatory bowel disease (IBD). - **Efficacy in Chronic Pouchitis**: According to the study, ustekinumab was associated with significantly lower relapse rates, a longer time to relapse, reduced hospitalization, and decreased need for steroids or antibiotics compared to vedolizumab. These findings suggest that ustekinumab may be more effective in controlling inflammation and maintaining remission in chronic pouchitis. 2. **Vedolizumab**: - **Mechanism of Action**: Vedolizumab is an integrin inhibitor that specifically targets the gut by blocking α4β7 integrin, which prevents lymphocyte trafficking to the intestinal mucosa. This gut-specific mechanism makes vedolizumab a preferred option for some IBD patients. - **Efficacy in Chronic Pouchitis**: While vedolizumab is effective for some patients, the study indicates that it may not be as effective as ustekinumab in reducing relapse rates and preventing hospitalizations in chronic pouchitis. However, no differences were observed in surgery rates or therapy switching between the two drugs. ### Summary of Findings: - Ustekinumab appears to offer advantages over vedolizumab in managing chronic pouchitis, with better outcomes in terms of relapse prevention, reduced hospitalizations, and decreased dependency on steroids or antibiotics. - Both biologics are valuable options, but patient-specific factors, including disease severity, prior treatment response, and comorbidities, should guide therapy selection. ### Future Directions: Research into biologics for chronic pouchitis is ongoing. Future studies may explore: - Long-term safety and efficacy of ustekinumab and vedolizumab. - Head-to-head comparisons with other biologics (e.g., anti-TNF agents like infliximab or adalimumab). - Biomarkers to predict response to biologic therapy. - Combination therapies or adjunctive treatments to enhance outcomes. If you have further questions or need clarification on specific aspects of biologics in chronic pouchitis, feel free to ask!

SHINE -1 - Mirikizumab in UC

The SHINE-1 trial was a multicentre, open-label, non-randomised phase 2 study designed to evaluate the efficacy, safety, and pharmacokinetics of mirikizumab in paediatric participants aged 2 to <18 years with moderately-to-severely active ulcerative colitis (UC). Mirikizumab is a humanised immunoglobulin G4 monoclonal antibody that targets the p19 subunit of IL-23, a cytokine implicated in inflammatory pathways. The study enrolled 26 participants from Canada, Israel, Japan, South Korea, and the USA who had inadequate response, loss of response, or intolerance to corticosteroids, immunomodulators, biologics, or JAK inhibitors. Participants received intravenous mirikizumab induction doses at weeks 0, 4, and 8, followed by subcutaneous maintenance doses for responders. At week 12, 69.2% of participants achieved clinical response by modified Mayo score (mMS), with 38.5% achieving clinical remission. By week 52, 53.8% maintained mMS-based clinical response, while 38.5% achieved clinical remission without corticosteroid use or UC-related surgery. Endoscopic remission, histologic-endoscopic mucosal improvement, and symptomatic remission were also observed. Mirikizumab demonstrated a favourable safety profile, with most adverse events being mild or moderate. Serious adverse events occurred in 12% of participants, with one leading to study discontinuation. These findings support further investigation of mirikizumab for paediatric UC treatment.

Etrasimod for the symptomatic relief of ulcerative colitis

Etrasimod is a novel oral medication approved for the treatment of moderately to severely active ulcerative colitis (UC). It is a selective sphingosine 1-phosphate (S1P) receptor modulator that targets S1P receptors 1, 4, and 5, which play a role in regulating immune cell migration and inflammation. By modulating these receptors, etrasimod helps reduce inflammation in the gastrointestinal tract, leading to symptomatic relief for patients with UC. ### Key Findings from the ELEVATE UC Clinical Programme: The efficacy of etrasimod for UC was evaluated in the phase III ELEVATE UC clinical trials, which included the ELEVATE UC 52 and ELEVATE UC 12 studies. These trials assessed the impact of etrasimod on key patient-reported symptoms, including stool frequency (SF), rectal bleeding (RB), bowel urgency, and abdominal pain. These symptoms are critical to address, as they significantly impair the quality of life and contribute to treatment dissatisfaction among UC patients. #### Study Design: - **Participants**: Adults with moderately to severely active UC. - **Treatment Groups**: Patients were randomized in a 2:1 ratio to receive either etrasimod 2 mg once daily or a placebo. - **Endpoints**: - **Symptomatic remission**: Normalization of RB and SF scores. - **Symptomatic response**: Significant improvement in RB and SF scores. - **Complete symptomatic remission**: Resolution of all symptoms, including bowel urgency and abdominal pain. #### Results: 1. **Rapid and Sustained Symptom Relief**: - Etrasimod provided significant improvements in symptoms compared to placebo as early as weeks 2 to 4. - Benefits were sustained through week 52, demonstrating the durability of its therapeutic effects. 2. **Improvement in Key Symptoms**: - Rapid reductions in rectal bleeding (RB) and stool frequency (SF) were observed in patients treated with etrasimod. - Clinically meaningful reductions in bowel urgency and abdominal pain were achieved, with higher rates of remission for these symptoms at weeks 12 and 52. 3. **Consistency Across Patient Subgroups**: - The benefits of etrasimod were observed regardless of baseline disease severity, prior exposure to biologics or JAK inhibitors, or corticosteroid use. - However, treatment-naïve patients (those who had not received prior biologic or advanced therapy) experienced more pronounced responses. 4. **Impact on Patient Well-Being**: - By addressing key symptoms like bowel urgency and abdominal pain, etrasimod significantly improved patient well-being and treatment satisfaction. ### Clinical Implications: Etrasimod represents a promising treatment option for UC patients due to its ability to provide rapid, durable, and clinically meaningful symptom relief. Its oral, once-daily administration is convenient for patients, and its efficacy in reducing debilitating symptoms such as bowel urgency, rectal bleeding, and abdominal pain can lead to improved quality of life. ### Summary: Etrasimod is a highly effective therapy for achieving symptomatic relief in patients with moderately to severely active ulcerative colitis. The results from the ELEVATE UC trials underscore its ability to deliver rapid and sustained improvements in key symptoms, making it a valuable addition to the therapeutic landscape for UC. Its consistent efficacy across diverse patient populations further supports its role in improving treatment outcomes and patient satisfaction.

Cardiovascular events observed among patients in the etrasimod clinical programme

The cardiovascular events observed among patients in the etrasimod clinical program were evaluated as part of an integrated safety analysis, focusing on treatment-emergent adverse events (TEAEs) associated with etrasimod. Here are the detailed findings: ### 1. **Bradycardia**: - Bradycardia (slower than normal heart rate) occurred more commonly in patients treated with etrasimod compared to placebo. - These events were generally mild or moderate in severity. - Bradycardia was most often observed on the first day of treatment initiation. - The events were transient and typically resolved without requiring medical intervention. - Serious conduction abnormalities related to bradycardia were rare. ### 2. **Atrioventricular (AV) Block**: - AV block (a type of heart block affecting electrical conduction between the heart's chambers) was also more frequent in the etrasimod group. - Similar to bradycardia, these events were mild or moderate, transient, and primarily occurred shortly after starting treatment. - Serious AV block events were rare. ### 3. **Hypertension**: - Hypertension-related events (elevated blood pressure) were slightly more common with etrasimod than with placebo. - These events were generally manageable and classified as non-serious. - Hypertension-related events did not lead to treatment discontinuation. ### 4. **Major Cardiovascular Events (CAD and CVD)**: - The analysis also monitored for major cardiovascular events such as coronary artery disease (CAD) and cerebrovascular disease (CVD). - The incidence rates of CAD and CVD were very low across all study cohorts, including both etrasimod-treated and placebo groups. ### Summary of Cardiovascular Safety: - Overall, cardiovascular-related TEAEs were infrequent in the etrasimod clinical program. - Most events were mild to moderate, transient, and resolved without intervention. - Serious cardiovascular events, including conduction abnormalities, were rare. - The results suggest that etrasimod has a favorable cardiovascular safety profile in patients with moderately to severely active ulcerative colitis. ### Conclusion: The study supports the continued use of etrasimod in this patient population, with appropriate clinical monitoring to manage cardiovascular risks, particularly during the initial stages of treatment.

QUOTIENT Trial: Treat-to-Target Endoscopic Remission in IBD on Advanced Therapies

The QUality Outcomes Treating IBD to Target (QUOTIENT) trial is a significant, pragmatic, open-label, multicentre randomised controlled study that addresses a critical question in the management of inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis. It focuses on the "treat-to-target" approach, specifically targeting endoscopic or radiological remission in patients who are already on advanced therapies. ### Objective: The trial investigates whether switching advanced therapies in asymptomatic patients with persistent subclinical inflammation (as seen on endoscopy or radiology) improves long-term outcomes. Persistent inflammation in these patients is linked to higher risks of disease relapse, complications, increased healthcare utilisation, and reduced quality of life. The study compares two treatment strategies: 1. **Continuing the current advanced therapy (index therapy).** 2. **Switching to an alternative advanced therapy.** The trial's overarching goal is to determine if switching therapies can help achieve endoscopic or radiological remission and improve patient outcomes in the long term, without adding harm or treatment burden. --- ### Study Design: - **Type of Study:** Pragmatic, open-label, multicentre randomised controlled trial. - **Participants:** Approximately 250 adult patients with Crohn’s disease or ulcerative colitis across the USA and Canada. - Inclusion criteria: Patients must be in corticosteroid-free symptomatic remission but have moderate-to-severe endoscopic or radiological inflammation. - **Randomisation:** Participants are randomised 1:1 to either continue their current advanced therapy or switch to an alternative advanced therapy. - **Duration:** Follow-up for 104 weeks in routine clinical practice. --- ### Primary Endpoint: The primary endpoint is **time to treatment failure**, which is a composite outcome including: - Symptomatic relapse requiring treatment escalation. - Corticosteroid use. - IBD-related hospitalisation or surgery. - Development of structural complications. - Treatment-emergent adverse events leading to discontinuation of therapy. --- ### Secondary Outcomes: The trial also evaluates several secondary outcomes, focusing on patient-centred measures: - **Quality of life:** Assessing how the disease and its treatment impact the patient’s overall well-being. - **Treatment burden:** Evaluating the effort, time, and resources required for treatment. - **Patient satisfaction:** Measuring how satisfied patients are with their treatment approach. - **Patient costs:** Understanding the financial impact of treatment strategies. - **Safety:** Monitoring adverse events and complications from treatments. --- ### Significance: The QUOTIENT trial is designed to reflect real-world clinical practice, moving beyond procedural or laboratory-driven targets to emphasise patient-reported outcomes and practical effectiveness. It aims to answer a key clinical question: should asymptomatic IBD patients with ongoing subclinical inflammation switch therapies to achieve deeper remission, or should they continue their current therapy? This study is expected to directly influence clinical guidelines, shared decision-making between patients and physicians, and patient education about treat-to-target strategies in IBD. By prioritising long-term outcomes and real-world applicability, QUOTIENT has the potential to significantly improve the standard of care for IBD patients on advanced therapies.

Biologic Switch Timing and Infection Risk in Ulcerative Colitis and Crohn’s Disease

The study in question investigates the timing of biologic switches and their impact on infection risk in patients with Ulcerative Colitis (UC) and Crohn’s Disease (CD). It specifically examines the difference in infection risk between overlapping switches (OS), where the switch occurs within less than 5 half-lives of the prior biologic, and non-overlapping switches (NOS), where the switch occurs after more than 5 half-lives. ### Key Findings: 1. **Study Population and Methodology**: - The study analyzed data from 11,992 biologic-naïve adults with UC or CD who initiated biologic therapy between 2017 and 2022. - Among these, 1,293 patients underwent a biologic switch and were categorized into OS (<5 half-lives) and NOS (>5 half-lives) groups. - Infection outcomes were evaluated over a 90-day follow-up using advanced statistical models to account for confounding variables. 2. **Prevalence of Overlapping Switches**: - Overlapping switches were common, comprising 64.2% of all biologic switches. 3. **Infection Risk Outcomes**: - The adjusted incidence rates of both any infection and serious infections (requiring hospitalization) were similar between the OS and NOS groups. - There were no statistically significant differences in the adjusted hazard ratios for serious infections between the two switching strategies. - Sensitivity analyses using alternative washout periods (e.g., 28 days or 3 half-lives) showed consistent results. However, a slight increase in non-serious infections was observed with very short washout periods. 4. **Implications for Clinical Practice**: - The findings suggest that overlapping biologic switches do not elevate the risk of serious infections in UC/CD patients. - Shorter washout periods may be safe and could enable more timely disease control, improving patient outcomes and clinical trial feasibility. - This challenges the FDA’s recommendation for a 5 half-life washout period, providing evidence for more flexible switching strategies in real-world clinical practice. ### Conclusion: The study provides reassurance that overlapping biologic switches can be safely performed without increasing the risk of serious infections in patients with UC or CD. This supports the adoption of more flexible switching strategies, which may help achieve better disease management and timely treatment adjustments.

Fecal Calprotectin Reflects Disease Extent and Mucosal Healing in Ulcerative Colitis

Yes, fecal calprotectin (FC) reflects both disease extent and mucosal healing in ulcerative colitis (UC), as demonstrated by the findings of the prospective observational study mentioned in the context. Here's a detailed explanation based on the study: ### Key Findings: 1. **FC as a Marker of Mucosal Inflammation:** - FC levels were found to correlate strongly with mucosal inflammation in UC patients. Higher FC concentrations were consistently associated with active inflammation, as assessed both endoscopically (using the Mayo Endoscopic Score, MES) and histologically (using the Nancy Histological Index, NHI). - This confirms FC as a robust and reliable biomarker for detecting mucosal inflammatory activity. 2. **Impact of Disease Extent on FC Levels:** - The study revealed that FC levels are influenced by the extent of UC, which is classified according to the Montreal classification into proctitis (limited to the rectum), left-sided colitis (involving up to the splenic flexure), and pancolitis (extending to the entire colon). - FC concentrations were progressively higher as disease extent increased, even in patients in remission. Patients with pancolitis had the highest FC levels, followed by those with left-sided colitis and proctitis. 3. **FC and Mucosal Healing Across Disease Extent:** - Despite the influence of disease extent on FC levels, the biomarker maintained high diagnostic accuracy for identifying mucosal healing across all disease extent categories. The area under the receiver-operating characteristic curve (AUROC) for FC ranged from 0.878 to 0.915, indicating excellent performance in detecting mucosal healing. - No statistically significant differences in diagnostic accuracy were observed between the different disease extent groups, highlighting FC's reliability regardless of whether the disease is limited or extensive. 4. **Primary vs. Secondary Determinants of FC Levels:** - The study concluded that inflammatory activity is the primary determinant of FC levels, while disease extent has a secondary effect. This means FC is mainly driven by the degree of mucosal inflammation, but disease extent also contributes to the observed FC values. ### Clinical Utility of FC: - FC serves as a noninvasive, reliable biomarker for monitoring mucosal healing in UC patients, which is critical for assessing disease activity and guiding treatment decisions. - It is effective across all disease extents, including limited forms such as proctitis, making it a valuable tool for clinicians managing UC patients. ### Conclusion: Fecal calprotectin reflects both the extent of disease and mucosal healing in ulcerative colitis. It is primarily influenced by inflammatory activity but also shows secondary variation based on disease extent. Importantly, FC remains highly accurate in diagnosing mucosal healing, regardless of the disease's extent, supporting its use as a noninvasive biomarker in clinical practice.

Long-Term Safety of Mirikizumab in Moderate-to-Severe Ulcerative Colitis

The long-term safety of mirikizumab, an anti–interleukin-23p19 monoclonal antibody, for the treatment of moderately to severely active ulcerative colitis was evaluated over a 2-year period of continuous treatment. This analysis pooled data from three phase 3 clinical trials—LUCENT-1 (induction phase), LUCENT-2 (maintenance phase), and LUCENT-3 (long-term extension phase)—and included 482 patients who were categorized as induction responders and extended-induction responders. ### Key Findings: 1. **Safety Profile Consistency**: - The safety profile of mirikizumab was consistent across both responder cohorts and aligned with previously reported findings from earlier studies. - No new safety signals emerged during the 2-year treatment period, indicating a stable long-term safety profile. 2. **Adverse Events (AEs)**: - Most adverse events were mild to moderate in severity. - The most frequently reported adverse events included: - **Nasopharyngitis** - **COVID-19** - **Arthralgia (joint pain)** - **Ulcerative colitis symptom worsening** - **Headache** - Serious adverse events (SAEs) occurred in fewer than 10% of patients, and treatment discontinuation due to adverse events was uncommon. 3. **Infections**: - Infections were reported in approximately half of the patients, but the majority were mild. - Rates of serious and opportunistic infections were low. 4. **Injection-Site Reactions**: - Injection-site reactions were infrequent and decreased over time, particularly after the initial subcutaneous doses. 5. **Subgroup Analysis**: - Rates of malignancy, major adverse cardiovascular events, depression, and hepatic abnormalities were low and comparable across clinically relevant subgroups. - Older patients (aged 60 years or older) had a higher incidence of hypertension but did not show a disproportionate increase in serious infections or malignancies. - Patients using corticosteroids and/or immunomodulators at baseline did not exhibit any significant safety concerns. ### Overall Conclusion: The findings from this integrated safety analysis support a favorable and stable long-term safety profile for mirikizumab in the treatment of moderately to severely active ulcerative colitis. The safety outcomes were consistent across various subgroups, including older patients and those receiving concomitant immunosuppressive therapy. These results provide reassurance for its use in clinical practice over extended treatment durations.

