{"title":"Letter: Affirming Cardiac Safety While Highlighting Areas for Further Research","authors":"Shanshan Huang, Jie Zhou","doi":"10.1111/apt.70387","DOIUrl":"https://doi.org/10.1111/apt.70387","url":null,"abstract":"","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"17 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Resmetirom, an oral selective thyroid hormone receptor beta agonist, is the first pharmacological agent approved by the Food and Drug Administration (FDA) of the United States in 2024 for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis stages F2 and F3. In the ongoing, registrational phase 3 MAESTRO-NASH study, the administration of resmetirom for 52 weeks led to MASH resolution and significant improvement in fibrosis by at least one stage as compared to placebo [<span>1</span>]. However, there remains a dearth of information about combining resmetirom with medications that are recommended for treating comorbidities of metabolic dysfunction-associated steatotic liver disease (MASLD), such as glucagon-like peptide 1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes (T2D) with and without obesity [<span>2, 3</span>]. Notably, around half of T2D patients have MASH [<span>4</span>]. Therefore, the prespecified analysis of MAESTRONASH by Noureddin et al. has provided timely evidence that in T2D patients, the efficacy of resmetirom on MASH end points was not affected by the stable background use of GLP1RA or SGLT2i [<span>5</span>], which are now commonly prescribed due to their established independent cardiovascular and kidney benefits.</p><p>Both GLP1RA and SGLT2i have been shown to resolve and improve MASH in the recent Effect of Semaglutide in Subjects with Non-cirrhotic non-alcoholic steatohepatitis (ESSENCE) and Dapagliflozin Efficacy and Action in Non-alcoholic steatohepatitis (DEAN) trials, respectively, but residual risk remains [<span>6, 7</span>]. Indeed, in around 40% of the T2D participants from the MAESTRONASH trial, at baseline, their MASH remained present despite the use of either GLP1RA or SGLT2i for a reasonable period (median duration 660 days for GLP1RA and 651 days for SGLT2i) [<span>5</span>]. Although the GLP1RA used were mostly liraglutide, dulaglutide and semaglutide 1 mg weekly instead of semaglutide 2.4 mg weekly as in the ESSENCE trial, it reinforces the need to combine pharmacotherapies to target the different pathophysiological pathways in MASH [<span>8</span>].</p><p>The authors also demonstrated that resmetirom-treated participants who had weight loss ≥ 5%, as compared to those without, showed higher rates of MASH resolution and fibrosis improvement [<span>5</span>]. Further studies should be conducted to investigate if the sequence of initiating these MASH pharmacotherapies matters, for instance, whether starting GLP1RA after resmetirom can enhance its effect through inducing weight loss. Moreover, as several new incretin co-agonists such as tirzepatide, a GLP1- and glucose-dependent insulinotropic polypeptide (GIP) receptors co-agonist, as well as survodutide, a GLP1- and glucagon receptors co-agonist, with more potent weight-reducing effects, have also been shown to improve MASH in phase 2 trials [<span>9,
{"title":"Editorial: An Important Step Towards Mastering Metabolic Dysfunction-Associated Steatohepatitis-Targeted Therapy in Diabetes","authors":"Johnny Yau-Cheung Chang, Chi-Ho Lee","doi":"10.1111/apt.70401","DOIUrl":"10.1111/apt.70401","url":null,"abstract":"<p>Resmetirom, an oral selective thyroid hormone receptor beta agonist, is the first pharmacological agent approved by the Food and Drug Administration (FDA) of the United States in 2024 for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis stages F2 and F3. In the ongoing, registrational phase 3 MAESTRO-NASH study, the administration of resmetirom for 52 weeks led to MASH resolution and significant improvement in fibrosis by at least one stage as compared to placebo [<span>1</span>]. However, there remains a dearth of information about combining resmetirom with medications that are recommended for treating comorbidities of metabolic dysfunction-associated steatotic liver disease (MASLD), such as glucagon-like peptide 1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes (T2D) with and without obesity [<span>2, 3</span>]. Notably, around half of T2D patients have MASH [<span>4</span>]. Therefore, the prespecified analysis of MAESTRONASH by Noureddin et al. has provided timely evidence that in T2D patients, the efficacy of resmetirom on MASH end points was not affected by the stable background use of GLP1RA or SGLT2i [<span>5</span>], which are now commonly prescribed due to their established independent cardiovascular and kidney benefits.</p><p>Both GLP1RA and SGLT2i have been shown to resolve and improve MASH in the recent Effect of Semaglutide in Subjects with Non-cirrhotic non-alcoholic steatohepatitis (ESSENCE) and Dapagliflozin Efficacy and Action in Non-alcoholic steatohepatitis (DEAN) trials, respectively, but residual risk remains [<span>6, 7</span>]. Indeed, in around 40% of the T2D participants from the MAESTRONASH trial, at baseline, their MASH remained present despite the use of either GLP1RA or SGLT2i for a reasonable period (median duration 660 days for GLP1RA and 651 days for SGLT2i) [<span>5</span>]. Although the GLP1RA used were mostly liraglutide, dulaglutide and semaglutide 1 mg weekly instead of semaglutide 2.4 mg weekly as in the ESSENCE trial, it reinforces the need to combine pharmacotherapies to target the different pathophysiological pathways in MASH [<span>8</span>].</p><p>The authors also demonstrated that resmetirom-treated participants who had weight loss ≥ 5%, as compared to those without, showed higher rates of MASH resolution and fibrosis improvement [<span>5</span>]. Further studies should be conducted to investigate if the sequence of initiating these MASH pharmacotherapies matters, for instance, whether starting GLP1RA after resmetirom can enhance its effect through inducing weight loss. Moreover, as several new incretin co-agonists such as tirzepatide, a GLP1- and glucose-dependent insulinotropic polypeptide (GIP) receptors co-agonist, as well as survodutide, a GLP1- and glucagon receptors co-agonist, with more potent weight-reducing effects, have also been shown to improve MASH in phase 2 trials [<span>9, ","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"63 1","pages":"165-166"},"PeriodicalIF":6.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.70401","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>We read with great interest the meta-analysis by Siddique et al. [<span>1</span>], which provides a timely synthesis of short-term mortality in severe alcohol-associated hepatitis (sAH). The application of both frequentist and Bayesian frameworks is a notable strength. However, we have profound concerns regarding the analytical approach to the primary conclusion that mortality has not improved in recent decades, which may be substantially flawed.</p><p>The authors' conclusion of no credible mortality improvement rests heavily on the non-significance of publication year as a covariate in their meta-regression. This model is critically compromised by the systematic and profound structural heterogeneity of the ‘standard care’ groups across decades. As illustrated in your table 1, the control arm for a 1978 trial was ‘diet’, while in 2023, it constituted ‘prednisolone’ combined with advanced prophylactic antibiotics [<span>2, 3</span>]. Pooling these fundamentally different clinical realities into a single ‘standard care’ cohort and then testing for a time trend creates a misleading null signal. The observed decline in 28-day mortality from > 50% to ~25%, as shown in your Bayesian analysis, likely represents the genuine, cumulative benefit of evolving standard care. To assert no improvement is to ignore this evident clinical progress captured by your own data.