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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.