Patient Risk Tolerance for Dual Biologic Therapy in Inflammatory Bowel Disease

The study on patient risk tolerance for dual biologic therapy (DBT) in inflammatory bowel disease (IBD) revealed several important insights into how patients with Crohn's disease (CD) and ulcerative colitis (UC) weigh the benefits and risks of treatment. Here is a detailed breakdown: ### 1. **Willingness to Accept Risk for Better Efficacy** - Patients demonstrated a clear willingness to accept significant risks, including the risk of serious infections, if it meant achieving meaningful improvements in remission rates. - Specifically, patients were willing to accept up to a **17.5% risk of serious infection** to improve the probability of remission from 50% to 70%. - This highlights the high value patients place on achieving remission, even in the context of potentially severe side effects. ### 2. **Efficacy as a Key Driver** - Across all patient groups, the **chance of remission** was a primary factor influencing treatment decisions. The possibility of achieving better disease control was prioritized over other considerations, such as treatment type. ### 3. **Safety as a Top Priority** - Despite their willingness to accept risks for better efficacy, safety concerns—particularly the **risk of serious infection**—were still the most important attribute overall in treatment decision-making. - This underscores the delicate balance between the desire for improved outcomes and the apprehension about adverse effects. ### 4. **Differences Between CD and UC Patients** - **Crohn’s disease patients** were more willing to accept higher infection risks in exchange for greater efficacy compared to **ulcerative colitis patients**. This difference may reflect variations in disease burden, treatment experiences, or perceived severity between the two conditions. ### 5. **Preference for DBT vs. Monotherapy** - Interestingly, patients did not show a strong preference for dual biologic therapy (DBT) over biologic monotherapy. This suggests that the type of therapy itself was less important than its ability to deliver effective and safe outcomes. ### 6. **Strong Aversion to Corticosteroids** - Patients expressed a strong dislike for corticosteroids, even when presented with scenarios involving zero risk of serious infection. This reflects the negative experiences and long-term side effects often associated with steroid use in IBD management. ### 7. **Quantified Risk Tolerance** - The study quantified risk tolerance, providing valuable insights into the trade-offs patients are willing to make. This information can guide clinicians and researchers in designing treatment strategies and clinical trials that align with patient priorities. ### 8. **Clinical Implications** - The findings emphasize the importance of incorporating patient preferences and risk tolerance into treatment planning for IBD. Shared decision-making is critical to ensure that therapies are tailored to individual needs and values. - The study also provides direct guidance for designing and interpreting clinical trials of dual biologic therapies, ensuring that outcomes align with patient expectations. ### 9. **Real-World Relevance** - The study recruited patients from a physician-verified IBD registry, ensuring that the findings are highly relevant to real-world clinical practice. All participants represented a difficult-to-treat population, having failed or currently receiving advanced therapies. ### Conclusion: Patients with IBD, especially those with prior treatment failures, are willing to accept substantial risks for treatments that offer higher chances of remission. While safety remains a top priority, efficacy is a key driver of treatment choices, and corticosteroids are strongly disliked. These insights underline the importance of personalized treatment strategies and shared decision-making, particularly for advanced therapies like dual biologic therapy.

Diagnostic Accuracy of Noninvasive Biomarkers and Imaging for Postoperative Crohn’s Disease Recurrence

The diagnostic accuracy of noninvasive biomarkers and imaging for detecting postoperative Crohn’s disease recurrence has been extensively studied and compared to the gold standard, ileocolonoscopy. Below is a detailed breakdown of the findings: ### 1. **C-Reactive Protein (CRP)** - **Sensitivity**: CRP exhibited **low sensitivity**, meaning it is not reliable for identifying all cases of postoperative Crohn’s disease recurrence. Many cases may go undetected if CRP is used as a standalone test. - **Specificity**: CRP showed **high specificity**, indicating that elevated CRP levels are strongly associated with the presence of recurrence. This makes CRP useful for confirming recurrence when levels are elevated. - **Conclusion**: Due to its poor sensitivity, CRP is not suitable as a standalone diagnostic tool but can complement other tests when recurrence is suspected. --- ### 2. **Fecal Calprotectin** - **Sensitivity**: Fecal calprotectin demonstrated **good sensitivity** at **low thresholds**, making it effective for detecting endoscopic recurrence after surgery. - **Specificity**: The specificity of fecal calprotectin was **limited**, especially at lower thresholds, leading to a higher rate of false positives. - **Threshold-Dependent Performance**: The diagnostic accuracy of fecal calprotectin varied significantly based on the cutoff value used. Lower thresholds improved sensitivity but reduced specificity, while higher thresholds improved specificity but missed some cases. - **Conclusion**: Fecal calprotectin is a valuable tool for identifying recurrence, especially when sensitivity is prioritized, but it requires careful interpretation based on the chosen threshold. --- ### 3. **Cross-Sectional Imaging (CT Enterography - CTE and MR Enterography - MRE)** - **Sensitivity**: Both CTE and MRE demonstrated **high sensitivity**, making them effective for detecting postoperative recurrence, including transmural or extraluminal disease not visible on endoscopy. - **Specificity**: The specificity of CTE and MRE was **moderate**, meaning that while they are effective at detecting recurrence, they may also yield false positives. - **Conclusion**: Cross-sectional imaging is particularly useful for identifying recurrence and assessing disease beyond the mucosal layer, but its moderate specificity necessitates confirmation with other tests in some cases. --- ### 4. **Intestinal Ultrasound (IUS)** - **Sensitivity**: IUS showed **high sensitivity**, comparable to cross-sectional imaging, for detecting recurrence. - **Specificity**: The specificity of IUS was **moderate to good**, depending on the criteria used. - **Optimized Criteria**: Using optimized sonographic definitions, such as higher bowel wall thickness thresholds, improved the specificity of IUS. - **Operator Dependence**: The performance of IUS is highly dependent on the expertise of the operator and the use of standardized techniques. - **Conclusion**: IUS is a promising noninvasive tool for detecting recurrence, particularly when performed by skilled operators using optimized criteria. --- ### 5. **Combined Testing Strategies** - Combining biomarkers (e.g., fecal calprotectin) with imaging (e.g., MRE, CTE, or IUS) improved diagnostic confidence compared to using single tests alone. - This approach leverages the strengths of each modality and reduces the likelihood of false negatives or false positives. --- ### 6. **Risk-Stratified Approach** - Noninvasive tools are most effective when applied according to a patient’s risk for postoperative recurrence. For example: - **Low-Risk Patients**: Normal fecal calprotectin and imaging results may allow for the safe deferral of routine colonoscopy. - **High-Risk Patients**: Abnormal noninvasive test results should prompt colonoscopy to confirm recurrence and guide treatment. --- ### 7. **Clinical Implications** - Incorporating noninvasive biomarkers and imaging into routine surveillance can significantly reduce the burden of colonoscopy while maintaining effective monitoring of postoperative Crohn’s disease recurrence. - However, colonoscopy remains essential when noninvasive tests yield abnormal results or when treatment escalation is being considered. --- ### Summary of Diagnostic Accuracy: | **Modality** | **Sensitivity** | **Specificity** | **Key Strengths** | **Limitations** | |-------------------------|-----------------|-------------------------|----------------------------------------------------|-------------------------------------------| | **CRP** | Low | High | Useful for confirming recurrence when elevated | Poor sensitivity; not reliable alone | | **Fecal Calprotectin** | High (low thresholds) | Moderate to Low (low thresholds) | Good for detecting recurrence; noninvasive | Threshold-dependent; false positives | | **CTE/MRE** | High | Moderate | Detects transmural/extraluminal disease | Moderate specificity | | **IUS** | High | Moderate to Good | Noninvasive; operator-dependent; optimized criteria improve accuracy | Operator-dependent; requires expertise | | **Combined Tests** | Improved | Improved | Higher diagnostic confidence | Resource-intensive | In conclusion, noninvasive biomarkers and imaging provide valuable tools for monitoring postoperative Crohn's disease recurrence. While they cannot completely replace colonoscopy, they offer effective alternatives for reducing the frequency of invasive procedures, particularly in low-risk patients.

Real-World Effectiveness and Safety of Upadacitinib in Crohn’s Disease

The real-world effectiveness and safety of upadacitinib in Crohn’s disease were assessed in a multicenter retrospective study involving 9 tertiary inflammatory bowel disease (IBD) centers across North America. This study provided insights into the use of upadacitinib in routine clinical practice, focusing on a large cohort of patients with moderate-to-severe Crohn’s disease who were often refractory to prior treatments. Below is a detailed summary of the findings: ### **Study Overview** - **Patient Population**: The study included 334 adults with active Crohn’s disease, most of whom had a long disease duration and significant prior exposure to advanced therapies, including biologics or small molecules. - **Treatment Protocol**: Upadacitinib, an oral JAK1 inhibitor, was administered as 45 mg daily for induction, followed by 30 mg daily for maintenance therapy in the majority of patients. --- ### **Effectiveness Outcomes** 1. **Clinical Remission**: - **At 12 Weeks**: Over half of the patients achieved clinical remission by the end of the induction period. - **At 6 Months**: Clinical remission rates were maintained or improved in patients who continued on treatment, demonstrating sustained effectiveness. 2. **Endoscopic Healing**: - Endoscopic remission, reflecting meaningful mucosal healing, was achieved in more than 40% of evaluated patients at 6 months. 3. **Therapy-Naïve Patients**: - Patients who were naïve to advanced therapies (biologics or small molecules) had the highest rates of clinical and endoscopic remission, suggesting upadacitinib may be particularly effective in this subgroup. 4. **Refractory Patients**: - Even in patients with prior exposure to multiple biologics or small molecules, upadacitinib demonstrated effectiveness, underscoring its utility in refractory cases. 5. **Impact of Disease Duration**: - Longer disease duration was associated with lower odds of achieving remission, indicating that earlier intervention may yield better outcomes. 6. **Predictors of Response**: - **Negative Predictor**: Higher body mass index (BMI) independently reduced the likelihood of achieving clinical remission. - **Positive Predictor**: Higher baseline albumin levels were associated with better clinical outcomes. 7. **Disease Location**: - Short-term remission rates were comparable between patients with ileal-dominant and colon-dominant Crohn’s disease. 8. **Biomarker and Imaging Improvement**: - Significant reductions in C-reactive protein (CRP) levels were observed, indicating biological anti-inflammatory effects. - Radiographic imaging showed improvement or resolution of inflammation in the majority of assessed patients. 9. **Histologic Outcomes**: - Histologic remission was achieved in a smaller subset of patients, reflecting stringent criteria and limited biopsy data. 10. **Steroid-Sparing Effect**: - Most patients who achieved remission were able to discontinue corticosteroids by follow-up, highlighting the steroid-sparing potential of upadacitinib. --- ### **Safety Profile** 1. **Adverse Events**: - Adverse events were reported in a minority of patients, and no new safety signals were identified. - The safety profile was consistent with prior clinical trials. 2. **Serious Adverse Events**: - Serious adverse events, including venous thromboembolism, were infrequent, suggesting an acceptable safety profile for upadacitinib in this population. --- ### **Clinical Implications** - **Effectiveness in Real-World Settings**: The study supports upadacitinib as an effective treatment option for moderate-to-severe Crohn’s disease, including in patients with refractory disease or prior treatment failures. - **Best Results in Therapy-Naïve Patients**: Upadacitinib may offer the greatest benefit when used earlier in the treatment course, particularly in therapy-naïve patients. - **Personalized Treatment**: Factors such as BMI, albumin levels, and disease duration should be considered when predicting treatment response and tailoring therapy. --- ### **Conclusion** Upadacitinib demonstrated robust real-world effectiveness and an acceptable safety profile in the treatment of moderate-to-severe Crohn’s disease. It was effective across various patient subgroups, including those with refractory disease, and showed meaningful clinical, endoscopic, and biomarker improvements. These findings support its role as a valuable therapeutic option in managing Crohn’s disease in routine clinical practice.

AGA Living Guideline on Pharmacologic Management of Moderate-to-Severe Crohn’s Disease

The American Gastroenterological Association (AGA) Living Guideline on the pharmacologic management of moderate-to-severe Crohn’s disease provides evidence-based recommendations to guide clinical decision-making for adult outpatients with moderate-to-severely active luminal Crohn’s disease. The guideline focuses on using advanced therapies to achieve disease remission and improve patient outcomes while minimizing risks. Below is a detailed breakdown of the guideline: ### **Scope and Approach** - **Patient Population**: Adult outpatients with moderate-to-severely active luminal Crohn’s disease. - **Development Framework**: Recommendations are based on the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework, incorporating evidence synthesis and network meta-analysis to position therapies according to efficacy and safety. - **Patient-Centered Focus**: Emphasis on tailoring therapy to individual patient needs, preferences, and clinical circumstances. --- ### **Key Recommendations** #### **Pretreatment Considerations** 1. **Confirm Active Inflammation**: Before initiating advanced therapy, confirm active inflammation through biomarkers (e.g., C-reactive protein, fecal calprotectin), endoscopic evaluation, or imaging studies. 2. **Core Pretreatment Screening**: - Screen for **hepatitis B** and **tuberculosis** prior to starting biologic or small molecule therapies. - Optimize vaccination status (e.g., influenza, pneumococcal, herpes zoster) before initiating immunosuppressive therapy to reduce the risk of serious infections. --- #### **Advanced Therapy Recommendations** 1. **Strong Recommendations**: - AGA strongly recommends using **advanced therapies** such as infliximab, adalimumab, ustekinumab, risankizumab, mirikizumab, guselkumab, or upadacitinib over no treatment. 2. **Conditional Recommendations**: - **Certolizumab pegol** and **vedolizumab** are suggested over no treatment, reflecting lower certainty or benefit compared to higher-efficacy options. 3. **Biosimilars**: - Biosimilars of infliximab, adalimumab, and ustekinumab are considered equivalent to their originator biologics in terms of efficacy and can be used interchangeably. 4. **Subcutaneous Maintenance Therapy**: - Subcutaneous formulations of infliximab and vedolizumab offer comparable efficacy to intravenous (IV) maintenance regimens. --- #### **Efficacy-Based Positioning** 1. **Therapy-Naïve Patients**: - For patients who have not previously received advanced therapy, AGA suggests starting with **higher-efficacy options** rather than lower-efficacy ones. - Higher-efficacy grouping is determined based on predefined criteria, including absolute benefit thresholds and network meta-analysis rankings. 2. **Advanced Therapy–Exposed Patients**: - For patients previously exposed to one or more advanced therapies, AGA suggests using higher- or intermediate-efficacy agents rather than lower-efficacy agents. --- #### **Special Considerations** 1. **Dose Optimization**: - Extended induction or dose escalation may benefit partial responders, particularly those with a higher disease burden. 2. **Safety Concerns with JAK Inhibitors**: - **Upadacitinib** (a Janus kinase [JAK] inhibitor) requires careful risk assessment due to potential cardiovascular and thrombotic risks. JAK inhibitors are generally avoided in patients planning pregnancy in the near term. 3. **Thiopurine Therapy**: - Thiopurine monotherapy (e.g., azathioprine, mercaptopurine) is **not recommended** for inducing remission in moderate-to-severe Crohn’s disease. - Thiopurine monotherapy is suggested over no treatment for **maintenance of remission**, particularly after steroid-induced remission. 4. **Methotrexate**: - Subcutaneous or intramuscular methotrexate is suggested for induction and maintenance therapy. - Oral methotrexate is **not recommended** for either induction or maintenance therapy. 5. **Combination Therapy**: - For patients naïve to thiopurines starting infliximab, **infliximab + thiopurine** is suggested over infliximab monotherapy to reduce the risk of immunogenicity. - No recommendations are made for infliximab + methotrexate, adalimumab + immunomodulator, or non-TNF biologic + immunomodulator due to insufficient evidence. --- #### **Treatment Strategies** 1. **Earlier Use of Advanced Therapy**: - The guideline suggests initiating advanced therapy upfront rather than relying on step-up approaches involving corticosteroids and/or immunomodulator monotherapy. 2. **Induction and Maintenance**: - Advanced therapies are positioned to induce remission and maintain it long-term, with dose optimization strategies for partial responders. --- ### **Knowledge Gaps** - Evidence is insufficient to recommend combination therapies involving infliximab + methotrexate, adalimumab + immunomodulators, or non-TNF biologics + immunomodulators. - Long-term comparative data on efficacy and safety for newer agents like risankizumab, mirikizumab, and guselkumab are still evolving. --- ### **Practical Implications** This guideline emphasizes the importance of: - Early use of advanced therapies for moderate-to-severe Crohn’s disease. - Confirming active inflammation and optimizing pretreatment screening and vaccination. - Selecting therapies based on efficacy rankings and individual patient factors. - Careful risk assessment for therapies with specific safety concerns (e.g., JAK inhibitors). Overall, the AGA guideline provides a structured framework to help clinicians navigate the complex landscape of Crohn’s disease management, prioritizing evidence-based, patient-centered care.