</p><p>Furthermore, the model selection strategy, which prioritised the corrected Akaike Information Criterion (AIC), is inappropriate for this context. The AIC favours parsimony but cannot distinguish a biologically implausible model from a correct one. Your final model identifies ‘follow-up duration’ as the principal mortality determinant—a tautological finding, as the probability of death intrinsically increases over time in a fatal disease. That this model was selected over one containing ‘treatment era’ underscores the limitation of a purely algorithmic approach over clinical reasoning.</p><p>Finally, the assertion of a significant association between MELD score and mortality (<i>β</i> = +0.20 per point, <i>p</i> = 0.037) is not robust. This analysis was based on a small, non-random subset of only 12 studies reporting MELD scores, heavily predisposed to publication and reporting biases. The conclusion lacks the reliability necessary to inform clinical prognostication, a point not adequately emphasised.</p><p>We believe a re-analysis comparing mortality between pre-specified, clinically distinct eras (e.g., pre- and post-corticosteroid standardisation) or using a network meta-analysis structure to account for evolving standard care, would provide a more valid assessment of temporal trends. In this context, recent reviews and consortium studies—such as those summarising current and emerging therapies for acute alcohol-associated hepatitis, outcomes of patients with sAH and acute kidney injury, interventions for alcohol use disorder in cirrhotic or sAH patients, and current criteria for
我们非常感兴趣地阅读了Siddique等人的荟萃分析，该分析及时综合了严重酒精相关性肝炎（sAH）的短期死亡率。频率主义者和贝叶斯框架的应用是一个显著的优势。然而，我们对最近几十年来死亡率没有改善这一主要结论的分析方法深感关切，这种分析方法可能存在重大缺陷。作者的结论没有可靠的死亡率改善很大程度上取决于在他们的元回归中，出版年份作为协变量的不显著性。几十年来，“标准护理”群体的系统性和深刻的结构异质性严重损害了这种模式。如表1所示，1978年的一项试验的对照组是“饮食”，而在2023年，对照组是“强的松龙”联合先进的预防性抗生素[2,3]。将这些根本不同的临床现实汇集到一个单一的“标准护理”队列中，然后对时间趋势进行测试，这会产生误导性的零信号。正如你的贝叶斯分析所显示的那样，观察到28天死亡率从50%下降到25%，这可能代表了不断发展的标准护理的真正累积效益。断言没有改善就是忽略了你自己的数据所显示的明显的临床进展。此外，模型选择策略优先考虑修正后的赤池信息标准（Akaike Information Criterion， AIC），不适合这种情况。AIC倾向于简约，但无法区分生物学上不合理的模型和正确的模型。你的最终模型将“随访时间”确定为主要的死亡率决定因素——这是一个反复的发现，因为致命疾病的死亡概率本质上随着时间的推移而增加。选择这个模型而不是包含“治疗时代”的模型，强调了纯算法方法相对于临床推理的局限性。最后，MELD评分与死亡率之间存在显著关联的断言（β = +0.20 /分，p = 0.037）并不可靠。该分析仅基于报告MELD评分的12项研究的一个小的非随机子集，严重倾向于发表和报告偏差。结论缺乏为临床预测提供必要信息的可靠性，这一点没有得到充分强调。我们认为，对预先指定的、临床不同时期（例如，皮质类固醇标准化前和标准化后）的死亡率进行重新分析，或使用网络荟萃分析结构来解释不断发展的标准护理，将提供更有效的时间趋势评估。在这种背景下，最近的综述和联合研究——例如总结急性酒精相关性肝炎的当前和新兴治疗方法、sAH和急性肾损伤患者的结局、肝硬化或sAH患者酒精使用障碍的干预措施、sAH早期肝移植的当前标准——共同强调了不断发展的管理格局，并加强了时代分层分析的必要性[4-7]。目前的结论有可能通过低估已建立的支持性护理的价值而误导临床和研究重点。Chao Zhao：写作-原稿，写作-审稿，编辑。作者声明无利益冲突。这篇文章链接到Siddique等人的论文。要查看这些文章，请访问https://doi.org/10.1111/apt.70383和https://doi.org/10.1111/apt.70488.The，根据通讯作者的合理要求，可以获得支持本研究结果的数据。
{"title":"Letter on ‘Meta-Analysis: Mortality Trends and Risk Factors in Severe Alcohol-Associated Hepatitis’","authors":"Chao Zhao","doi":"10.1111/apt.70441","DOIUrl":"10.1111/apt.70441","url":null,"abstract":"<p>We read with great interest the meta-analysis by Siddique et al. [<span>1</span>], which provides a timely synthesis of short-term mortality in severe alcohol-associated hepatitis (sAH). The application of both frequentist and Bayesian frameworks is a notable strength. However, we have profound concerns regarding the analytical approach to the primary conclusion that mortality has not improved in recent decades, which may be substantially flawed.</p><p>The authors' conclusion of no credible mortality improvement rests heavily on the non-significance of publication year as a covariate in their meta-regression. This model is critically compromised by the systematic and profound structural heterogeneity of the ‘standard care’ groups across decades. As illustrated in your table 1, the control arm for a 1978 trial was ‘diet’, while in 2023, it constituted ‘prednisolone’ combined with advanced prophylactic antibiotics [<span>2, 3</span>]. Pooling these fundamentally different clinical realities into a single ‘standard care’ cohort and then testing for a time trend creates a misleading null signal. The observed decline in 28-day mortality from > 50% to ~25%, as shown in your Bayesian analysis, likely represents the genuine, cumulative benefit of evolving standard care. To assert no improvement is to ignore this evident clinical progress captured by your own data.