2项研究凸显3种内镜下IBD活动度评分的实用性

国际炎症性肠病研究组织的Marc Ferrante医生及其合作者报告称，治疗26周后2次克罗恩病内镜下活动度评分中任意1次降低至少50%，提示可能在皮质激素治疗大约1年之后停止治疗，敏感性接近75%。这项研究证明，该切点可作为临床应答的可靠预测因素，但还有待进一步研究。这项研究发表在11月刊《胃肠病学》杂志上。

同期发表的另一项研究评估了溃疡性结肠炎内镜下严重度指数(UCEIS)的可靠性。UCEIS是一种近期被创建出来用于评估UC内镜下严重度的工具。英国牛津John Radcliffe医院的Simon Travis医生及其合作者随机选取了25名研究者，评估28段UC患者的内镜视频——在大多数情况下不了解临床特征。结果表明，UCEIS可提供“令人满意”的研究者自身和研究者之间的一致性，是“一种检测内镜下UC疾病活动度的可靠工具”。研究者总结称，这个版本的UCEIS可根据血管样式、出血和糜烂/溃疡得出从0到8的评分，是“最受欢迎的版本”，但需要进一步验证(Gastroenterol. 2013 July 29 [doi: 10.1053/j.gastro.2013.07.024])。

比利时鲁汶大学医院消化内科的Ferrante医生介绍，这项克罗恩病(CD)研究中采用了SONIC (克罗恩病中的生物制剂和免疫调节剂初治患者)中172例患者的数据。他与同事在治疗26周后的2次内镜应答评分中找出了切点，可预测50周时的临床应答。

基线时，这些患者具有内镜下病变和220~450(中位值，277)的CD活动度指数(CDAI)。他们的中位年龄为34岁，被诊断为CD的中位时间为2.5年。这些患者均依赖于皮质激素，并被随机分组，接受英夫利昔单抗(Remicade)输液和/或口服硫唑嘌呤治疗，随访50周。

这项研究的主要终点是26周时无皮质激素临床缓解(CFREM)，次要终点中有一项是黏膜溃疡完全愈合。研究人员评估了采用2种内镜下病变严重度评分方法得出的内镜应答切点：SES-CD(简明CD内镜评分)和CDEIS(CD内镜下严重度指数)。

近半数患者在第26周时达到了黏膜愈合。26周时SES-CD相对于基线水平下降至少50%似乎是“预测患者最可能发生临床缓解(50周时停用激素)”的最好判别切点。112例(65%)患者达到了这种程度的SES-CD应答，预测50周时CFREM的敏感性为74%，特异性为48%。

对于CDEIS值，预测患者最可能在50周时达到CFREM的最佳切点为26周时相对于基线水平下降至少45%，敏感性为75%，特异性为45%。由于这两种指标之间存在“微妙”差异(切点分别为50%和45%)，研究者提出了26周时CDEIS相对于基线水平下降至少50%的内镜应答定义。(对于CDEIS，50%切点的敏感性为73%，特异性为46%)

“这一内镜终点可以作为临床治疗中期结局的可靠预测因素。”内镜下活动度相对于基线下降 50%还可能作为一个终点，用于评价药物治疗或治疗策略的愈合能力的研究。研究者补充道，这些切点还有待前瞻性研究的验证，并且还需要探讨内镜应答与“疾病调整长期结局”之间的相关性，例如持续临床应答或手术。

在评估UCEIS可靠性的研究中，25名来自北美和欧洲的研究者被随机分组，评估了UC患者的乙状结肠镜检查视频，其中包括一些重复视频(用于评估观察者的可靠性)。只有2段视频提供了诸如每日大便次数等临床细节。

UCEIS根据三方面描述得出0~8的评分：血管模式(正常、斑片状闭塞，或闭塞)、出血(无、黏膜、管腔轻度、管腔中度，或重度)和糜烂、溃疡(无、糜烂、浅表性溃疡，或深部溃疡)。共评估了约700段视频。