Whole Food Diet Induces Remission in Pediatric and Young Adult Crohn’s Disease

Yes, a whole food diet, specifically the Tasty&Healthy (T&H) diet, has been shown to induce remission in pediatric and young adult patients with mild to moderate Crohn’s disease. Here's a detailed explanation based on the TASTI-MM trial: ### Background and Unmet Need: Exclusive enteral nutrition (EEN) is an established treatment for inducing remission in Crohn's disease, but its use is often limited by poor tolerability, especially in children and young adults. This creates a need for alternative dietary approaches that are both effective and more tolerable. ### Tasty&Healthy (T&H) Diet Concept: The T&H diet is a whole food-based dietary intervention that excludes processed foods, gluten, red meat, and dairy while avoiding the need for formula-based nutrition. It is designed to be palatable and easier to adhere to, making it a more practical option for patients. ### Study Design: The TASTI-MM trial was a multicenter, clinician-blinded, randomized controlled trial that compared the T&H diet with EEN in biologic-naïve patients aged 6–25 years with mild to moderate Crohn’s disease. The trial aimed to evaluate tolerability, clinical remission rates, and other health outcomes over an 8-week induction period. ### Key Findings: 1. **Tolerability and Adherence:** - The T&H diet was significantly better tolerated than EEN. - A substantially higher proportion of patients completed the 8-week intervention in the T&H group compared to the EEN group. - Most discontinuations in the EEN group occurred within the first four weeks, highlighting early intolerance issues. 2. **Clinical Remission Rates:** - Both diets achieved similar rates of symptomatic remission at week 8 in intention-to-treat analyses. - Among patients who completed the therapy (per-protocol analysis), remission rates were high and comparable between the two dietary approaches. 3. **Biological and Noninvasive Markers:** - Markers of inflammation, such as calprotectin, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), improved significantly in both groups. - Noninvasive markers of mucosal inflammation, such as the MINI index, showed comparable improvement in both groups. 4. **Microbiome Effects:** - The T&H diet promoted gut microbiome stability over time, whereas microbial diversity declined in the EEN group. - T&H increased microbial richness and diversity, which are associated with better gut health. - Proinflammatory bacterial species decreased, and beneficial species linked to intestinal health and mucosal healing were enriched in the T&H group. 5. **Dietary Pattern and Nutritional Benefits:** - The T&H diet increased fiber and potassium intake, reflecting a shift toward minimally processed, plant-based foods. - This dietary pattern aligns with general recommendations for promoting gut health and reducing inflammation. 6. **Quality of Life and Patient Satisfaction:** - Quality-of-life scores improved in both groups, with no significant differences between them. - Patients reported higher satisfaction with the T&H diet compared to EEN, likely due to its palatability and flexibility. 7. **Safety Profile:** - Both dietary interventions were safe, with only mild adverse events reported. ### Clinical Implications: The T&H diet represents a feasible, effective, and well-tolerated alternative to exclusive enteral nutrition for inducing remission in pediatric and young adult patients with mild to moderate Crohn’s disease. Its benefits include greater adherence, improved patient satisfaction, and positive effects on the gut microbiome, making it a promising option for nutrition therapy in this population. In summary, the T&H diet offers a whole food-based approach that is not only effective in inducing remission but also addresses the limitations of EEN by improving tolerability and quality of life for patients.

International Consensus on Corticosteroid Use in IBD Clinical Trials

The **International Consensus on Corticosteroid Use in Inflammatory Bowel Disease (IBD) Clinical Trials** represents the first global, expert-driven guidance to standardize corticosteroid management in IBD drug trials. This guidance aims to address the challenges and inconsistencies in corticosteroid use that have historically complicated the interpretation of trial outcomes, reduced comparability across studies, and posed barriers to patient participation. ### Key Highlights of the Consensus: 1. **Need for Standardization**: - Corticosteroid management in IBD trials has been highly variable. - This variability can bias trial outcomes by masking true disease activity or inflating placebo response rates. - Standardized protocols are essential to ensure consistency and reliability in trial results. 2. **Impact on Trial Outcomes**: - Inconsistent corticosteroid handling can lead to incorrect efficacy assessments. - Standardization reduces the risk of bias and improves the comparability of clinical trials. 3. **Barrier to Patient Participation**: - Prolonged corticosteroid exposure, often required by trial protocols, discourages patient enrollment due to the associated risks and side effects. - The new recommendations aim to reduce corticosteroid exposure, making trials more patient-friendly. 4. **Defined Trial Phases**: - The consensus provides specific recommendations for corticosteroid management across all trial phases: screening, induction, maintenance, and endpoint assessment. 5. **Screening Phase Recommendations**: - **Permitted Oral Steroids**: Oral systemic corticosteroids (e.g., prednisone) and oral enteric- or colonic-release corticosteroids (e.g., budesonide) are allowed under defined conditions. - **Intravenous Steroid Exclusion**: Use of intravenous corticosteroids during screening is exclusionary due to concerns about disease severity and excessive exposure. - **Rectal Steroid Discontinuation**: Rectal corticosteroids must be stopped at least two weeks before the baseline assessment. - **Stable Pretrial Dosing**: Corticosteroid doses must remain stable for at least two weeks before randomization to ensure reliable baseline disease activity measurement. - **Maximum Screening Dose**: The maximum allowed oral systemic corticosteroid dose is 20 mg/day (prednisone equivalent). - **Budesonide Dose Limit**: Budesonide use before randomization should not exceed 9 mg/day. 6. **Induction Phase Recommendations**: - **Fixed Dosing Period**: Corticosteroid doses should remain fixed for at least two weeks after randomization during the induction phase. - **Protocol-Mandated Tapering**: Tapering decisions must be mandated by the trial protocol and not left to investigator discretion. - **Standardized Taper Schedule**: A tapering schedule of 5 mg prednisone equivalent per week is recommended to minimize variability and exposure. - **Budesonide Exception**: Enteric- or colonic-release budesonide formulations can be discontinued without tapering. - **Rescue Therapy Defines Failure**: Initiation of any corticosteroid as rescue therapy during the induction phase is considered treatment failure. 7. **Maintenance Phase Recommendations**: - **Tapering at Start of Maintenance**: If tapering was not completed during induction, it should begin at the start of the maintenance phase. - **Deviation Equals Failure**: Any escalation or deviation from the mandated tapering schedule during maintenance is considered treatment failure. - **Steroid-Free Remission Denominator**: Only patients using corticosteroids at the start of induction or maintenance phases should be included when calculating steroid-free remission rates. 8. **Goals of the Consensus**: - Shorten corticosteroid exposure to reduce patient harm and align trial protocols with clinical practice. - Minimize variability in corticosteroid use to improve the reliability and comparability of trial outcomes. - Encourage patient participation in trials by reducing the burden of corticosteroid-related side effects. ### Broader Implications: This consensus-driven guidance is expected to significantly enhance the quality and interpretability of IBD clinical trials. By standardizing corticosteroid use, the recommendations aim to achieve more accurate assessments of drug efficacy, reduce the risk of bias, and improve patient safety. Additionally, the focus on reducing corticosteroid exposure aligns with the broader goal of minimizing steroid-related harm in clinical practice. This international effort marks a critical step forward in harmonizing trial protocols and ensuring that outcomes are meaningful, reproducible, and clinically relevant.

The adoption of a westernized gut microbiome in Indian Immigrants and Indo-Canadians is associated with dietary acculturation

Yes, the adoption of a westernized gut microbiome in Indian immigrants and Indo-Canadians is strongly associated with dietary acculturation. The study highlights that dietary acculturation—defined as the shift from traditional dietary practices to the consumption of a more Westernized diet—plays a significant role in shaping the gut microbiome of Indian immigrants and their descendants in Canada. Key findings from the study demonstrate that: 1. **Shift in Gut Microbial Composition**: Indian immigrants to Canada show partial shifts in their gut microbiome after migration, while Indo-Canadians exhibit a more pronounced transition toward a westernized gut microbiome. This transition includes a decline in microbes associated with traditional Indian diets (high in fiber and plant-based foods) and an increase in microbes linked to Western dietary patterns (high in fats, processed foods, and lower fiber). 2. **Impact of Westernized Diets**: The study identifies that westernized diets, characterized by higher consumption of ultra-processed foods and lower intake of fiber, are a major driver of microbiome changes. These dietary changes lead to a reduction in traditional diet-associated microbes and an enrichment of microbes suited to metabolizing fats and processed foods, which are common in industrialized environments. 3. **Functional Changes in the Microbiome**: Alongside compositional changes, the functional potential of the gut microbiome also shifts. Indians living in India have gut microbiomes enriched in pathways related to complex carbohydrate metabolism and stress tolerance, reflective of their traditional, plant-rich diets. In contrast, westernized cohorts, including Indo-Canadians, exhibit microbiomes with increased functional pathways for fat metabolism and processed food digestion. 4. **Dietary Acculturation vs. Ethnicity**: The study underscores that dietary acculturation has a more pronounced influence on the gut microbiome than ethnicity alone. This means that the microbiome changes observed in Indian immigrants and Indo-Canadians are primarily driven by their adoption of Western dietary patterns, rather than inherent genetic or ethnic factors. 5. **Health Implications**: The westernization of the gut microbiome in Indian immigrants and Indo-Canadians is associated with a decline in microbial diversity and the loss of traditional diet-associated microbes, which may increase the risk of inflammatory bowel disease (IBD) and other metabolic diseases. This underscores the importance of preserving traditional dietary practices to mitigate these health risks. In summary, the study firmly establishes that dietary acculturation is a key factor driving the adoption of a westernized gut microbiome in Indian immigrants and Indo-Canadians. This highlights the dynamic nature of the gut microbiome in response to lifestyle changes and emphasizes the need to consider dietary preservation as a strategy for promoting gut health and reducing disease risk in immigrant populations.

Interplay between creeping fat and gut microbiota: A brand-new perspective on fecal microbiota transplantation in Crohn’s disease

The interplay between creeping fat (CrF) and gut microbiota offers a novel perspective on the use of fecal microbiota transplantation (FMT) in Crohn's disease (CD). Creeping fat, a hallmark feature of CD, is a specific type of mesenteric adipose tissue (MAT) that surrounds inflamed intestinal segments. It is closely associated with disease activity, severity, and postoperative recurrence. Historically considered a passive bystander, creeping fat is now understood as an active immunometabolic organ that significantly contributes to the progression of CD through its interaction with the gut microbiota. ### Key Insights into the Interplay: 1. **Creeping Fat's Role in CD Pathogenesis:** - Creeping fat is not merely a structural feature but actively participates in the inflammatory processes of CD. - In CD, intestinal barrier dysfunction allows translocation of gut-derived bacteria into MAT. These bacteria interact with immune cells, polarizing macrophages and promoting adipogenesis (the accumulation of fat cells), which leads to the expansion of creeping fat. - Creeping fat produces proinflammatory cytokines and adipokines, further amplifying inflammation. It also disrupts immune balance and contributes to fibrosis through interactions with T helper cell pathways and macrophage subtypes. - This creates a vicious cycle where intestinal inflammation, microbial dysbiosis (an imbalance in gut microbiota), and mesenteric fat expansion continuously reinforce each other. 2. **Gut Microbiota's Influence on Creeping Fat:** - The gut microbiota plays a critical role in shaping the behavior of creeping fat. Microbial dysbiosis in CD has been shown to exacerbate intestinal inflammation and alter MAT's function. - Specific bacterial communities may drive the persistence of creeping fat by modulating immune responses and promoting inflammatory signaling. 3. **Fecal Microbiota Transplantation (FMT) as a Therapeutic Tool:** - FMT involves transferring fecal material, including beneficial microbiota, from healthy donors to patients with dysbiosis. It has been explored as a potential treatment for CD, particularly due to its ability to restore microbial balance. - Recent experimental studies highlight the impact of FMT on the gut–fat axis: - In animal models, FMT from healthy donors improved intestinal inflammation, enhanced barrier integrity, and reduced inflammatory signaling. This, in turn, mitigated the expansion and inflammatory activity of creeping fat. - Conversely, FMT from CD donors worsened intestinal inflammation, barrier dysfunction, and creeping fat activity. - These findings suggest that the composition of the microbiota is a critical determinant of MAT behavior and disease outcomes. 4. **Therapeutic Implications:** - Targeting the interaction between gut microbiota and creeping fat represents a novel and promising therapeutic avenue for CD. - FMT or related microbiota-modulating strategies could potentially disrupt the self-reinforcing loop between intestinal inflammation, microbial dysbiosis, and creeping fat expansion. - By restoring a healthy microbial balance, FMT may not only improve intestinal health but also mitigate the pathological role of creeping fat in CD. ### A New Perspective: This emerging perspective emphasizes the importance of the gut–fat axis in CD pathogenesis and introduces the possibility of using FMT as a targeted therapy to modulate this interaction. By addressing both microbial dysbiosis and the immunometabolic activity of creeping fat, FMT could offer a dual benefit in managing CD. Future research should focus on identifying the specific microbial species or metabolites that influence MAT behavior, optimizing FMT protocols, and exploring other microbiota-based therapies to refine this innovative approach. In summary, the interplay between creeping fat and the gut microbiota provides a groundbreaking framework for understanding CD and highlights fecal microbiota transplantation as a novel strategy to disrupt the pathogenic cycle underlying the disease.

Prediction and Prevention of Inflammatory Bowel Disease

The prediction and prevention of Inflammatory Bowel Disease (IBD) represent a transformative approach to addressing the challenges posed by this chronic, immune-mediated condition. IBD, which primarily includes Crohn's disease and ulcerative colitis, is characterized by inflammation of the intestinal tract. Despite advancements in pharmacologic therapies, sustained remission remains elusive for many patients, and irreversible intestinal damage often occurs by the time symptoms appear. This highlights the need to move beyond treatment-focused strategies toward prediction and prevention. ### Key Insights into Prediction and Prevention of IBD: #### 1. **Preclinical Phase of IBD:** - **Prolonged Preclinical Phase:** Emerging evidence suggests that IBD has a prolonged preclinical phase, during which biological and immunological changes occur years before clinical symptoms manifest. This phase is akin to other immune-mediated diseases, such as rheumatoid arthritis and type 1 diabetes. - **Gradual Disease Development:** IBD does not begin abruptly; instead, it follows a measurable trajectory of disease initiation. This gradual progression offers a critical window for early detection and intervention. #### 2. **Biomarkers for Early Detection:** - **Circulating Biomarkers:** Studies using pre-disease cohorts have identified various biomarkers that can signal the onset of IBD long before diagnosis. These include: - **Immune Markers:** Indicators of immune system dysregulation. - **Serologic Markers:** Antibodies and proteins found in blood that may predict disease risk. - **Microbial Markers:** Alterations in gut microbiota composition, which play a key role in intestinal health and immune function. - **Time Frame:** Some biomarkers have been detected up to a decade prior to the formal diagnosis of IBD, suggesting the potential for early intervention. #### 3. **Risk Prediction Models:** - **Integration of Biomarker Data:** By combining data from immune, serologic, and microbial markers, researchers are constructing risk prediction models to identify individuals at high risk of developing IBD. - **Mapping Disease Pathways:** These models enable researchers to understand the pathways driving early disease development, providing insights into the mechanisms of IBD initiation. - **Personalized Risk Assessment:** Prediction models could allow for personalized monitoring and preventive strategies tailored to individual risk profiles. #### 4. **Preventive Interventions:** - **Novel Therapeutic Targets:** The identification of pathways involved in early IBD development opens the door to discovering therapeutic targets that may be suitable for preventive interventions. - **Intervening in Early Stages:** Preventive strategies could be implemented during the preclinical or very early stages of disease, potentially delaying, attenuating, or even preventing the onset of IBD altogether. - **Transformative Goal:** This paradigm shift toward prevention represents a fundamental change in how IBD is approached in research and clinical practice. #### 5. **Global Implications:** - **Burden of Disease:** IBD imposes a significant global burden, particularly in low-resource settings where access to care is limited. Early detection and prevention could alleviate this burden by reducing the need for long-term treatment and managing complications. - **Equity in Care:** A focus on prediction and prevention may also improve health equity by enabling earlier and more accessible interventions for at-risk populations. ### Conclusion: The prediction and prevention of IBD are emerging as transformative goals in the field of gastroenterology. By leveraging insights from biomarkers and risk prediction models, researchers and clinicians can shift the focus from reactive treatment to proactive intervention. This approach has the potential to revolutionize IBD care by preventing irreversible intestinal damage, reducing disease burden, and improving outcomes for patients. Future research should prioritize the development of predictive tools, the identification of preventive therapies, and the implementation of strategies to intervene during the preclinical phase of IBD.