</p><p>Furthermore, the model selection strategy, which prioritised the corrected Akaike Information Criterion (AIC), is inappropriate for this context. The AIC favours parsimony but cannot distinguish a biologically implausible model from a correct one. Your final model identifies ‘follow-up duration’ as the principal mortality determinant—a tautological finding, as the probability of death intrinsically increases over time in a fatal disease. That this model was selected over one containing ‘treatment era’ underscores the limitation of a purely algorithmic approach over clinical reasoning.</p><p>Finally, the assertion of a significant association between MELD score and mortality (<i>β</i> = +0.20 per point, <i>p</i> = 0.037) is not robust. This analysis was based on a small, non-random subset of only 12 studies reporting MELD scores, heavily predisposed to publication and reporting biases. The conclusion lacks the reliability necessary to inform clinical prognostication, a point not adequately emphasised.</p><p>We believe a re-analysis comparing mortality between pre-specified, clinically distinct eras (e.g., pre- and post-corticosteroid standardisation) or using a network meta-analysis structure to account for evolving standard care, would provide a more valid assessment of temporal trends. In this context, recent reviews and consortium studies—such as those summarising current and emerging therapies for acute alcohol-associated hepatitis, outcomes of patients with sAH and acute kidney injury, interventions for alcohol use disorder in cirrhotic or sAH patients, and current criteria for ","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"63 2","pages":"314-315"},"PeriodicalIF":6.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.70441","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Editorial: High‐Grade Dysplasia in Colonic Inflammatory Bowel Disease Is Associated With a High Risk of Synchronous or Metachronous Colorectal Cancer—Authors' Reply","authors":"Monica E. W. Derks, Frank Hoentjen","doi":"10.1111/apt.70473","DOIUrl":"https://doi.org/10.1111/apt.70473","url":null,"abstract":"","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Appendectomy before the age of 20 appears to reduce the risk of acquiring ulcerative colitis (UC) [<span>1</span>], by regulating mucosal immunity and affecting the gut microbiome [<span>2</span>]. However, from a clinical perspective, the potential of appendicectomy to reduce disease severity in those who already have UC is more important. Being able to intervene and affect the course of the disease by the relatively simple procedure of laparoscopic appendicectomy for non-appendicitis would be a significant step forward in the management of UC.</p><p>Small case–control and cohort studies (e.g., [<span>3</span>]) have reported that appendectomy may reduce disease severity, whereas meta-analyses have shown conflicting results [<span>4-7</span>]. Positive findings in the small open studies have, however, prompted larger, well-controlled studies on the effect of appendectomy, where data are now emerging. In ACCURE, an open-label RCT on laparoscopic appendicectomy for maintaining remission in UC (<i>n</i> = 201), the 1-year relapse rate was reduced by appendicectomy and maintenance treatment (RR 0.65) compared with medication only [<span>8</span>]. Despite a 50% loss of eligible patients (202 patients declined to participate), the results of ACCURE strongly suggest that appendicectomy has a role in the treatment of UC. Results of a recently finalised study on appendicectomy as a colonic salvage procedure in active colitis (https://clinicaltrials.gov/study/NCT03912714) are awaited.</p><p>The report by Mark-Christensen et al. [<span>9</span>] is timely. Here, a nationwide health registry study is reported, covering all public hospitals in Denmark, with a median follow-up of 10 years in over 22,000 patients with UC, of whom 2014 had undergone appendicectomy. Uniquely, the appendicitis diagnoses were pathology-based, which further strengthens the validity of the data. There were no signs of a milder disease course in the patients who had undergone appendicectomy. Instead, colorectal resection rates and the number of hospitalisations were increased in the appendicectomy group, whereas treatment rates with biologics were similar. The same group has also shown a doubled risk of colorectal cancer in patients with UC who had undergone appendicectomy [<span>10</span>]. Even if the registry data lack details on disease severity and indications for colorectal resection, these two studies form valid, population-based, real-world data showing no positive effects of appendicectomy but a potentially increased risk of cancer.</p><p>The role of appendicectomy in UC is complex, and its effectiveness may depend on patient-specific factors and disease characteristics. Recent trial-based data in favour of appendicectomy (at least in select cases) need to be confirmed in long-term follow-up. Also, the population-based data need to be verified in non-Northern European populations for generalisability. Moreover, molecular mapping of large UC cohorts will be needed to pred
20岁前阑尾切除术似乎可以通过调节粘膜免疫和影响肠道微生物组[2]来降低患溃疡性结肠炎（UC）[1]的风险。然而，从临床角度来看，阑尾切除术降低已经患有UC的患者疾病严重程度的潜力更为重要。能够通过相对简单的腹腔镜阑尾切除术干预和影响非阑尾炎的病程，将是UC治疗的重要一步。小型病例对照和队列研究（如[3]）报道阑尾切除术可能降低疾病严重程度，然而荟萃分析显示了相互矛盾的结果[4-7]。然而，小型公开研究的积极结果促使了对阑尾切除术效果的更大规模、控制良好的研究，这些研究的数据正在出现。ACCURE是一项关于腹腔镜阑尾切除术维持UC缓解的开放标签随机对照试验（n = 201），阑尾切除术和维持治疗与仅用药相比降低了1年复发率（RR 0.65）。尽管有50%的符合条件的患者（202例患者拒绝参加），ACCURE的结果强烈表明阑尾切除术在UC的治疗中发挥了作用。一项关于阑尾切除术作为活动性结肠炎的结肠挽救手术的最新研究结果正在等待中（https://clinicaltrials.gov/study/NCT03912714）。马克-克里斯滕森等人的报告是及时的。本文报道了一项覆盖丹麦所有公立医院的全国性健康登记研究，对2.2万多名UC患者进行了中位随访10年，其中2014名患者接受了阑尾切除术。独特的是，阑尾炎的诊断是基于病理的，这进一步加强了数据的有效性。阑尾切除术患者没有出现较轻病程的迹象。相反，阑尾切除术组的结直肠切除率和住院次数增加，而生物制剂组的治疗率相似。同一组研究还表明，接受阑尾切除术的UC患者患结直肠癌的风险增加了一倍。即使登记数据缺乏疾病严重程度和结直肠切除术适应症的详细信息，这两项研究形成了有效的、基于人群的、真实世界的数据，显示阑尾切除术没有积极效果，但可能增加癌症风险。阑尾切除术在UC中的作用是复杂的，其效果可能取决于患者特异性因素和疾病特征。最近的基于试验的数据支持阑尾切除术（至少在某些情况下）需要在长期随访中得到证实。此外，基于人口的数据需要在非北欧人口中进行验证，以获得普遍性。此外，需要对大型UC队列进行分子定位，以预测哪些患者对阑尾切除术有反应，病程较轻，哪些患者患结直肠癌的风险进一步增加。换句话说，阑尾切除或不切除UC仍然存在争议。Johan D. Söderholm：概念化，写作-原稿，写作-审查和编辑，项目管理，资源。作者声明无利益冲突。这篇文章链接到Mark-Christensen等人的论文。要查看本文，请访问https://doi.org/10.1111/apt.70279.Data分享不适用于本文，因为在当前研究期间没有生成或分析数据集。
{"title":"Editorial: The Appendix—A Dead End for Treating Ulcerative Colitis, After All?","authors":"Johan D. Söderholm","doi":"10.1111/apt.70370","DOIUrl":"10.1111/apt.70370","url":null,"abstract":"<p>Appendectomy before the age of 20 appears to reduce the risk of acquiring ulcerative colitis (UC) [<span>1</span>], by regulating mucosal immunity and affecting the gut microbiome [<span>2</span>]. However, from a clinical perspective, the potential of appendicectomy to reduce disease severity in those who already have UC is more important. Being able to intervene and affect the course of the disease by the relatively simple procedure of laparoscopic appendicectomy for non-appendicitis would be a significant step forward in the management of UC.</p><p>Small case–control and cohort studies (e.g., [<span>3</span>]) have reported that appendectomy may reduce disease severity, whereas meta-analyses have shown conflicting results [<span>4-7</span>]. Positive findings in the small open studies have, however, prompted larger, well-controlled studies on the effect of appendectomy, where data are now emerging. In ACCURE, an open-label RCT on laparoscopic appendicectomy for maintaining remission in UC (<i>n</i> = 201), the 1-year relapse rate was reduced by appendicectomy and maintenance treatment (RR 0.65) compared with medication only [<span>8</span>]. Despite a 50% loss of eligible patients (202 patients declined to participate), the results of ACCURE strongly suggest that appendicectomy has a role in the treatment of UC. Results of a recently finalised study on appendicectomy as a colonic salvage procedure in active colitis (https://clinicaltrials.gov/study/NCT03912714) are awaited.