Inflammatory Potential of the Diet and Risk of Crohn's Disease and Ulcerative Colitis

The study you are referring to explores the relationship between the inflammatory potential of overall dietary patterns and the risk of developing inflammatory bowel diseases (IBD), specifically Crohn’s disease (CD) and ulcerative colitis (UC). Here's a detailed breakdown of the findings and implications: ### Objective of the Study: The primary goal of the study was to determine whether diets with varying inflammatory potential, as measured by the Inflammatory Score of the Diet (ISD), influence the risk of developing Crohn’s disease and ulcerative colitis. While prior research has focused on individual dietary components, this study examined dietary patterns as a whole to provide a more comprehensive understanding of the diet-disease relationship. ### Methodology: 1. **Data Source**: The study used data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, a large-scale, long-term study. 2. **Dietary Assessment**: Participants’ dietary intake was assessed at the study's baseline using validated food frequency questionnaires. These data were used to calculate ISD scores, which reflect the overall inflammatory potential of the diet. 3. **Follow-Up**: Participants were followed for over a decade to track the development of Crohn’s disease and ulcerative colitis. 4. **Statistical Analysis**: Cox proportional hazard models were employed to estimate associations between ISD scores and disease risk. The analysis adjusted for key confounding factors such as lifestyle, demographic, and behavioral variables. ### Key Findings: 1. **Crohn’s Disease (CD)**: - Diets with a **higher inflammatory potential** (higher ISD scores) were associated with an **increased risk of developing Crohn’s disease**. - The association was particularly pronounced among women. - Subgroup analyses revealed that the link between high ISD scores and Crohn’s disease was largely driven by **lower consumption of anti-inflammatory dietary components**, such as: - Fiber - Mono-unsaturated fatty acids - Vitamin C - Magnesium - Onion - Alcohol (in moderate amounts) 2. **Ulcerative Colitis (UC)**: - No significant association was found between the inflammatory potential of the diet and the risk of developing ulcerative colitis. - This suggests that the mechanisms driving Crohn’s disease and ulcerative colitis may differ in their relationship to dietary factors. ### Implications of the Study: 1. **Dietary Inflammatory Potential**: - The findings underscore the importance of considering the overall inflammatory potential of dietary patterns, rather than focusing solely on individual nutrients or foods, when assessing disease risk. - Pro-inflammatory dietary patterns, characterized by low intake of anti-inflammatory components, may contribute to the development of Crohn’s disease. 2. **Prevention Strategies**: - These results highlight the potential for dietary interventions to reduce the risk of Crohn’s disease, particularly in populations at higher risk. - Encouraging the consumption of anti-inflammatory foods, such as those rich in fiber, vitamins, and healthy fats, may be a valuable preventive strategy. 3. **Gender-Specific Findings**: - The stronger association observed in women suggests that sex-specific factors may play a role in the relationship between diet and Crohn’s disease risk. Further research may be needed to explore these differences in more detail. 4. **Differential Impact on IBD Subtypes**: - The lack of association between diet and ulcerative colitis risk suggests that dietary inflammatory potential may not be a universal risk factor for all forms of inflammatory bowel disease. This highlights the need for tailored approaches to understanding and managing different IBD subtypes. ### Conclusion: The study provides strong evidence that diets with a high inflammatory potential are associated with an increased risk of Crohn’s disease, particularly among women, while no such association exists for ulcerative colitis. These findings emphasize the importance of dietary patterns in the prevention of Crohn’s disease and suggest that public health strategies should focus on promoting anti-inflammatory dietary components to mitigate disease risk. Further research is needed to explore the underlying mechanisms and to confirm these findings in diverse populations.

ultraprocessed grains and IBD

The relationship between ultraprocessed grains and inflammatory bowel disease (IBD) has been examined in the context of the Prospective Urban Rural Epidemiology (PURE) study. This study highlights a significant association between the consumption of ultraprocessed grains and an increased risk of developing IBD, which includes conditions such as Crohn's disease and ulcerative colitis. Below is a detailed explanation based on the findings: ### What Are Ultraprocessed Grains? Ultraprocessed grains are a category of foods that undergo extensive refining processes. These processes often remove beneficial nutrients, such as fiber, and incorporate additives like preservatives, flavor enhancers, and texturizers to improve shelf life, taste, and texture. Examples include white bread, certain breakfast cereals, instant noodles, and other refined grain products commonly found in Western diets. ### The PURE Study Findings The PURE study evaluated dietary habits across diverse populations using long-term, multinational cohort data. Key findings include: 1. **Increased Risk of IBD**: Higher consumption of ultraprocessed grains was associated with a greater risk of developing IBD. This relationship remained significant even after adjusting for major lifestyle and demographic factors. 2. **Protective Effect of Less Processed Grains**: In contrast, consuming less processed grain staples, such as fresh bread and rice, was linked to a reduced risk of IBD. 3. **Broader Implications for Ultraprocessed Foods**: The study also observed that diets high in overall ultraprocessed foods, not just grains, were associated with negative impacts on intestinal health, further emphasizing the role of food processing levels. ### Mechanisms Linking Ultraprocessed Grains to IBD The study suggests several mechanisms through which ultraprocessed grains may contribute to intestinal inflammation and increase IBD risk: 1. **Altered Gut Microbiota**: Ultraprocessed grains may disrupt the gut microbiome, leading to imbalances that promote inflammation. 2. **Reduced Fiber Intake**: The refining process removes dietary fiber, which is essential for maintaining gut health and reducing inflammation. 3. **Exposure to Food Additives**: Additives in ultraprocessed grains, such as emulsifiers and artificial flavors, may irritate the intestinal lining, exacerbate inflammation, or negatively affect gut bacteria. ### Recommendations The study's authors recommend minimizing the consumption of ultraprocessed grains as part of a healthy dietary pattern to reduce the risk of IBD. Instead, individuals are encouraged to prioritize less processed grain options and whole foods that retain their natural fiber and nutrient content. Additionally, further research is suggested to pinpoint the specific components of ultraprocessed grains responsible for the increased risk of IBD. ### Conclusion Ultraprocessed grains are linked to a heightened risk of developing IBD due to their potential to disrupt gut health through mechanisms such as microbiota alterations, reduced fiber levels, and exposure to additives. Adopting a diet that emphasizes whole, minimally processed grains can play a protective role against IBD and improve overall intestinal health.

Global evolution of inflammatory bowel disease across epidemiologic stages

The global evolution of inflammatory bowel disease (IBD) can be understood through its progression across four distinct epidemiologic stages, which reflect the changing patterns of incidence, prevalence, and disease burden over time. This evolution is shaped by global socioeconomic, environmental, and healthcare changes, as well as advancements in medical diagnostics and treatment. Below is a detailed explanation of how IBD has evolved across these stages: ### **1. Global Shift of IBD** - Historically, IBD was concentrated in early industrialized regions such as North America, Europe, and Oceania. However, over the past few decades, it has transitioned into a global disease, increasingly affecting newly industrialized and emerging regions, such as parts of Asia, Latin America, and the Middle East. - This shift is driven by global socioeconomic and environmental transformations, including industrialization, urbanization, and changes in diet and lifestyle. --- ### **2. The Four Epidemiologic Stages of IBD** The progression of IBD follows four epidemiologic stages, each defined by specific patterns of incidence and prevalence: #### **Stage 1: Emergence** - **Characteristics**: Very low incidence and prevalence of IBD. - **Regions**: Typically observed in low-income or emerging regions with limited healthcare infrastructure and diagnostic capacity. - **Challenges**: Sparse epidemiologic data due to underreporting and lack of surveillance. - **Example**: Many regions in Africa remain in this stage, where the true burden of IBD is likely underestimated. #### **Stage 2: Acceleration** - **Characteristics**: Rapidly increasing incidence of IBD, while prevalence remains relatively low. - **Drivers**: This stage reflects both a true increase in disease occurrence and improved detection due to better healthcare infrastructure, including access to colonoscopy and specialist care. - **Regions**: Newly industrialized regions, such as parts of Asia, Latin America, and the Middle East, are currently in this stage. - **Environmental Factors**: Industrialization, urbanization, and westernization-related factors, such as dietary changes, obesity, and altered hygiene practices, are strongly associated with the sharp rise in incidence. #### **Stage 3: Compounding Prevalence** - **Characteristics**: Incidence stabilizes or slows, but prevalence rises steadily as more individuals live longer with IBD due to the chronic nature of the disease and low mortality rates. - **Regions**: Early industrialized regions, including North America, Europe, and Oceania, largely transitioned to this stage by the late 20th century. - **Challenges**: Healthcare systems in these regions face sustained pressure due to the growing number of people living with IBD, particularly as the population ages and comorbidities increase. - **Projections**: Mathematical modeling suggests that prevalence will continue to grow in these regions, with a gradual slowing as populations age and incidence stabilizes. #### **Stage 4: Prevalence Equilibrium (Proposed)** - **Characteristics**: Prevalence plateaus as mortality approximates incidence. This stage is driven by an ageing IBD population and the stabilization of new cases. - **Current Status**: Few regions have reached this stage, as it requires decades of data and trends to emerge. - **Potential Impact**: Modest reductions in incidence through prevention strategies could help accelerate the transition toward this stage in high-burden regions. --- ### **3. Factors Influencing the Evolution of IBD** Several factors contribute to the global evolution of IBD and the transition between epidemiologic stages: #### **Environmental and Socioeconomic Drivers** - Westernization-related factors, such as changes in diet, urban living, obesity, and hygiene practices, are strongly associated with the transition from low to high IBD incidence stages. - Industrialization and urbanization play a critical role in increasing disease incidence in newly industrialized regions. #### **Healthcare Infrastructure** - Improved access to diagnostic tools, such as colonoscopy and specialist care, contributes to the “unmasking” of IBD, particularly during the transition from stage 1 to stage 2. - Regions with advanced healthcare systems have better capacity to manage the growing prevalence of IBD, but they also face challenges in addressing the long-term care needs of an ageing IBD population. #### **Changing Disease Patterns** - The ratio of ulcerative colitis (UC) to Crohn’s disease (CD) decreases across stages, reflecting improved recognition and diagnosis of CD as healthcare infrastructure and diagnostic capacity improve. --- ### **4. Challenges and Burden in Stage 3 Regions** - **Prevalence Growth**: Stage 3 regions are experiencing rapidly increasing numbers of people living with IBD, placing significant pressure on healthcare systems. - **Ageing Population**: The accumulation of prevalence over decades has led to a higher proportion of older adults with IBD, complicating disease management due to comorbidities and increased treatment risks. --- ### **5. Future Projections and Policy Implications** - **Mathematical Modelling**: Partial differential equation models predict continued prevalence growth in stage 3 regions, with a gradual slowing as populations age and incidence stabilizes. - **Incidence Reduction**: Even modest reductions in incidence through prevention strategies could accelerate the transition toward prevalence equilibrium in high-burden regions. - **Policy and Planning**: Understanding the stage-specific evolution of IBD enables governments and healthcare systems to anticipate future disease burden, allocate resources efficiently, and prioritize prevention and surveillance strategies. --- ### **6. Summary of Global Trends** - Early industrialized regions (e.g., North America, Europe, Oceania) have largely transitioned to stage 3, with stabilized incidence but rapidly growing prevalence. - Newly industrialized regions (e.g., Asia, Latin America, the Middle East) are in stage 2, experiencing sharp increases in incidence due to industrialization and urbanization. - Emerging regions (e.g., parts of Africa) remain in stage 1, with limited data and diagnostic capacity likely underestimating the true burden of IBD. --- ### **Conclusion** The global evolution of IBD across epidemiologic stages reflects the interplay between environmental, socioeconomic, and healthcare factors. While early industrialized regions are grappling with the challenges of compounding prevalence and ageing populations, newly industrialized and emerging regions are experiencing rapid increases in incidence. Understanding these stage-specific trends is crucial for policymakers and healthcare systems to effectively manage the growing burden of IBD and prioritize prevention, surveillance, and resource allocation strategies.

Diagnostic performance of intestinal ultrasound compared with CT enterography in Crohn’s disease: single-center experience

The study conducted a retrospective single-center analysis to evaluate the diagnostic performance of transabdominal bowel ultrasonography (TBUS) compared with computed tomography enterography (CTE) in identifying intestinal lesions and complications in patients with Crohn’s disease (CD). Crohn’s disease is a chronic inflammatory condition that can affect any part of the gastrointestinal tract and is often associated with complications such as intestinal wall thickening, stenosis, fistulas, and abdominal abscesses. Accurate imaging is critical for diagnosis, monitoring, and long-term follow-up in these patients. ### Key Findings: 1. **Diagnostic Accuracy of TBUS vs. CTE**: - TBUS demonstrated comparable diagnostic accuracy to CTE for detecting diseased bowel segments, intestinal wall abnormalities, and complications such as stenosis, fistulas, and abdominal abscesses. - TBUS effectively visualized bowel wall thickness, layered structure, vascular changes, and extraintestinal complications. - Diagnostic interpretations of TBUS showed strong consistency between different observers, indicating its reliability. 2. **Postoperative Assessment**: - TBUS remained effective in patients who had undergone prior intestinal surgery, highlighting its utility in postoperative follow-up. 3. **Advantages of TBUS**: - **Non-invasive**: TBUS does not require radiation exposure, making it safer than CTE, particularly for long-term disease monitoring. - **Repeatable**: TBUS can be performed frequently without concerns about radiation or invasive procedures. - **Practical for Long-Term Monitoring**: TBUS is well-suited for ongoing assessment and follow-up, as it can detect disease progression and complications over time. - **Extraintestinal Complications**: TBUS showed strengths in identifying complications outside the intestine, which may guide clinical decision-making. 4. **Clinical Utility**: - TBUS proved to be a valuable imaging tool for routine practice and long-term disease management in Crohn’s disease patients. - Its ability to provide detailed imaging without the risks associated with CTE makes it an attractive option for clinicians. ### Conclusion: The study concludes that transabdominal bowel ultrasonography is a highly useful diagnostic tool for Crohn’s disease, offering performance comparable to CT enterography while providing significant advantages in safety, flexibility, and practicality. TBUS is especially beneficial for long-term monitoring, postoperative follow-up, and identifying extraintestinal complications, making it a preferred imaging modality in routine clinical practice for Crohn’s disease management.

Efficacy and safety of IL-23 inhibitors in the treatment of moderate to severe UC

The meta-analysis conducted on randomized controlled trials provides comprehensive insights into the efficacy and safety of IL-23 inhibitors for the treatment of moderate to severe ulcerative colitis (UC). Below is a detailed summary of the findings: ### Efficacy of IL-23 Inhibitors 1. **Central Role of IL-23 in UC Pathogenesis**: - IL-23 is a critical driver of immune-mediated intestinal inflammation in UC via activation of the Th17 pathway, making it a promising therapeutic target. 2. **Agents Evaluated**: - The analysis assessed three primary IL-23p19 inhibitors: **Mirikizumab**, **Guselkumab**, and **Risankizumab**. 3. **Induction Phase Effectiveness**: - IL-23 inhibitors consistently demonstrated strong efficacy during the induction phase of treatment, rapidly reducing disease activity. 4. **Clinical Remission**: - Patients treated with IL-23 inhibitors were more likely to achieve clinical remission, characterized by symptom control and resolution of inflammation. 5. **Clinical Response**: - Significant improvements were observed in disease symptoms, including reductions in abdominal pain, diarrhea, and rectal bleeding. 6. **Endoscopic Healing**: - IL-23 inhibitors were associated with improved mucosal appearance on endoscopy, indicative of reduced inflammation and healing. 7. **Histologic Improvement**: - Treatment benefits extended beyond symptom relief to microscopic mucosal healing, emphasizing the profound anti-inflammatory effects of IL-23 inhibition. 8. **Effectiveness in Biologic-Naïve Patients**: - IL-23 inhibitors demonstrated robust efficacy in patients who had not previously received biologic therapy, making them an excellent option for first-line advanced therapy. 9. **Utility in Refractory Disease**: - Patients with prior inadequate response or intolerance to biologics or JAK inhibitors also experienced meaningful clinical benefits, highlighting their utility in difficult-to-treat cases. 10. **Consistency Across Patient Subgroups**: - Treatment efficacy was stable across diverse patient histories, disease severities, and backgrounds, demonstrating the broad applicability of IL-23 inhibitors. ### Safety of IL-23 Inhibitors 1. **Favorable Safety Profile**: - IL-23 inhibitors were generally well tolerated, with no significant increase in overall safety concerns. 2. **Low Risk of Serious Infections**: - Selective IL-23 blockade did not show a heightened risk of serious infections, a common concern with immunosuppressive therapies. 3. **Reduced Treatment Discontinuation**: - Patients receiving IL-23 inhibitors were less likely to discontinue therapy due to adverse events, suggesting high tolerability. 4. **Mechanistic Advantage**: - By selectively targeting IL-23p19 and sparing IL-12–related immune functions, IL-23 inhibitors preserve interferon signaling, potentially reducing systemic immunosuppression and associated risks. ### Position in Treatment Algorithms - **Advanced Therapy Option**: - IL-23 inhibitors represent an important addition to the therapeutic armamentarium for moderate to severe UC, offering a targeted and effective anti-inflammatory approach. - **Personalization and Future Research**: - While IL-23 inhibitors show promise, further head-to-head trials and long-term real-world studies are needed to refine their positioning in treatment algorithms and optimize their use in personalized care. ### Conclusion IL-23 inhibitors, including Mirikizumab, Guselkumab, and Risankizumab, are highly effective and well-tolerated treatments for moderate to severe UC. Their ability to induce clinical remission, improve endoscopic and histologic outcomes, and benefit both biologic-naïve and refractory patients underscores their therapeutic value. The favorable safety profile, combined with mechanistic advantages, positions IL-23 inhibitors as a vital option in the management of UC, with promising potential for further advancements through ongoing research.