</p><p>The report by Mark-Christensen et al. [<span>9</span>] is timely. Here, a nationwide health registry study is reported, covering all public hospitals in Denmark, with a median follow-up of 10 years in over 22,000 patients with UC, of whom 2014 had undergone appendicectomy. Uniquely, the appendicitis diagnoses were pathology-based, which further strengthens the validity of the data. There were no signs of a milder disease course in the patients who had undergone appendicectomy. Instead, colorectal resection rates and the number of hospitalisations were increased in the appendicectomy group, whereas treatment rates with biologics were similar. The same group has also shown a doubled risk of colorectal cancer in patients with UC who had undergone appendicectomy [<span>10</span>]. Even if the registry data lack details on disease severity and indications for colorectal resection, these two studies form valid, population-based, real-world data showing no positive effects of appendicectomy but a potentially increased risk of cancer.</p><p>The role of appendicectomy in UC is complex, and its effectiveness may depend on patient-specific factors and disease characteristics. Recent trial-based data in favour of appendicectomy (at least in select cases) need to be confirmed in long-term follow-up. Also, the population-based data need to be verified in non-Northern European populations for generalisability. Moreover, molecular mapping of large UC cohorts will be needed to pred","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"63 1","pages":"145-146"},"PeriodicalIF":6.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.70370","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ikuo Hirano, Glenn T. Furuta, Gary W. Falk, Christopher Ma, Nirmala Gonsalve, Evan S. Dellon
Background
Eosinophilic oesophagitis (EoE) is a major contributor to upper gastrointestinal morbidity. Although an increasing number of treatment modalities have been developed, most are assessed by symptoms and the histologic metric of peak eosinophil count (PEC).
Aim
To review current evidence regarding limitations of reliance on PEC as a co-primary endpoint while making a case for endoscopic assessment as a “trial-ready” outcome to supplement or replace it.
Methods
Directed literature review, including a summary of EoE clinical trials and outcome metrics, combined with expert discussion, input, and consensus on reviewed topics.
Results
Clinical trials in EoE established efficacy based on co-primary endpoints of clinically meaningful symptom improvement and PEC as an objective biomarker of activity. However, endoscopic features of EoE have a critical role in determining disease activity. The Hirano EoE Endoscopic Reference Score (EREFS) is a uniform nomenclature system that classifies five key oesophageal findings. EREFS has been validated, shown to be highly accurate and responsive, and incorporated into clinical trials. An association between EREFS and clinically meaningful disease outcomes and complications has been demonstrated, heightening its relevance to clinical care and as a clinical trial endpoint. Defined thresholds for response of EREFS to therapy have been shown to be responsive to therapy.
Conclusions
PEC has a role in histologic response assessment and should not be completely discounted. Evidence demonstrates that EREFS accurately reflects EoE disease activity and global oesophageal severity, and is ready to be used as a co-primary biologic endpoint in clinical trials.