Upadacitinib in a real-world data from UK

The real-world data on the use of upadacitinib for Crohn’s disease (CD) in the UK provides valuable insights into its effectiveness and safety in a challenging, clinically refractory patient population. Here is a detailed summary of the findings from a multicentre retrospective cohort analysis conducted across 19 UK hospitals: Background: - Upadacitinib is the first Janus kinase (JAK) inhibitor and oral advanced therapy approved for Crohn’s disease. - In 2023, NICE (National Institute for Health and Care Excellence) approved upadacitinib for CD treatment, but real-world data on its outcomes had been limited until now. Study Design: - The study included **312 adult patients** with active Crohn’s disease who initiated upadacitinib treatment between April 2023 and October 2023. - Patients were followed for a minimum of 12 weeks, with outcomes assessed at 12 and 24 weeks. - The cohort included patients with difficult-to-treat disease, with: - 64% having failed three or more biologics. - 51% exhibiting penetrating or stricturing disease. - 41% requiring prior surgical resection. Key Outcomes: 1. Clinical Remission: - Defined as achieving a Harvey Bradshaw Index (HBI) score of <4. - At 12 weeks: **50% (113/227)** of patients achieved clinical remission. - At 24 weeks: **45% (77/172)** of patients achieved clinical remission. - Patients with colonic disease had higher remission rates at 24 weeks compared to those with other disease locations. 2. Biochemical and Endoscopic Remission: - Biochemical remission was assessed using faecal calprotectin (<200 μg/g) and C-reactive protein (≤5). - Endoscopic remission was defined as a Simple Endoscopic Score for Crohn’s Disease (SES-CD) ≤3. - These outcomes were also evaluated at 12 and 24 weeks, but specific percentages were not detailed in the summary. 3. **Treatment Persistence**: - Persistence rates were high: - **90.3% at 12 weeks.** - **84.1% at 24 weeks.** - This indicates that most patients continued treatment with upadacitinib during the study period. 4. **Adverse Events (AEs)**: - AEs were reported in **28%** of patients. - Serious AEs occurred in **18%**, and **16.6%** of patients required hospitalization. - Despite the AEs, the treatment was generally well-tolerated in this cohort. 5. **Drug Discontinuation**: - By 24 weeks, **16% (51 patients)** had discontinued upadacitinib. ### Conclusion: - The study demonstrated **good short-term effectiveness and tolerance** of upadacitinib in a clinically refractory population with Crohn’s disease. - The clinical remission rate of **45% at 24 weeks** and **high drug persistence rates** suggest that upadacitinib is a promising treatment option for patients with difficult-to-treat CD. - The favorable outcomes, including steroid-free clinical remission and high persistence rates, highlight the potential of upadacitinib in managing challenging cases of Crohn’s disease. ### Implications for Research, Practice, and Policy: - The findings support the use of upadacitinib as an effective treatment for patients with refractory Crohn’s disease. - The real-world data aligns with clinical trial outcomes (U-EXCEED, U-EXCEL, and U-ENDURE) and provides additional evidence for its role in clinical practice. - The high persistence rates and favorable remission outcomes could influence future treatment guidelines and policies for managing Crohn's disease. This study represents a significant step in understanding the real-world impact of upadacitinib and demonstrates its potential as a viable treatment option for patients with Crohn’s disease who have limited therapeutic options.

single-wavelength endoscopy technology in UC

Single-wavelength endoscopy (SWE) is an advanced imaging technology that uses light of a specific wavelength to enhance visualization of tissue characteristics during endoscopic procedures. In the context of ulcerative colitis (UC), a chronic inflammatory bowel disease, SWE is designed to provide real-time insights into the histological state of the intestinal lining without the need for invasive biopsies. ### How Single-Wavelength Endoscopy Works SWE technology employs monochromatic light, meaning light of a single wavelength, to illuminate the tissue being examined. In the study referenced, a wavelength of 410 nm was used, which falls within the visible spectrum of light. This wavelength is specifically chosen to interact with certain tissue properties, such as blood vessel density, tissue architecture, and inflammatory markers, which are relevant to detecting inflammation in UC. The reflected light is analyzed by a computer-aided diagnostic (CAD) system, which interprets the tissue characteristics and provides a visual output. ### Application in UC In ulcerative colitis, the severity of the disease is typically assessed through a combination of endoscopic evaluation and histological analysis of biopsies. However, traditional methods have limitations: - **Biopsies** require time for processing and analysis, delaying treatment decisions. - **White-light endoscopy** (the standard method) can miss subtle histological changes, leading to underestimation of disease activity. SWE overcomes these limitations by offering **real-time histological assessment** during the endoscopic procedure itself. The CAD system integrated with SWE can classify tissue into categories such as histological remission (indicating no significant inflammation) or non-remission (indicating active inflammation). It provides immediate visual feedback to the clinician, such as color-coded signals (e.g., blue for remission and red for inflammation). ### Benefits of SWE in UC Management 1. **Real-Time Diagnosis**: SWE enables immediate assessment of histological disease activity, eliminating the need to wait for biopsy results. 2. **Improved Accuracy**: It helps detect subtle inflammation that may not be visible with standard white-light endoscopy, ensuring a more precise evaluation of disease severity. 3. **Personalized Treatment Decisions**: By providing instant insights into the histological state of the colon, SWE can guide clinicians in tailoring treatments to the patient's current condition. 4. **Non-Invasive Evaluation**: While biopsies are still the gold standard, SWE reduces the reliance on invasive sampling, making the procedure less uncomfortable for patients. 5. **Enhanced Monitoring**: SWE can be used during routine colonoscopies to monitor disease progression or remission, aiding in long-term disease management. ### Future Implications SWE technology has the potential to revolutionize how UC is managed by integrating histological assessment into routine endoscopic procedures. This could lead to faster, more accurate diagnoses and more effective treatment strategies, ultimately improving patient outcomes. Moreover, as the technology evolves, it may be adapted for use in other gastrointestinal conditions that require detailed tissue analysis. In summary, single-wavelength endoscopy represents a significant advancement in the real-time, non-invasive evaluation of histological disease activity in ulcerative colitis, offering clinicians a powerful tool to enhance both diagnosis and treatment.

ESD for high-risk colorectal colitis-associated neoplasia in IBD

Endoscopic submucosal dissection (ESD) has emerged as a highly effective and safe treatment for high-risk colorectal colitis-associated neoplasia (HR-CAN) in patients with inflammatory bowel disease (IBD), according to a multicenter Italian study. HR-CAN in IBD patients, particularly those with long-standing ulcerative colitis or colonic Crohn's disease, poses a significant risk for colorectal cancer and presents unique challenges due to chronic inflammation, scarring, and altered anatomy. The study included 91 IBD patients with 96 HR-CAN lesions, with an average lesion size of 35 mm. Most lesions exhibited high-grade dysplasia or early adenocarcinoma. Conventional ESD was performed in 82% of cases, while 18% underwent hybrid ESD (hESD). Despite the complexity of the lesions, the outcomes were excellent. En bloc resection (complete removal of the lesion in one piece) was achieved in 95.8% of cases, and R0 resection (clear margins) was successful in 85.4%. Curative resection, meaning no further surgery was needed, was achieved in 83.3% of patients. Adverse events were low (12.5%) and managed non-invasively. During a mean follow-up of two years, local recurrence and metachronous lesion rates were only 3.1% each, showing durable outcomes. Approximately 11.5% of patients required surgery post-resection, often for reasons unrelated to ESD. This study underscores that ESD is a highly promising, minimally invasive option for managing HR-CAN in IBD patients, providing strong long-term outcomes, low recurrence rates, and reduced need for surgical interventions.

A Consensus Blueprint for Steroid Stewardship in IBD Trials

The "Consensus Blueprint for Steroid Stewardship in IBD Trials" is a globally agreed-upon framework developed by a panel of 45 international experts through the Delphi process to standardize and optimize the use of steroids in clinical trials for inflammatory bowel disease (IBD). This blueprint addresses the critical need to reduce the adverse effects associated with long-term steroid use and improve the reliability, efficiency, and patient-centered approach of IBD trials. ### Key Components of the Blueprint: #### 1. **Need for Steroid Stewardship** - **Rationale:** Long-term steroid use in IBD leads to serious adverse effects, including infections, metabolic complications, osteoporosis, mood swings, insomnia, weight gain, and increased mortality risks (e.g., during the COVID-19 pandemic). These issues highlight the necessity for tighter control of steroid exposure. - **Objective:** To reduce steroid dependency and exposure in IBD trials while maintaining therapeutic efficacy and ensuring patient safety. #### 2. **Challenges in Current Clinical Trials** - Many IBD trials permit high or prolonged steroid use, which results in: - Inflated placebo responses. - Inconsistent efficacy estimates for investigational therapies. - Reduced patient recruitment due to steroid-related side effects. - Patients often avoid trials with long "stable-dose" steroid phases due to the negative impact on quality of life. #### 3. **Baseline Steroid Use Criteria** - **Entry Criteria:** Participants must limit baseline steroid doses to ≤20 mg prednisone-equivalent or ≤9 mg budesonide. - **Stabilization Period:** Reduced from the traditional 6 weeks to just 2 weeks to align with real-world practices and minimize prolonged exposure. #### 4. **Mandatory Early Tapering** - **Timing:** Steroid tapering must begin within 2 weeks of randomization. - **Protocol:** Reduce steroid doses by 5 mg per week, irrespective of patient response, to align with rapid-onset therapies like upadacitinib and guselkumab. - This approach ensures faster withdrawal of systemic steroids while maintaining therapeutic goals. #### 5. **Maintenance Phase Rules** - **Systemic Steroids:** All systemic steroids must be discontinued before entering the maintenance phase of the trial. - **Re-escalation:** Any need to reintroduce systemic steroids is considered treatment failure. - **Budesonide Exception:** Budesonide can be stopped abruptly due to its minimal impact on adrenal suppression. #### 6. **Endpoint Definition Clarity** - **Corticosteroid-Free Clinical Remission (CSF-CR):** This endpoint should only be calculated for participants who were using steroids at the start of the maintenance phase, avoiding inflated success rates. - Clear endpoint definitions improve data comparability across trials. #### 7. **Patient-Centered Trial Design** - **Shorter Steroid Exposure:** Patients strongly prefer trials with shorter steroid phases, as prolonged use leads to significant side effects like mood swings, insomnia, and weight gain—59% of patients reported such experiences. - **Improved Recruitment:** Patient-friendly designs, including reduced steroid exposure, enhance trial participation and retention. #### 8. **Clinical Impact** - **Standardization:** Uniform tapering protocols and clear remission definitions will improve the comparability of trial data across studies. - **Efficiency:** Reducing placebo effects and shortening steroid phases will make trials more efficient and effective. - **Patient Experience:** By prioritizing patient preferences, trials become more appealing and less burdensome. #### 9. **Future Directions** - **Real-World Adoption:** Encourage early steroid tapering protocols in clinical practice to mirror trial designs. - **Patient-Reported Outcomes:** Integrate measures like sleep quality, mood, and overall well-being to assess patient-centric endpoints. - **Biomarker Integration:** Use biomarkers such as fecal calprotectin to personalize steroid withdrawal strategies, ensuring tailored treatment approaches. ### Conclusion: The Consensus Blueprint for Steroid Stewardship in IBD Trials represents a significant step forward in optimizing the use of steroids in clinical research. By addressing the adverse effects of long-term steroid use, standardizing tapering protocols, and focusing on patient-centered designs, the blueprint aims to enhance the reliability, efficiency, and appeal of IBD trials. It also sets the stage for real-world adoption of these practices, paving the way for improved patient outcomes and more personalized treatment strategies.

Noninvasive Imaging in and IBD

Noninvasive imaging techniques are revolutionizing the diagnosis, monitoring, and management of inflammatory bowel disease (IBD), which includes conditions like Crohn’s disease (CD) and ulcerative colitis (UC). These methods are increasingly favored for their ability to provide accurate assessments without the need for invasive procedures like ileocolonoscopy, which, while considered the gold standard, is often uncomfortable and less repeatable for patients. Below is a comprehensive overview of noninvasive imaging in IBD: --- ### **Key Noninvasive Imaging Modalities** 1. **Intestinal Ultrasound (IUS):** - **Accuracy:** IUS has high sensitivity (~86%) and specificity (~88%) for detecting colonic inflammation, comparable to MRI and CT. - **Advantages:** - Radiation-free, immediate, cost-effective, and suitable for repeated evaluations. - Provides real-time, point-of-care assessment, enabling treatment adjustments during consultations. - Well-suited for monitoring disease activity and tracking transmural remission (TR), which reflects deeper healing beyond mucosal recovery. - **Limitations:** - Reduced accuracy in obese patients and for detecting deep or proximal small bowel lesions. - May require oral contrast or complementary imaging for full evaluation. 2. **Magnetic Resonance Enterography (MRE):** - **Role:** MRE is considered the reference standard for imaging small bowel Crohn’s disease. - **Accuracy:** Near 97% sensitivity and 80% specificity for identifying active disease and complications like strictures, abscesses, and fistulas. - **Advantages:** Provides detailed anatomical imaging without radiation exposure. - **Applications:** Particularly useful for detecting transmural healing and monitoring disease progression or relapse. 3. **Computed Tomography Enterography (CTE):** - **Role:** CTE is an alternative imaging tool, often used when MRE access is limited or in emergencies. - **Advantages:** Accurate and widely accessible. - **Limitations:** Involves radiation exposure, making it less suitable for repeated evaluations. 4. **Video Capsule Endoscopy (VCE):** - **Role:** Excels at detecting small bowel and proximal lesions that may be missed by MRE or IUS. - **Advantages:** Minimally invasive and provides detailed visualization of the bowel mucosa. - **Limitations:** Carries a 3–10% risk of capsule retention, especially in patients with strictures. 5. **Transperineal Ultrasound (TPUS):** - **Role:** Effective for detecting proctitis, rectal wall thickening, and perianal complications in UC and CD. - **Advantages:** Useful for localized disease monitoring, particularly in perianal Crohn’s disease. --- ### **Applications in IBD Management** 1. **Diagnosis:** - Noninvasive imaging methods like IUS, MRE, and CTE provide accurate alternatives for diagnosing IBD. - Combining imaging with biomarkers such as fecal calprotectin (FC) and C-reactive protein (CRP) enhances diagnostic precision, though these biomarkers are not disease-specific. 2. **Monitoring Disease Activity:** - IUS and MRE have >80% sensitivity and specificity for detecting disease relapse or progression. - These methods enable real-time monitoring, allowing clinicians to adjust treatments based on disease activity. 3. **Detection of Complications:** - Imaging techniques are essential for identifying strictures, abscesses, fistulas, and inflammatory masses. - IUS and MRE are particularly effective at differentiating inflammation from fibrosis, guiding appropriate interventions. 4. **Postoperative Assessment:** - IUS, MRE, and VCE are valuable for detecting postoperative recurrence. - IUS demonstrates 82%–88% accuracy compared to colonoscopy in assessing postoperative disease activity. 5. **Perianal Crohn’s Disease:** - MRI remains the preferred tool for evaluating perianal disease and therapy response, offering greater anatomical detail than TPUS or endoanal ultrasound. 6. **Transmural Remission (TR):** - Imaging is increasingly used to assess TR—a deeper indicator of long-term disease control beyond mucosal healing. - IUS and MRE are particularly effective for tracking transmural healing. 7. **Point-of-Care Decisions:** - Bedside IUS has transformed IBD care, allowing clinicians to make immediate treatment decisions and engage patients by visually demonstrating disease progression or improvement. --- ### **Advantages of Noninvasive Imaging in IBD** - **Patient-Friendly:** Reduces the discomfort and invasiveness associated with traditional colonoscopy. - **Repeatable:** Suitable for ongoing monitoring without concerns about radiation exposure (especially with IUS and MRE). - **Cost-Effective:** IUS, in particular, is a sustainable and affordable option for regular assessments. - **Safety:** Noninvasive methods minimize risks while providing reliable diagnostic and monitoring capabilities. - **Improved Outcomes:** Early diagnosis, real-time monitoring, and personalized treatment adjustments contribute to better disease management and patient outcomes. --- ### **Challenges and Limitations** - **IUS:** Accuracy may be compromised in obese patients or for deep/proximal small bowel lesions. - **CTE:** Radiation exposure limits its use for repeated assessments. - **VCE:** Risk of capsule retention in patients with strictures. - **Training Needs:** Structured training programs like IBUS are essential to ensure competency in IUS and other imaging modalities. - **Standardization:** Consistent imaging protocols and structured reporting are necessary to optimize the utility of these techniques. --- ### **Future Innovations** - **Artificial Intelligence (AI):** AI is being integrated into imaging workflows to automate image analysis, improve diagnostic precision, and detect fibrosis. - **Elastography:** Offers potential for detecting fibrosis and further enhancing imaging capabilities. --- ### **Conclusion** Noninvasive imaging has become central to IBD care, replacing or complementing traditional invasive methods for diagnosis and monitoring. Techniques like IUS, MRE, CTE, and VCE provide accurate, patient-friendly, and repeatable solutions that promote early diagnosis, safer monitoring, and personalized management. IUS, in particular, is emerging as the dominant frontline imaging tool globally due to its accessibility, cost-effectiveness, and ability to support point-of-care decisions. As technology advances, innovations like AI and elastography are expected to further enhance the precision and utility of noninvasive imaging in IBD.

Corticosteroids in Clinical Trials in Inflammatory Bowel Disease

Corticosteroids play a significant role in managing inflammatory bowel disease (IBD), but their use in clinical trials has been inconsistent, leading to challenges in interpreting study outcomes. To address this issue, an international consensus was developed to standardize corticosteroid management in randomized controlled trials (RCTs) involving adult patients with moderate-to-severe Crohn's disease (CD) and ulcerative colitis (UC). Below is a detailed overview of corticosteroid use in clinical trials for IBD based on the consensus recommendations: ### Purpose of the Consensus The consensus aims to address the heterogeneity in corticosteroid dosing, tapering schedules, and remission definitions across IBD trials. By establishing standardized guidelines, the consensus seeks to: - Minimize prolonged corticosteroid exposure. - Improve patient safety and participation in trials. - Reduce bias in therapeutic outcomes. - Align trial practices with real-world clinical management. ### Key Recommendations for Corticosteroid Use in IBD Trials #### 1. **Corticosteroids During Screening** - Only oral systemic and oral enteric/colonic-release corticosteroids are permitted during the screening phase of the trial. - Patients receiving intravenous corticosteroids during screening are disqualified from participating in the trial. #### 2. **Rectal Corticosteroid Restrictions** - Patients with UC or CD must discontinue rectally administered corticosteroids at least two weeks before screening or randomization. #### 3. **Dose Limitations Before Randomization** - Prednisone-equivalent doses should not exceed **20 mg/day**. - Budesonide doses should not exceed **9 mg/day**. - This ensures participants enter the trial with a manageable corticosteroid exposure level. #### 4. **Stable Dose Period** - Patients must maintain a stable corticosteroid dose for at least **two weeks** prior to baseline or randomization to ensure consistent baseline disease activity. #### 5. **Tapering During Induction** - Tapering of corticosteroids must begin within **two weeks** of randomization. - A fixed tapering rate of **5 mg/week** is recommended for prednisone-equivalent doses. - The tapering schedule should be protocol-defined to ensure uniform application across participants. #### 6. **Defining Treatment Failure** - Patients who start corticosteroids de novo during induction or maintenance phases, or require intravenous rescue therapy, are considered treatment failures. - This definition helps identify patients who do not respond adequately to the trial intervention. #### 7. **Maintenance Phase Guidelines** - Oral corticosteroids should begin tapering at the start of the maintenance phase if tapering has not already been initiated. - Budesonide may be discontinued without tapering during the maintenance phase. #### 8. **Rescue Steroid Use** - Patients requiring more than **one rescue corticosteroid course** during the maintenance phase are deemed treatment failures. - An exception is made for short-term steroid use to manage unrelated conditions, such as asthma. #### 9. **Corticosteroid-Free Remission Definition** - Only patients who were using corticosteroids at the start of the trial should be included in the denominator for calculating corticosteroid-free remission rates. - The consensus debated the withdrawal duration for remission; most experts supported defining remission as withdrawal of corticosteroids for **≥12 weeks** before the final study visit. #### 10. **Standardized Reporting** - The consensus strongly recommends transparent reporting of cumulative corticosteroid exposure, rescue therapy use, and tapering deviations in future trials. - This will improve comparability across studies and provide better insights into therapeutic outcomes. ### Patient Feedback Patients expressed a preference for earlier tapering and minimized steroid use due to adverse effects such as: - Weight gain. - Mood swings. - Sleep disturbances. This feedback highlights the importance of balancing corticosteroid use with patient quality of life during trials. ### Clinical Implications The standardized corticosteroid management framework aims to: - Optimize trial design and execution. - Reduce steroid-related harm. - Enhance the validity and interpretability of therapeutic outcomes. - Align trial practices with real-world clinical scenarios. ### Future Outlook This is the first international corticosteroid management framework specifically designed for IBD RCTs. It is expected to: - Improve patient safety. - Increase trial validity globally. - Serve as a blueprint for future clinical trials focusing on IBD and other inflammatory conditions. ### Scope of Consensus It is important to note that these recommendations apply only to adult patients with moderate-to-severe CD or UC in pharmacologic RCTs. The guidelines do not address pediatric populations or surgical interventions. ### Conclusion The consensus on corticosteroid use in IBD clinical trials represents a groundbreaking effort to harmonize trial protocols, improve patient outcomes, and enhance the reliability of therapeutic evaluations. By implementing these standardized practices, researchers can ensure a consistent approach to corticosteroid management while addressing patient concerns and minimizing adverse effects.