{"title":"Review article: Seeing Is Believing–The Eosinophilic Oesophagitis Endoscopic Reference Score Can Serve as a Valuable Clinical Trial Endpoint in Eosinophilic Oesophagitis","authors":"Ikuo Hirano, Glenn T. Furuta, Gary W. Falk, Christopher Ma, Nirmala Gonsalve, Evan S. Dellon","doi":"10.1111/apt.70474","DOIUrl":"10.1111/apt.70474","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Eosinophilic oesophagitis (EoE) is a major contributor to upper gastrointestinal morbidity. Although an increasing number of treatment modalities have been developed, most are assessed by symptoms and the histologic metric of peak eosinophil count (PEC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To review current evidence regarding limitations of reliance on PEC as a co-primary endpoint while making a case for endoscopic assessment as a “trial-ready” outcome to supplement or replace it.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Directed literature review, including a summary of EoE clinical trials and outcome metrics, combined with expert discussion, input, and consensus on reviewed topics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Clinical trials in EoE established efficacy based on co-primary endpoints of clinically meaningful symptom improvement and PEC as an objective biomarker of activity. However, endoscopic features of EoE have a critical role in determining disease activity. The Hirano EoE Endoscopic Reference Score (EREFS) is a uniform nomenclature system that classifies five key oesophageal findings. EREFS has been validated, shown to be highly accurate and responsive, and incorporated into clinical trials. An association between EREFS and clinically meaningful disease outcomes and complications has been demonstrated, heightening its relevance to clinical care and as a clinical trial endpoint. Defined thresholds for response of EREFS to therapy have been shown to be responsive to therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>PEC has a role in histologic response assessment and should not be completely discounted. Evidence demonstrates that EREFS accurately reflects EoE disease activity and global oesophageal severity, and is ready to be used as a co-primary biologic endpoint in clinical trials.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"63 3","pages":"341-351"},"PeriodicalIF":6.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marlene Padilla‐Lopez, María Carlota Londoño, Pinelopi Arvaniti
{"title":"Letter on ‘Clinical Features of Portal Hypertension and Their Prognostic Implications in Patients With Autoimmune Hepatitis’","authors":"Marlene Padilla‐Lopez, María Carlota Londoño, Pinelopi Arvaniti","doi":"10.1111/apt.70437","DOIUrl":"https://doi.org/10.1111/apt.70437","url":null,"abstract":"","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"8 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Head-to-head randomised studies comparing pharmacological and non-pharmacological therapies in patients with irritable bowel syndrome (IBS) are uncommon. Likewise, studies of efficacy across patient groups irrespective of bowel habits have been limited where dogma suggests (usually erroneously) that specific therapies were only suitable for subgroups. Hence, the randomised study from Malaysia by Chua et al. [<span>1</span>] comparing the efficacy over 4 weeks of rifaximin 400 mg three times daily with education in a low FODMAP diet in a cross-section of all types of IBS is of great interest. Key findings were that efficacy was similar (one in two patients responded according to a composite measure of abdominal pain/discomfort and stool consistency/frequency), although rifaximin had a better adherence rate and faster clinical improvement. The response rate to rifaximin was in line with that previously reported in patients with non-constipation-predominant IBS [<span>2</span>]. The low FODMAP diet was dietitian-taught, but the response rate was relatively low, perhaps reflecting differences in the ease of diet application compared to countries where instructed low FODMAP diets had higher adherence rates [<span>3, 4</span>]. Importantly, glucose breath tests aiming to identify those with small intestinal bacterial overgrowth did not predict the efficacy of either therapy, in line with their poor performance characteristics and predictive value [<span>5</span>].</p><p>The key issue now is how such data inform treatment strategies offered to patients. As an induction therapy (to gain rapid control of symptoms), rifaximin was superior to the low FODMAP diet, reducing symptoms more rapidly over the four-week measured duration. Rifaximin has fewer hassles for the doctor (needs only a simple prescription) and requires little effort from the patient other than ingesting the pills three times daily for 2 weeks, in contrast to the need for at least a 30-min consultation with a dietitian and considerable effort by the patient to follow the diet. However, IBS is a chronic condition with symptoms that fluctuate over time. Rifaximin has benefits that outlive the duration of therapy, but most patients seem to need retreatment [<span>6</span>]. In contrast, the low FODMAP diet, when taught with the rechallenge phase and subsequent personalisation, empowers the patient to alter the level of FODMAP restriction according to symptom severity [<span>7</span>].</p><p>Hence, Chua et al. [<span>1</span>] provide four messages. First, rifaximin and a low FODMAP diet have similar efficacy—at least at 4 weeks. Second, rifaximin, like a low FODMAP diet [<span>8</span>], also has efficacy in patients with constipation-predominant IBS. Third, glucose breath tests have no value in predicting outcome or choice of therapy. Fourth, the choice of initial therapy lies between the quick-fix pharmacological approach versus the more challenging, but empowering, dietary approach that
比较肠易激综合征（IBS）患者的药物和非药物治疗的头对头随机研究并不常见。同样，不考虑排便习惯的患者群体的疗效研究也受到限制，因为教条认为（通常是错误的）特定疗法只适用于亚组。因此，Chua等人在马来西亚进行的一项随机研究，在所有类型IBS的横截面中，比较每日三次400 mg利福昔明4周的疗效与低FODMAP饮食的教育是非常有趣的。主要发现是疗效相似（根据腹痛/不适和大便一致性/频率的综合测量，两名患者中有一名有反应），尽管利福昔明有更好的依从率和更快的临床改善。利福昔明的反应率与先前报道的非便秘为主的IBS患者一致。低FODMAP饮食是由营养师指导的，但反应率相对较低，这可能反映了与指导低FODMAP饮食的国家相比，饮食应用的难易程度存在差异[3,4]。重要的是，旨在识别小肠细菌过度生长的葡萄糖呼吸试验不能预测任何一种治疗的疗效，这与它们较差的性能特征和预测值[5]一致。现在的关键问题是这些数据如何为患者提供治疗策略。作为一种诱导疗法（快速控制症状），利福昔明优于低FODMAP饮食，在四周的测量持续时间内更迅速地减轻症状。利福昔明给医生带来的麻烦更少（只需要一个简单的处方），患者只需每天服用三次，持续两周，而不需要至少30分钟的营养师咨询和患者遵循饮食的相当大的努力。然而，肠易激综合征是一种慢性疾病，症状会随着时间的推移而波动。利福昔明的疗效超过治疗时间，但大多数患者似乎需要再次治疗。相比之下，低FODMAP饮食，在再挑战阶段和随后的个性化教学中，使患者能够根据症状严重程度改变FODMAP限制水平。因此，Chua等人提供了四个消息。首先，利福昔明和低FODMAP饮食具有相似的疗效——至少在4周内。其次，利福昔明与低FODMAP饮食一样，对便秘为主的IBS患者也有疗效。第三，葡萄糖呼吸试验在预测预后或选择治疗方面没有价值。第四，初始治疗的选择在于快速修复的药理学方法与更具挑战性但更有效的饮食方法之间的选择，后者提供了长期的策略和益处。有选择的感觉真好。艾玛·哈尔莫斯：概念，写作-原稿，写作-审查和编辑。Peter R. Gibson：概念化，写作-原稿，写作-审查和编辑。eph：获得Mindset Health Pty Ltd.和澳大利亚胃肠病学会IBD临床项目奖的研究资助。她曾获得ferling， Janssen, Abbvie, Takeda, Shire， Sandoz和Dr. Falk Pharma的酬金或咨询。p.r.g.: Anatara、Atmo Biosciences和Comvita的顾问或顾问委员会成员；由Atmo生物科学公司的心态健康股东为研究者驱动的研究提供研究资助。他的工资来源于一款数字应用程序（莫纳什大学FODMAP饮食应用程序）、患者手册、烹饪书和在线课程的销售收入，这些都与低FODMAP饮食疗法有关。本文链接到Chuah等人的论文。要查看这些文章，请访问https://doi.org/10.1111/apt.70420和https://doi.org/10.1111/apt.70469.Data分享不适用于本文，因为在当前研究中没有生成或分析数据集。
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