GI infections and IBD Flare

Gastrointestinal (GI) infections are closely linked to flare-ups in inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease. Here’s a detailed breakdown of the relationship between GI infections and IBD flares: ### 1. **Increased Risk of IBD Flare After GI Infection** - Patients with IBD who experience GI infections are significantly more likely to develop flare-ups within 1–6 months following the infection. Studies show that 37% of infected patients had flare-ups compared to only 11% of non-infected patients. - This suggests that GI infections act as potent inflammatory triggers, exacerbating the underlying disease. ### 2. **Impact on Disease Control and Treatment Intensification** - GI infections often worsen disease control in IBD patients, leading to more frequent treatment escalations. About 37% of infected patients required intensified medication, such as corticosteroids, biologics, or immunosuppressants, compared to 20% of non-infected patients. - This highlights the need for proactive management in infected patients to prevent disease progression. ### 3. **Differences Between Ulcerative Colitis and Crohn’s Disease** - Ulcerative colitis patients appear to be more sensitive to GI infections compared to Crohn’s disease patients. They have higher rates of hospital admissions post-infection, reflecting differing disease responses to inflammatory triggers. ### 4. **Role of Systemic Inflammation (CRP Levels)** - Elevated C-reactive protein (CRP) levels, a marker of systemic inflammation, are strongly associated with worse outcomes in IBD patients with GI infections. High CRP levels significantly increase the likelihood of hospitalization (P = .008), indicating that infections can amplify systemic inflammatory responses. ### 5. **Vulnerability During Early-Stage IBD** - Patients in the early stages of IBD (less than two years since diagnosis) are particularly vulnerable to GI infections. These individuals have 2.3 times greater odds of developing infections compared to those with longer disease durations. - This underscores the importance of vigilant monitoring and preventive strategies in newly diagnosed patients. ### 6. **Common Pathogens in GI Infections** - Key bacterial pathogens associated with GI infections in IBD patients include: - **Campylobacter spp.** - **Yersinia spp.** - **Salmonella spp.** - **Enterohemorrhagic E. coli** - These organisms are known to provoke intestinal inflammation, which can mimic or worsen IBD symptoms. ### 7. **Diagnostic Recommendations** - During an IBD flare, it is crucial to test for bacterial infections as they can either mimic or exacerbate inflammatory activity. Diagnostic methods include: - **Endoscopy:** To visualize inflammation and confirm IBD activity. - **Biopsy-based histology:** To identify tissue changes. - **Biomarkers like fecal calprotectin:** To differentiate between infection and IBD-related inflammation. ### 8. **Post-Infection Monitoring** - Continuous follow-up for at least six months after a GI infection is essential for IBD patients. This monitoring helps detect delayed relapses and allows healthcare providers to optimize treatment strategies. ### 9. **Limitations in Understanding the Relationship** - Current knowledge on the link between GI infections and IBD flares is limited by the retrospective design of studies. Challenges include non-uniform diagnostic records, evolving testing standards, and unclear medication adherence among patients, which complicates establishing causality. ### Clinical Implications: - **Proactive Testing:** During any IBD flare, clinicians should rule out bacterial infections to ensure accurate diagnosis and treatment. - **Early Intervention:** Patients in the early stages of IBD should be monitored more closely for signs of GI infections. - **Treatment Adjustment:** Infected patients may require prompt medication intensification to manage exacerbated disease activity. - **Long-Term Monitoring:** A six-month follow-up post-infection is crucial to detect relapses and improve disease management. In summary, GI infections are a significant risk factor for triggering IBD flares, especially in early-stage patients and those with elevated systemic inflammation. Understanding this relationship is vital for optimizing diagnostic approaches, treatment strategies, and long-term care in IBD patients.

Monogenic Verus Polygenic IBD

Inflammatory Bowel Disease (IBD) is a chronic condition characterized by inflammation in the gastrointestinal tract. It is broadly categorized into two main types: Crohn's Disease (CD) and Ulcerative Colitis (UC). IBD is a complex disorder with genetic, environmental, and immunological factors contributing to its pathogenesis. When discussing the genetic basis of IBD, we often refer to **monogenic** and **polygenic** forms of the disease. Below is a detailed explanation of the differences between these two forms: --- ### **Monogenic IBD** Monogenic IBD refers to cases of IBD caused by mutations in a single gene. These are rare forms of IBD and are typically observed in very early-onset IBD (VEO-IBD), which occurs in children younger than 6 years of age. Monogenic IBD is often associated with severe disease phenotypes and may present atypically compared to the classic forms of Crohn's disease or ulcerative colitis. #### **Key Features of Monogenic IBD:** 1. **Single-Gene Mutation:** - Monogenic IBD results from mutations in a single gene that disrupts immune regulation, intestinal barrier function, or microbial tolerance. - Examples of implicated genes include **IL10**, **IL10RA**, **IL10RB**, **XIAP**, **FOXP3**, **NOD2**, and others. 2. **Early-Onset Disease:** - It is most commonly observed in very young children (VEO-IBD), often within the first few years of life. - Symptoms might be more severe and refractory to conventional treatments. 3. **Immune Dysregulation:** - The mutations often affect pathways involved in immune homeostasis, such as interleukin signaling (e.g., IL-10 signaling defects) or regulatory T-cell function (e.g., FOXP3 mutations). - These defects lead to uncontrolled inflammation and impaired tolerance to gut microbiota. 4. **Diagnostic Approach:** - Genetic testing is essential for identifying monogenic causes. - Whole-exome sequencing (WES) or targeted gene panels are often employed, especially in cases of VEO-IBD or atypical presentations. 5. **Treatment:** - Standard IBD therapies (e.g., immunosuppressants, biologics) may not be effective. - Treatment often involves addressing the underlying genetic defect, which may include hematopoietic stem cell transplantation (HSCT) for severe immune deficiencies. 6. **Examples of Monogenic IBD Disorders:** - **IL10/IL10 receptor mutations:** Lead to severe, early-onset colitis due to defective anti-inflammatory signaling. - **Chronic Granulomatous Disease (CGD):** Caused by mutations in genes affecting the NADPH oxidase complex, leading to impaired microbial killing and granuloma formation. - **IPEX Syndrome:** Caused by mutations in FOXP3, leading to immune dysregulation and severe enteropathy. --- ### **Polygenic IBD** Polygenic IBD refers to the more common forms of IBD (Crohn's disease and ulcerative colitis) that result from the combined effects of multiple genetic variants, each contributing a small risk to disease development. These variants interact with environmental factors, such as diet, smoking, and microbiota composition, to trigger disease onset. #### **Key Features of Polygenic IBD:** 1. **Multiple Genetic Variants:** - Polygenic IBD is associated with variations in multiple genes, each with a modest effect on disease susceptibility. - Genome-wide association studies (GWAS) have identified over **200 genetic loci** associated with IBD. - Examples of implicated genes include **NOD2**, **ATG16L1**, **IL23R**, **IRGM**, and **CARD9**. 2. **Complex Inheritance:** - Unlike monogenic IBD, polygenic IBD does not follow Mendelian inheritance patterns. - The risk is determined by the cumulative effect of genetic variants, often in combination with environmental triggers. 3. **Age of Onset:** - Polygenic IBD typically presents later in childhood, adolescence, or adulthood. - It is the predominant form of IBD seen in clinical practice. 4. **Environmental Influence:** - Environmental factors, such as diet, smoking, infections, and gut microbiota, play a significant role in modulating the risk and course of polygenic IBD. - These factors interact with genetic predispositions to trigger disease onset. 5. **Diagnostic Approach:** - Genetic testing is not routinely used for polygenic IBD diagnosis, as the presence of risk alleles does not guarantee disease development. - Diagnosis is based on clinical presentation, endoscopic findings, and histological examination. 6. **Treatment:** - Management typically involves anti-inflammatory medications, immunosuppressants, and biologics (e.g., anti-TNF agents, anti-integrins, anti-IL12/23 agents). - Lifestyle modifications, dietary interventions, and microbiota-targeted therapies (e.g., probiotics) may also play a role. --- ### **Comparison of Monogenic vs. Polygenic IBD** | **Aspect** | **Monogenic IBD** | **Polygenic IBD** | |---------------------------|--------------------------------------------|-------------------------------------------| | **Cause** | Single gene mutation | Multiple genetic variants with small effects | | **Age of Onset** | Very early (infancy or childhood) | Later childhood, adolescence, or adulthood | | **Prevalence** | Rare | Common | | **Inheritance Pattern** | Mendelian (autosomal dominant/recessive) | Complex, multifactorial | | **Severity** | Often severe and refractory | Variable (mild to severe) | | **Environmental Role** | Minimal | Significant | | **Diagnosis** | Genetic testing (WES, targeted panels) | Clinical evaluation, endoscopy, histology | | **Treatment** | Targeted therapies, HSCT in some cases | Standard IBD therapies, biologics | | **Examples of Genes** | IL10, FOXP3, XIAP, NOD2 | NOD2, ATG16L1, IL23R, CARD9 | --- ### **Clinical Implications** 1. **Importance of Early Diagnosis in Monogenic IBD:** - Early identification of monogenic causes is critical because these patients may require unique treatments, such as HSCT, which can be life-saving. - Delay in diagnosis can lead to significant morbidity and complications. 2. **Personalized Medicine in Polygenic IBD:** - Understanding the genetic basis of polygenic IBD can help identify patients who may benefit from specific therapies, such as biologics targeting IL-23 or TNF-alpha. 3. **Research Opportunities:** - Monogenic IBD provides insights into key pathways involved in intestinal inflammation, which may inform the development of novel therapies for polygenic forms of the disease. - Polygenic IBD research focuses on gene-environment interactions and the role of microbiota in disease pathogenesis. --- ### **Conclusion** Monogenic and polygenic IBD represent two distinct categories of inflammatory bowel disease with differing genetic mechanisms, clinical presentations, and therapeutic approaches. Monogenic IBD is rare, severe, and typically presents in early childhood due to single-gene defects affecting immune regulation. Polygenic IBD, on the other hand, is more common and results from the cumulative effects of multiple genetic variants interacting with environmental factors. Understanding these differences is crucial for accurate diagnosis, appropriate treatment, and advancing research into the underlying mechanisms of IBD.

IL-23 inhibitors and IBD

IL-23 inhibitors represent a significant advancement in the treatment landscape for inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC). These biologic agents target the interleukin-23 (IL-23) cytokine, specifically its p19 subunit, which plays a crucial role in driving the chronic inflammation underlying IBD. By selectively inhibiting IL-23, these therapies aim to reduce inflammation, promote mucosal healing, and improve patient outcomes. ### **Role of IL-23 in IBD Pathogenesis** IL-23 is a pro-inflammatory cytokine that is part of the IL-12 family. It is composed of two subunits: p19 (unique to IL-23) and p40 (shared with IL-12). IL-23 is produced by antigen-presenting cells such as dendritic cells and macrophages and plays a central role in the differentiation and maintenance of Th17 cells, a subset of CD4+ T cells. Th17 cells, in turn, produce inflammatory cytokines like IL-17, IL-22, and TNF-α, which contribute to the inflammation and tissue damage seen in IBD. By targeting the p19 subunit, IL-23 inhibitors selectively block IL-23 signaling without affecting IL-12, thereby preserving the protective immune functions of IL-12. ### **Approved IL-23 Inhibitors for IBD** Several IL-23 inhibitors have demonstrated efficacy and safety in clinical trials and are either approved or under investigation for the treatment of IBD: 1. **Risankizumab**: - Approved for moderate-to-severe Crohn’s disease. - Clinical trials (e.g., ADVANCE and MOTIVATE) have shown significant improvements in clinical remission, endoscopic response, and quality of life in patients with CD. - Demonstrated a favorable safety profile with low rates of infections and adverse events. 2. **Mirikizumab**: - Recently approved for moderate-to-severe ulcerative colitis. - Clinical trials (e.g., LUCENT-1 and LUCENT-2) showed significant efficacy in inducing and maintaining clinical remission, endoscopic improvement, and histologic remission in UC patients. - Safety data suggest a low risk of serious infections and adverse events. 3. **Guselkumab**: - Currently approved for psoriasis and psoriatic arthritis, with ongoing trials for Crohn’s disease (e.g., GALAXI-1). - Preliminary data suggest promising efficacy and safety in CD. 4. **Tildrakizumab**: - Primarily approved for psoriasis but being investigated for IBD. - Early-phase trials are ongoing to evaluate its effectiveness in CD and UC. ### **Efficacy of IL-23 Inhibitors** Clinical trials and real-world studies have demonstrated the efficacy of IL-23 inhibitors in both induction and maintenance phases of treatment: - **Induction Phase**: IL-23 inhibitors have shown rapid reductions in disease activity, with many patients achieving clinical remission and endoscopic improvement within 8-12 weeks. - **Maintenance Phase**: These agents have demonstrated sustained efficacy over long-term treatment, with many patients maintaining remission and mucosal healing for up to a year or longer. ### **Safety Profile** IL-23 inhibitors have a favorable safety profile compared to other biologics. Key findings include: - Low risk of serious infections. - Minimal immunosuppression compared to anti-TNF agents. - Rare adverse events, with most being mild-to-moderate in severity (e.g., upper respiratory tract infections, injection site reactions). ### **Position in Treatment Algorithm** According to the **American Gastroenterological Association (AGA)** and **European Crohn’s and Colitis Organisation (ECCO)** guidelines, IL-23 inhibitors are increasingly being positioned as a valuable option in the treatment of IBD: 1. **Moderate-to-Severe Crohn’s Disease**: - IL-23 inhibitors, such as risankizumab, are recommended for patients who have failed conventional therapies (e.g., corticosteroids, immunomodulators) or other biologics (e.g., anti-TNF agents, anti-IL-12/23 agents like ustekinumab). - They are also considered for biologic-naïve patients due to their targeted mechanism of action and favorable safety profile. 2. **Moderate-to-Severe Ulcerative Colitis**: - Mirikizumab is recommended for patients with inadequate response or intolerance to conventional or biologic therapies. - Emerging data suggest that IL-23 inhibitors may be particularly effective in patients with a higher inflammatory burden, as evidenced by elevated biomarkers like CRP and fecal calprotectin. 3. **Combination Therapy**: - Preliminary evidence suggests that IL-23 inhibitors may be used in combination with other biologics (e.g., anti-TNF agents) or small-molecule drugs (e.g., JAK inhibitors like tofacitinib or upadacitinib) to achieve deeper remission in refractory cases. - However, more research is needed to establish the safety and efficacy of combination regimens. ### **Advantages Over Other Biologics** IL-23 inhibitors offer several advantages over existing biologics: - **Selective Targeting**: By targeting the IL-23p19 subunit, these agents avoid inhibiting IL-12, which plays a protective role in immune defense against infections and malignancies. - **Durable Remission**: IL-23 inhibitors have demonstrated sustained efficacy in maintaining remission and mucosal healing, even in patients who have failed other biologics. - **Convenient Dosing**: Most IL-23 inhibitors are administered subcutaneously every 4-8 weeks, offering convenience and improved patient adherence. ### **Challenges and Future Directions** Despite their promise, IL-23 inhibitors face several challenges: - **Cost**: Like other biologics, IL-23 inhibitors are expensive, which may limit access for some patients. - **Long-Term Safety**: While short-term safety data are reassuring, long-term safety, particularly regarding the risk of infections or malignancies, needs further evaluation. - **Biomarker Development**: Identifying biomarkers to predict response to IL-23 inhibitors remains an area of active research, with the goal of personalizing treatment for individual patients. ### **Conclusion** IL-23 inhibitors represent a major advancement in the management of IBD, addressing unmet needs for patients with moderate-to-severe disease who do not respond adequately to existing therapies. With their targeted mechanism of action, robust efficacy, and favorable safety profile, these agents are poised to play a central role in personalized treatment strategies for Crohn’s disease and ulcerative colitis. Ongoing research, including head-to-head trials and studies exploring combination therapies, will further clarify their place in the therapeutic landscape and expand the possibilities for improving patient outcomes.

Gut inflammation and axial spondyloarthritis –SPARTAKUS cohor

The relationship between gut inflammation and axial spondyloarthritis (axSpA) has been extensively studied, and the SPARTAKUS cohort plays a key role in advancing our understanding of this association. Below is a detailed explanation of the gut-joint hypothesis, the influence of gut inflammation on joint inflammation, and the significance of the SPARTAKUS cohort in studying these phenomena. --- ### **Gut-Joint Hypothesis** The gut-joint hypothesis posits that inflammation in the gut can influence inflammation in distant sites like the spine and joints, contributing to the development and progression of diseases such as axial spondyloarthritis (axSpA). This connection is thought to occur through several mechanisms: 1. **Immune System Crosstalk**: - The gut is a central hub for immune system regulation. Dysbiosis (imbalance in gut microbiota) or subclinical gut inflammation can lead to aberrant activation of immune pathways, particularly the IL-23/IL-17 axis, which is implicated in axSpA pathogenesis. - These inflammatory cytokines can travel through the bloodstream and contribute to systemic inflammation, including inflammation in the joints and spine. 2. **Molecular Mimicry**: - Certain gut microbial antigens may resemble self-antigens, leading to an autoimmune response that targets both the gut and musculoskeletal system. 3. **Leaky Gut Syndrome**: - Gut inflammation can result in increased intestinal permeability ("leaky gut"), allowing microbial products like lipopolysaccharides (LPS) to enter the bloodstream and trigger systemic inflammation. 4. **Shared Genetic Susceptibility**: - Genetic factors like HLA-B27, which are strongly associated with axSpA, may also predispose individuals to gut inflammation, creating a bidirectional relationship between gut health and musculoskeletal disease. --- ### **How Gut Inflammation Influences Joint Inflammation** Gut inflammation, as measured by biomarkers like fecal calprotectin (F-calprotectin), has been shown to correlate with joint and spinal inflammation in axSpA. Key mechanisms include: 1. **Cytokine Pathways**: - Elevated gut inflammation activates pro-inflammatory cytokines such as IL-17, IL-23, and TNF-alpha, which are directly involved in the chronic inflammation seen in axSpA. - These cytokines promote the recruitment of immune cells to the joints and spine, leading to inflammation and structural damage. 2. **Systemic Inflammatory Burden**: - Persistent gut inflammation contributes to an overall heightened inflammatory state, which can exacerbate joint and spinal damage over time. 3. **Subclinical Gut Inflammation**: - Even in the absence of overt symptoms of inflammatory bowel disease (IBD), subclinical gut inflammation (detected via elevated F-calprotectin) can influence musculoskeletal disease severity in axSpA patients. 4. **Radiographic Progression**: - Studies, including the SPARTAKUS cohort, have demonstrated that elevated F-calprotectin levels are independently associated with greater structural spinal damage, as measured by the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). This suggests that gut inflammation contributes to long-term radiographic progression in axSpA. --- ### **SPARTAKUS Cohort and Its Importance** The SPARTAKUS cohort is a population-based study conducted in southern Sweden, involving 228 patients with well-characterized axial spondyloarthritis (axSpA). Its primary goal is to investigate the underlying mechanisms, clinical characteristics, and progression of axSpA, with a particular focus on gut inflammation. #### **Key Features of the SPARTAKUS Cohort**: 1. **Large Sample Size**: - The cohort includes 228 patients, divided into non-radiographic axSpA (nr-axSpA, n=76) and radiographic axSpA (r-axSpA, n=152) groups. This allows researchers to explore disease differences across varying severity levels. 2. **Comprehensive Data Collection**: - Participants are well-characterized, with detailed information on demographics, genetic markers (e.g., HLA-B27), disease activity scores (ASDAS, BASDAI), imaging (mSASSS), and biomarkers like fecal calprotectin and C-reactive protein (CRP). 3. **Focus on Gut Inflammation**: - The cohort specifically examines the role of gut inflammation in axSpA progression, using F-calprotectin as a biomarker to assess subclinical intestinal inflammation. 4. **Robust Statistical Analysis**: - The study adjusts for confounding factors such as sex, smoking, NSAID use, TNF inhibitor therapy, and comorbidities like inflammatory bowel disease (IBD), ensuring the reliability of its findings. #### **Significance of SPARTAKUS Cohort Findings**: 1. **Gut-Spine Connection**: - The study provides strong evidence for the gut-joint axis hypothesis, showing that elevated F-calprotectin levels are independently associated with greater structural spinal damage in axSpA. 2. **Radiographic Progression**: - Patients with higher F-calprotectin levels consistently exhibit more severe radiographic damage, particularly in the r-axSpA subgroup. This highlights the potential of gut inflammation as a driver of disease progression. 3. **Clinical Correlations**: - Elevated F-calprotectin levels are also associated with higher CRP levels, longer symptom duration, and higher disease activity scores (ASDAS, BASDAI), reinforcing the role of inflammation in cumulative spinal damage. 4. **IBD Independence**: - The association between gut inflammation and spinal damage persists even after excluding patients with IBD, suggesting that subclinical gut inflammation alone can contribute to axSpA severity. 5. **Diagnostic and Prognostic Utility**: - F-calprotectin testing may serve as a non-invasive biomarker for identifying patients at risk of progressive spinal ankylosis, aiding in early intervention and personalized treatment strategies. 6. **Pathophysiological Insights**: - The study supports the hypothesis that gut inflammation, possibly mediated by the IL-23/IL-17 pathway, plays a central role in axSpA pathogenesis and progression. --- ### **Future Directions** The SPARTAKUS cohort findings underscore the need for further research into the gut-joint axis in axSpA. Future studies should focus on: 1. **Longitudinal Analysis**: - Tracking patients over time to determine whether elevated F-calprotectin predicts future radiographic progression. 2. **Intervention Trials**: - Investigating whether targeting gut inflammation (e.g., through dietary modification, probiotics, or anti-inflammatory therapies) can alter spinal outcomes in axSpA. 3. **Advanced Imaging**: - Incorporating spinal MRI data to directly assess concurrent inflammatory activity and structural damage. 4. **Mechanistic Studies**: - Exploring the molecular pathways linking gut and joint inflammation, particularly the role of microbiota and cytokines like IL-23 and IL-17. --- ### **Conclusion** The SPARTAKUS cohort has provided compelling evidence that gut inflammation, as measured by fecal calprotectin, is independently associated with greater structural spinal damage in axial spondyloarthritis. These findings highlight the gut’s central role in disease pathogenesis and progression, supporting the gut-joint hypothesis. F-calprotectin testing may emerge as a valuable tool for predicting radiographic progression and guiding personalized treatment strategies, emphasizing the need for further research into the gut-joint axis in axSpA.

Oral lyophilized donor FMT in ulcerative colitis

**Oral Lyophilized Donor FMT in Ulcerative Colitis:** Oral lyophilized donor fecal microbiota transplantation (FMT) involves encapsulated, freeze-dried fecal microbiota from a healthy donor, designed for oral administration. This innovative approach simplifies the logistics of FMT compared to traditional frozen formulations, providing a practical, non-invasive treatment option. The goal of FMT is to restore microbial diversity and balance in the gut, which is often disrupted in ulcerative colitis (UC). UC is a chronic inflammatory bowel disease characterized by dysbiosis—reduced microbial diversity and loss of beneficial short-chain fatty acid-producing bacteria, such as Faecalibacterium prausnitzii and Akkermansia muciniphila. Dysbiosis contributes to intestinal inflammation, impaired barrier function, and disease progression. The study investigated oral lyophilized FMT in mild-to-moderate UC patients, showing promising results. FMT significantly increased gut microbial diversity, shifting the microbiome toward the donor’s composition. Key beneficial taxa, such as Clostridium SGB6179, Faecalibacterium prausnitzii, and Alistipes finegoldii, engrafted efficiently into patients' microbiomes, promoting anti-inflammatory effects and epithelial repair. Functional changes included enhanced microbial pathways for L-citrulline biosynthesis and the urea cycle, vital for intestinal repair and immune modulation. Clinically, 53% of FMT-treated patients achieved corticosteroid-free remission with endoscopic response by week 8, compared to 15% in the placebo group. Long-term low-dose FMT maintained remission for up to 56 weeks. Furthermore, FMT reduced antibiotic resistance gene abundance, restoring a healthier resistome profile. This study highlights oral lyophilized FMT as an effective, accessible therapy for UC, paving the way for targeted microbial therapeutics in chronic inflammatory bowel diseases.

Upadacitinib in a real-world cohort of patients with Crohn’s disease in the UK

The real-world study on upadacitinib in patients with moderate-to-severe Crohn’s disease (CD) was conducted across 19 hospitals in the UK between April and October 2023. The study aimed to evaluate the effectiveness, persistence, and safety of upadacitinib in a challenging cohort of patients with active CD. Below is a detailed overview of the study findings: ### Study Design and Patient Cohort: 1. **Multicentre Retrospective Cohort Study**: The study involved data collection from 19 hospitals in the UK. 2. **Patient Population**: Included 312 adults with active moderate-to-severe Crohn’s disease. - 64% of patients had failed three or more biologic therapies, indicating a highly refractory population. - 51% had penetrating or stricturing disease, which are more severe phenotypes of Crohn’s disease. ### Effectiveness: 1. **Primary Endpoint**: Clinical remission was defined as a Harvey Bradshaw Index (HBI) score of <4, assessed at 12 and 24 weeks. 2. **Induction Remission** (12 weeks): - 50% (113/227) of patients achieved clinical remission. - Of those achieving remission, 93% were steroid-free, highlighting the efficacy of upadacitinib without reliance on corticosteroids. 3. **Maintenance Remission** (24 weeks): - 45% (77/172) of patients maintained clinical remission. - 96% of these patients were steroid-free. 4. **Biochemical Remission**: - Faecal calprotectin and C-reactive protein (CRP) levels normalized in 28% of patients by week 12 and 18% by week 24. 5. **Endoscopic Remission**: - Mucosal healing (endoscopic remission) was slower compared to symptomatic improvements, with 6% achieving remission at 12 weeks and 12% at 24 weeks. ### Persistence: 1. **Drug Persistence**: Upadacitinib showed strong adherence and tolerability. - Persistence rates were 90.3% at 12 weeks and 84.1% at 24 weeks. ### Predictors of Remission: 1. **Disease Location**: - Patients with colonic (L2) and ileocolonic (L3) disease had higher odds of remission compared to those with isolated ileal (L1) disease. - Colonic disease was the strongest predictor of remission (OR 9.16, p=0.003), followed by ileocolonic disease (OR 3.44, p=0.043). 2. **Smoking Status**: - Ex-smokers had significantly lower odds of achieving remission compared to never-smokers (OR 0.08, p=0.006). 3. **Stoma Patients**: - Patients with stomas had reduced remission rates due to limitations in the Harvey Bradshaw Index (HBI), which does not accurately measure stool frequency in stoma patients. 4. **Early Response**: - Early response was predictive of long-term success; 80% of patients in remission at 12 weeks remained in remission at 24 weeks. ### Safety Profile: 1. **Adverse Events (AEs)**: - AEs were reported in 28% of patients, with 18% experiencing serious AEs. - The most frequent AEs included infections (7.7%) and lipid abnormalities (4.8%). 2. **Severe Events**: - Serious AEs included resections (5.4%), symptom worsening (4.8%), obstructions (2.2%), and venous thromboembolism (1%). 3. **Discontinuation Rate**: - 8% of patients discontinued upadacitinib due to side effects, which aligns with rates observed in prior real-world studies. ### Comparison with Clinical Trials: - Remission rates in this real-world study (45%) were consistent with results from clinical trials such as U-EXCEL and U-EXCEED (39–50%), validating the efficacy of upadacitinib in real-world settings. ### Limitations: 1. **Retrospective Design**: The study's retrospective nature may introduce biases. 2. **Incomplete Endoscopy Data**: Limited availability of endoscopic data restricts the ability to comprehensively assess mucosal healing. 3. **Challenges in Stoma Patients**: Difficulty in quantifying outcomes for stoma patients due to limitations in the HBI scoring system. ### Conclusion: Upadacitinib demonstrated good short-term effectiveness, strong drug persistence, and an acceptable safety profile in a highly refractory population of Crohn’s disease patients in the UK. The study supports upadacitinib as an effective oral therapy for moderate-to-severe Crohn’s disease in real-world clinical practice. Despite certain limitations, the findings align closely with clinical trial data, further validating the use of upadacitinib in managing this chronic inflammatory condition.

Psychological interventions and IBD Management

Psychological interventions have been increasingly recognized as valuable components in the management of inflammatory bowel disease (IBD). This is because IBD is not only a physical condition but also closely intertwined with psychological and emotional well-being. The study you provided offers a comprehensive analysis of various psychological interventions and their effectiveness in addressing key outcomes such as depression, anxiety, stress, disease activity, and quality of life (QoL) in individuals with IBD. Here is a detailed breakdown of the role of psychological interventions in IBD management based on the study findings: ### 1. **Psychological Interventions Evaluated** The study analyzed 12 psychological interventions, including: - **Mindfulness Interventions (MI)** - **Cognitive Behavioral Therapy (CBT)** - **Acceptance and Commitment Therapy (ACT)** - **Multicomponent ACT (compassion-focused)** - **Hypnotherapy** - **Relaxation Training** - **Psychoeducation** These interventions aim to address the psychological challenges often faced by IBD patients, such as depression, anxiety, and stress, which can exacerbate disease symptoms and reduce quality of life. --- ### 2. **Key Psychological Outcomes** The study focused on three primary psychological outcomes—depression, anxiety, and stress—and their management through various interventions: #### **Depression** - **Mindfulness Interventions (MI)** and **CBT** were found to significantly reduce depressive symptoms compared to waiting list (WL) controls. - MI had the strongest effect (Standardized Mean Difference [SMD]: −0.63) and ranked the highest in effectiveness (SUCRA: 77.2%). - Mechanism: MI likely reduces depressive symptoms by promoting emotional regulation, reducing rumination, and fostering acceptance. Neuroimaging evidence supports that MI induces positive changes in brain regions associated with mood regulation. #### **Anxiety** - **ACT**, **Multicomponent ACT (compassion-focused)**, and **CBT** were the most effective interventions for reducing anxiety: - Multicomponent ACT had the strongest effect (SMD: −1.15), followed by ACT (SMD: −1.01) and CBT (SMD: −0.75). - Mechanism: ACT-based therapies work by increasing psychological flexibility and encouraging self-acceptance through mindfulness and value-based actions. #### **Stress** - **CBT** emerged as the most effective intervention for stress reduction, achieving the top SUCRA ranking (97.2%), followed by ACT (78.1%) and psychoeducation (74.7%). - Mechanism: CBT targets stress by addressing maladaptive thought patterns and behaviors and incorporating relaxation techniques. --- ### 3. **Quality of Life (QoL)** - **Mindfulness Interventions (MI)** were particularly effective in improving health-related QoL: - MI significantly enhanced QoL compared to WL controls (SMD: 2.21) and usual care (SMD: 1.82), ranking the highest overall (SUCRA: 99.9%). - This suggests that mindfulness practices can play a transformative role in improving the overall well-being of IBD patients. --- ### 4. **Disease Activity** - No psychological intervention showed a statistically significant improvement in disease activity. However, **Multicomponent ACT** ranked highest in SUCRA (90.4%). - While psychological therapies may not directly impact disease activity, they can indirectly influence disease outcomes by addressing the brain–gut axis. Psychosocial stress and neuroimmune responses are known to contribute to IBD exacerbations, highlighting the importance of psychological care. --- ### 5. **Mechanistic Insights** The study emphasizes the role of the brain–gut axis in IBD management. Psychological interventions likely influence this axis by: - Reducing psychosocial stress, which is a known trigger for IBD flare-ups. - Modulating neuroimmune responses that contribute to inflammation. - Enhancing emotional regulation, which can mitigate the impact of chronic stress on disease progression. --- ### 6. **Limitations of Current Research** While the study provides valuable insights, it also highlights several limitations that should be addressed in future research: - Small sample sizes in the included randomized controlled trials (RCTs). - Lack of blinding and allocation concealment in many studies, which may introduce bias. - Reliance on waiting list (WL) controls rather than active comparators, which limits the robustness of conclusions. - Heterogeneity among the interventions analyzed, making it challenging to generalize findings. --- ### 7. **Clinical Implications** - Psychological therapies should be considered **adjunctive treatments** rather than replacements for traditional IBD treatments such as pharmacological and surgical interventions. - These therapies are particularly effective for improving quality of life and managing emotional outcomes (depression, anxiety, and stress) in IBD patients. - Tailored psychological interventions can help address individual patient needs. For instance: - **Mindfulness Interventions** are most effective for depression and QoL. - **ACT-based therapies** are highly effective for managing anxiety. - **CBT** is the leading intervention for stress management. --- ### 8. **Future Research Directions** The study calls for further research to address the limitations and enhance the understanding of the long-term benefits of psychological interventions in IBD management. Recommendations include: - Conducting large multicenter RCTs with robust designs. - Direct head-to-head comparisons of different psychological interventions. - Standardizing outcome measures across studies. - Incorporating objective biomarkers to assess the impact of psychological interventions on disease activity and progression. --- ### 9. **Conclusion** The study highlights the importance of integrating psychological interventions into the care of IBD patients, aligning with a biopsychosocial model of treatment. While traditional medical therapies remain essential for managing disease activity, psychological therapies can significantly enhance emotional well-being and quality of life. Tailoring interventions to address specific psychological challenges (e.g., depression, anxiety, stress) can improve overall outcomes for individuals living with IBD.

Therapy of iPSC-derived CD146+ mesenchymal stem cells in ulcerative colitis

The study explored the therapeutic potential of induced pluripotent stem cell-derived CD146+ mesenchymal stem cells (CD146+iMSCs) for treating ulcerative colitis (UC). These stem cells were compared to CD146+ umbilical cord mesenchymal stem cells (UCMSCs) in terms of biological traits, anti-inflammatory effects, and immune modulation mechanisms. CD146+iMSCs demonstrated stronger proliferation, self-renewal, and differentiation abilities, maintaining classical mesenchymal stem cell markers. They effectively shifted macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, showing superior immune modulation compared to CD146+UCMSCs. Transcriptome analysis revealed that CD146+iMSCs upregulated pathways involved in calcium signaling, TGF-β, and immune regulation, while suppressing TNF signaling, enhancing their anti-inflammatory activity. In a UC mouse model, CD146+iMSCs significantly alleviated symptoms, reduced weight loss, restored colon length, repaired intestinal barriers, and improved mucosal architecture. They reduced inflammatory cytokines (IL-6, TNF-α, IL-1β) and normalized immune cell populations, restoring immune homeostasis. The study identified the suppression of the IL-17 signaling pathway as a critical mechanism for UC treatment. Additionally, nine key inflammatory hub genes were downregulated by CD146+iMSCs, further supporting their anti-inflammatory effects. CD146+iMSCs also regulated the cGAS-STING pathway, promoting immune tolerance and enhancing mucosal healing. Their regenerative effects were linked to genes involved in tissue repair (TGFB2, CXCL12, VEGF, FGF). Intraperitoneal injection provided better therapeutic outcomes by improving biodistribution to inflamed sites. Overall, CD146+iMSCs demonstrated robust regenerative, anti-inflammatory, and immunomodulatory potential, offering a promising therapy for UC through immune regulation and tissue repair mechanisms.

Decoding IBD progression

Decoding Inflammatory Bowel Disease (IBD) progression involves understanding how gut microbiota and host genetic changes correlate with disease severity. A recent study developed a multi-omics framework combining gut microbiota profiling (via fecal 16S rRNA sequencing) and host transcriptomics (RNA-seq) to accurately stage IBD. This approach aimed to enable non-invasive disease monitoring and personalized therapeutic strategies. The study analyzed 97 participants (74 IBD patients and 23 healthy controls) and found that IBD patients exhibited systemic inflammation and gut barrier dysfunction, reflected in abnormal clinical markers like CRP, ESR, and fecal calprotectin. Microbial diversity was significantly reduced in IBD patients, worsening with disease severity due to dysbiosis. Key microbial biomarkers were identified for each disease stage, such as Bifidobacterium catenulatum in remission and Bacteroides uniformis in severe cases. Host transcriptomic analysis revealed stage-specific genes like YIPF4 and ALAS2, highlighting immune and metabolic changes. Functional pathway analysis showed dynamic immune responses, with remission linked to healing and severe IBD associated with inflammation and tissue damage. Machine learning models achieved high predictive accuracy (AUC = 0.79–0.80) for staging IBD, leveraging microbial and genetic data. Cross-omics analysis demonstrated coordinated shifts between gut microbes and host gene expression, emphasizing their interplay in disease progression. Despite limitations like small sample size and taxonomic resolution, the study's multi-omics approach offers a robust tool for understanding IBD and guiding precision treatments. Future research with larger cohorts and real-time biomarker tracking could transform IBD management, enabling personalized care and non-invasive monitoring.

Ustekinumab trough level and perianal fistulizing Crohn’s disease

In the context of perianal fistulizing Crohn's disease (PFCD), ustekinumab (UST) trough concentrations play a critical role in predicting clinical and radiological remission. A recent study has identified optimal trough levels for achieving fistula remission and managing the condition effectively. The study found that UST trough concentrations ≥3.95 µg/mL at weeks 16/20 are predictive of fistula clinical remission, with an area under the curve (AUC) of 0.791, as determined by receiver operating characteristic (ROC) analysis. This threshold serves as a benchmark for therapeutic drug monitoring (TDM), helping to optimize dosing strategies for patients with PFCD. Additionally, the study highlighted that UST concentrations ≥2.75 µg/mL are associated with intestinal remission, indicating that fistulizing and luminal Crohn's disease may require different pharmacokinetic targets. The findings underscore the importance of TDM in managing PFCD, as maintaining adequate UST trough levels can improve clinical outcomes, including fistula healing and systemic inflammation control. However, achieving and maintaining these trough levels may require dose adjustments or increased dosing frequency, which could lead to higher treatment costs. Despite this, the clinical benefits, such as reduced relapse rates, improved healing, and enhanced quality of life, justify the consideration of TDM in routine clinical practice for PFCD patients.

Novel antibiotic targets IBD—and AI

The novel antibiotic targeting inflammatory bowel disease (IBD) is called **enterololin**, and it represents a groundbreaking achievement in medical research, combining cutting-edge artificial intelligence (AI) with pharmacological science. Here's a detailed breakdown of its significance and the role AI played in its discovery: ### 1. **Enterololin: A Novel Antibiotic for IBD** - **Purpose**: Enterololin was specifically designed to treat IBD, which includes conditions like Crohn's disease and ulcerative colitis. These diseases often involve chronic inflammation and damage to the intestinal lining, partly caused by harmful bacterial overgrowth. - **Mechanism**: Unlike broad-spectrum antibiotics, enterololin is a **narrow-spectrum antibiotic**. It selectively targets harmful bacteria, particularly those from the **Enterobacteriaceae family**, such as *E. coli*, while preserving beneficial gut microbiota. This approach minimizes the risk of secondary infections and dysbiosis, a disruption of microbial balance that can worsen gut health. ### 2. **AI’s Role in the Discovery** - **Predictive Power**: Researchers used a generative AI model called **DiffDock**, developed by MIT’s Regina Barzilay. This model accurately predicted the mechanism of action (MOA) of enterololin before laboratory experiments confirmed it. This is the first time globally that AI successfully predicted a drug’s biological mechanism prior to experimental validation. - **Target Identification**: DiffDock identified that enterololin targets a critical bacterial protein complex known as **LolCDE**, which is essential for bacterial survival and membrane maintenance. This prediction was later validated experimentally by McMaster University scientists. - **Efficiency**: The AI-assisted process shaved **18 months off traditional mechanistic studies** and reduced costs from approximately **$2 million** to just **$60,000**, demonstrating AI's potential to revolutionize drug development. ### 3. **Impact on IBD Management** - **Current Limitations**: Traditional IBD therapies focus on suppressing the immune system rather than addressing bacterial infections contributing to intestinal inflammation. - **Enterololin’s Novel Approach**: This antibiotic introduces a new treatment paradigm by directly targeting harmful bacteria that exacerbate inflammation and mucosal injury in IBD patients. It provides hope for more effective, targeted therapies that improve microbial stability and gut health. ### 4. **Advantages of Narrow-Spectrum Antibiotics** - **Preservation of Gut Microbiota**: Enterololin avoids the harmful effects of broad-spectrum antibiotics, which often kill beneficial bacteria and lead to complications like secondary infections. - **Reduced Drug Resistance**: By specifically targeting harmful pathogens, enterololin minimizes the risk of promoting antibiotic-resistant bacterial strains—a common issue in chronic conditions like IBD. ### 5. **Validation and Human-AI Collaboration** - **Experimental Confirmation**: McMaster scientists experimentally validated DiffDock’s AI prediction, proving the accuracy of the model and establishing a precedent for future AI-assisted drug development. - **Human-AI Synergy**: The study exemplifies how AI and human expertise can complement each other. AI generated hypotheses about the drug’s mechanism, while scientists performed laboratory testing to confirm the results. ### 6. **Broader Implications of AI in Drug Research** - **Efficiency and Cost Reduction**: AI significantly accelerates the research pipeline, reducing the number of trial-and-error experiments and the environmental impact of drug development. - **Beyond Discovery**: AI’s role has expanded from identifying promising molecules to explaining how drugs function, bridging computational prediction with biochemical understanding. ### 7. **Future Prospects** - **Clinical Trials**: Enterololin is being further developed by **Stoked Bio**, a spin-out company from McMaster University, which aims to optimize the drug for human trials within the next three years. - **Potential Beyond IBD**: Enterololin is also being tested against other drug-resistant pathogens, such as *Klebsiella*, suggesting its mechanism could be applied to broader infectious diseases. - **Paradigm Shift**: The success of AI-guided drug discovery and validation could redefine the standard practices for developing therapies for complex diseases like IBD and beyond. ### 8. **Societal and Ethical Impact** - **Improved Patient Outcomes**: Millions of IBD patients currently rely on symptom management rather than curative treatments. Enterololin could become the first antibiotic-based therapy designed to directly address bacterial contributors to IBD. - **Ethical Benefits**: AI-driven methods reduce costs, minimize animal testing, and streamline regulatory processes, paving the way for more sustainable and ethical drug development. ### Conclusion: The discovery of enterololin and the use of AI to predict its mechanism of action represent a **major leap in medical research**. This achievement not only introduces a promising new therapy for IBD but also showcases the transformative potential of AI in accelerating drug discovery, reducing costs, and improving efficiency. Within a few years, AI-integrated drug pipelines could become standard practice, revolutionizing the development of treatments for complex diseases and redefining the future of antibiotic innovation.

Extended risankizumab treatment for Crohn’s disease

Extended risankizumab (RZB) therapy has shown promising results for Crohn’s disease patients who fail to respond to the standard 12-week induction phase. Phase 3 trials (ADVANCE, MOTIVATE, FORTIFY) evaluated the efficacy of an additional 12 weeks of RZB treatment, administered intravenously (1200 mg) or subcutaneously (180 mg or 360 mg). Among initial nonresponders, over 60% achieved stool frequency/abdominal pain score (SF/APS) clinical response by week 24, while 43–45% attained clinical remission. Endoscopic response or remission was observed in 32–40% of patients by week 24, highlighting mucosal healing. Delayed responders maintained these benefits during the maintenance phase, with clinical response rates of 56.7% (180 mg SC) and 69.7% (360 mg SC) persisting through week 52. Endoscopic remission continued or improved, demonstrating sustained mucosal healing. Higher efficacy was observed with the 360 mg SC dose compared to 180 mg SC during maintenance. Combining early and delayed responders, total clinical response reached 89.1%, emphasizing the cumulative benefit of extended therapy. Predictive factors for delayed response included older age and prior failure of more than one biologic therapy. Despite 75% of patients being highly treatment-experienced, the majority benefited from extended RZB therapy. Safety data revealed a well-tolerated profile, with mild hypersensitivity and injection site reactions as the most common adverse events. Serious adverse events were rare, and no new safety concerns emerged. The study concluded that extending RZB therapy is effective in recapturing delayed responders, offering sustained clinical and endoscopic remission for Crohn’s disease patients, even in difficult-to-treat populations.

Fidaxomicin and Crohn's Disease

Fidaxomicin has emerged as a promising therapeutic candidate for intestinal fibrosis in Crohn’s disease, a condition where up to 50% of patients develop strictures due to excessive collagen deposition and tissue scarring. Currently, no antifibrotic drugs are available for this complication. A study employing advanced multi-omics analysis and high-throughput drug screening identified platelet-derived growth factor receptor beta (PDGFRβ) and glycogen synthase kinase-3 beta (GSK3β) as key molecular regulators of collagen production in intestinal fibroblasts. Fidaxomicin, an FDA-approved antibiotic, was discovered to potently inhibit PDGFRβ activity. Mechanistic studies revealed that fidaxomicin binds strongly to PDGFRβ (binding score: −8.5 kcal/mol), reducing its phosphorylation and mRNA expression. This inhibition led to decreased collagen I and II (COL1A1/COL1A2) expression in patient-derived fibroblasts and tissues. Additionally, fidaxomicin maintained GSK3β in its active, antifibrogenic state by preventing its phosphorylation. The antifibrotic effects were confirmed to depend on the PDGFRβ–GSK3β signaling pathway, as external stimulation with PDGF-BB or IGF-1 reversed its beneficial impact. In vivo validation using a Crohn’s-like fibrosis mouse model demonstrated that oral fidaxomicin significantly reduced ileal fibrosis, inflammation, and disease activity scores. Importantly, fidaxomicin’s antifibrotic effects were localized to the gut, avoiding systemic toxicity and preserving gut microbiota diversity. Moreover, fidaxomicin exhibited anti-inflammatory benefits by reducing IL8 and TNFα secretion in immune cells. With its gut-restricted action and minimal adverse effects compared to cytotoxic PDGFR inhibitors, fidaxomicin holds potential for repurposing as a targeted antifibrotic therapy for Crohn’s disease strictures.

FACILE Classification: A New Era in IBD

The **FACILE Classification** represents a groundbreaking advancement in the way **Inflammatory Bowel Disease (IBD)**, including **Crohn's Disease (CD)** and **Ulcerative Colitis (UC)**, is categorized. Moving beyond traditional frameworks like the **Montreal Classification**, it introduces a **multidimensional approach** that integrates clinical, molecular, functional, lifestyle, and imaging parameters to address the heterogeneity of IBD. This innovative system aims to enhance precision in diagnosis, prognostication, and treatment strategies, marking a significant shift toward personalized medicine. --- ### **Overview of FACILE Classification** The acronym **FACILE** stands for: - **F**: **Functional** parameters (e.g., gut motility, epithelial barrier integrity, microbiome composition) - **A**: **Anatomical** location and extent of disease - **C**: **Clinical** presentation and disease behavior - **I**: **Immunological** and **Inflammatory** markers - **L**: **Lifestyle** and environmental factors - **E**: **Endoscopic**, radiologic, and histologic findings This approach integrates diverse dimensions of disease characterization, providing a **comprehensive view** of IBD that goes beyond conventional clinical phenotyping. --- ### **Key Features of FACILE Classification** 1. **Functional Parameters**: - Focuses on gut motility, epithelial barrier function, and microbiome dysbiosis. - Examples: - **Microbiome alterations**: Reduced diversity in CD and UC. - **Barrier dysfunction**: Increased intestinal permeability in CD. 2. **Anatomical Location**: - Uses advanced imaging techniques for precise mapping of disease involvement. - Differentiates between disease locations such as **ileal**, **colonic**, **perianal**, and **upper GI involvement** in CD, and **proctitis**, **left-sided colitis**, or **extensive colitis** in UC. 3. **Clinical Behavior**: - Categorizes IBD based on disease progression (e.g., stricturing, penetrating, or inflammatory in CD). - Incorporates disease activity indices such as **Simple Clinical Colitis Activity Index (SCCAI)** for UC and **Crohn’s Disease Activity Index (CDAI)** for CD. 4. **Immunological and Inflammatory Biomarkers**: - Utilizes biomarkers like **fecal calprotectin**, **C-reactive protein (CRP)**, and serological markers (e.g., ASCA, ANCA). - Includes genetic and molecular signatures, such as **NOD2 mutations** in CD and **IL-23/IL-17 pathway dysregulation**. 5. **Lifestyle and Environmental Factors**: - Accounts for smoking status, dietary patterns, stress, and socioeconomic factors. - Recognizes the role of urbanization and Westernized diets in IBD pathogenesis. 6. **Endoscopic, Radiologic, and Histologic Findings**: - Integrates findings from colonoscopy, MRI enterography, and histopathology. - Examples: - **Endoscopic healing** as a therapeutic goal. - **Transmural healing** assessed via imaging in CD. --- ### **Advantages of FACILE Classification** 1. **Precision Medicine**: - Tailors therapeutic approaches by identifying disease subtypes with distinct molecular and clinical profiles. - Facilitates the use of **biologic therapies** (e.g., anti-TNF agents, IL-12/23 inhibitors) and **small molecules** (e.g., JAK inhibitors, S1P modulators) based on patient-specific characteristics. 2. **Prognostication**: - Predicts disease course and complications, such as strictures, fistulas, or colectomy risk. - Biomarker-driven stratification aids in identifying aggressive versus mild disease phenotypes. 3. **Treatment Optimization**: - Supports **treat-to-target (T2T)** strategies, focusing on achieving clinical remission, biomarker normalization, and mucosal healing. - Incorporates novel therapeutic targets like **histological healing** and **intestinal barrier restoration**. 4. **Enhanced Research Framework**: - Provides a standardized classification system to improve patient selection in clinical trials. - Facilitates biomarker discovery and validation for future therapies. --- ### **Comparison: FACILE vs Montreal Classification** | **Parameter** | **Montreal Classification** | **FACILE Classification** | |-----------------------------|---------------------------------------|----------------------------------------| | **Focus** | Clinical and anatomical phenotypes | Multidimensional (clinical, molecular, functional, lifestyle) | | **Biomarkers** | Limited use of serological markers | Integrates advanced biomarkers (genetic, immunological, microbiome) | | **Imaging** | Basic radiologic findings | Advanced imaging (MRI, ultrasound, etc.) | | **Therapeutic Goals** | Clinical remission | Treat-to-target approach (mucosal and histological healing) | | **Personalization** | Generalized classification | Precision medicine tailored to individual patients | --- ### **Clinical Applications of FACILE Classification** 1. **Early Diagnosis**: - Improves early detection of IBD, even in atypical presentations, by incorporating functional parameters and biomarkers. 2. **Risk Stratification**: - Identifies patients at risk for severe disease progression or complications, aiding in proactive management. 3. **Treatment Selection**: - Guides the choice of biologics, small molecules, and combination therapies based on patient-specific characteristics. 4. **Monitoring and Follow-Up**: - Facilitates longitudinal assessment of disease activity through biomarkers, imaging, and endoscopic findings. --- ### **Challenges and Limitations** 1. **Complexity**: - Requires advanced diagnostic tools and multidisciplinary expertise, which may limit its application in resource-limited settings. 2. **Standardization**: - Integration of diverse parameters necessitates global consensus and validation across different populations. 3. **Cost Implications**: - Biomarker and imaging-based approaches may increase healthcare costs, requiring cost-effectiveness analyses. --- ### **Future Directions** 1. **Biomarker Validation**: - Large-scale studies to validate novel biomarkers such as **PredictSURE IBD** (17-gene signature for aggressive disease). 2. **Integration of Artificial Intelligence (AI)**: - AI-driven algorithms to analyze multidimensional data for FACILE classification and personalized treatment recommendations. 3. **Global Implementation**: - Development of simplified protocols for FACILE application in diverse healthcare settings. --- ### **Summary** The **FACILE Classification** introduces a **new era in IBD management** by offering a **multidimensional, personalized approach** to disease characterization. By integrating functional, molecular, clinical, lifestyle, and imaging parameters, it surpasses traditional classifications like Montreal, enabling precision medicine, improved prognostication, and optimized treatment strategies. While promising, challenges such as complexity, cost, and standardization need to be addressed to ensure widespread adoption.