结果包括研究者自身和研究者之间的可靠性满意程度，表明UCEIS使用简单，并且“能可靠地评估UC的总体内镜下严重度，能覆盖内镜医师之间不一致的88%”。

这项研究是验证UCEIS的第一步，确认了UCEIS的可靠性，不过其判断缓解的阈值、不同UCEIS评分的临床意义，以及UCEIS对疾病状态改变的反应，尚有待进一步验证。

CD研究的部分资金来自杨森生物技术；Ferrante医生获得了比利时胃肠内镜学会和比利时科学研究基金的支持。

作者们披露为多家制药企业提供咨询等服务，并从这些公司(包括杨森和雅培)获得补助金或研究支持。多名作者是杨森生物技术和杨森生物制剂(英夫利昔的生产商)的员工。1名作者无利益冲突披露。

UCEIS研究由Warner Chilcott资助，1名作者是该公司的员工。作者们披露担任多家制药公司的顾问和/或讲者，或从这些公司获得研究补助。多名作者无利益冲突披露。

随刊述评：切点值仍然不固定

检测手段研究领域是改进炎症性肠病(IBDs)管理策略的基础。近年来，人们对黏膜愈合作为CD和UC的治疗目标产生了越来越大的兴趣，因为黏膜愈合似乎是长期康乐和并发症减少(我们真正的最终治疗目标) 的一个替代指标。

然而，有关如何能最好地衡量黏膜愈合的数据非常有限，这制约了我们达到这一治疗目标的能力。黏膜大体外观是黏膜愈合的最佳指标吗？如果是这样的话，我们如何能准确地量化评估炎症程度，怎样的切点分值与我们的最终目标相关？也许黏膜愈合的其他标志物更好，如组织学、钙卫蛋白(可能对微观炎症更敏感)或磁共振(MR)小肠造影(测量肠壁的整体厚度和小肠的全长)。

甚至在确定了最佳测量工具及其切点值之后，在将其用于临床之前还必须确定随时间的变化(即，响应性)和可靠性。

在11月《胃肠病学》杂志上，Ferrante等人展示了有说服力的SONIC数据集，证明26周时CDEIS(CD内镜下严重度评分)和简明SES-CD(简明CD内镜评分)减少50%或黏膜愈合，可在一定程度上预测1年时CD临床缓解。

在第二项研究中，Travis等人优雅地报告了唯一一种经过验证的UC内镜评分——UCEIS(溃疡性结肠炎内镜下严重度指数)评分的可靠性和初步验证。这两项研究呈现了重要的数据，推动我们朝着IBD“治疗达标”迈出了一步。

然而，这2项研究也凸显了我们在黏膜愈合内镜定义方面的不足，以及现有检测工具在可靠性、有效性和预测效能方面的不足。Ferrante等人不仅报告了诊断效用统计学数据和预测效能的P值，这一点值得赞赏。74%~75% 的敏感性和45%~48%的特异性表明，黏膜愈合可被看作治疗决策过程中的另一个重要预测变量，但尚不能单独作为金标准指导治疗升级。

述评作者Dan Turner医生是耶路撒冷希伯来大学小儿胃肠病学和营养学单元主任。他没有相关的利益冲突。

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By: ELIZABETH MECHCATIE, Internal Medicine News Digital Network

A reduction of at least 50% in either of two different Crohn’s disease endoscopic activity scores after 26 weeks of treatment predicted those patients likely to be off of corticosteroid therapy after about 1 year of treatment, with a sensitivity approaching 75%, reported Dr. Marc Ferrante and his coinvestigators.

The study provides evidence that this cutoff could be used as a reliable predictor of clinical response, but it needs to be studied further, according to the authors, who are members of the International Organization for the Study of Inflammatory Bowel Diseases. The study was published in the Novemberissue of Gastroenterology.

Another study, published in the same issue of Gastroenterology, evaluated the reliability of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), an instrument recently created to assess the endoscopic severity of UC.

This study randomized 25 investigators to assess and score 28 endoscopic videos of patients with UC – without knowledge of clinical features in most cases.

The results indicated that the UCEIS provides a "satisfactory" level of intra investigator and interinvestigator agreement and that it is "a reliable instrument for measuring the endoscopic disease activity of UC," according to Dr. Simon Travis, of the translational gastroenterology unit at John Radcliffe Hospital, Oxford, England, and his coinvestigators.

The version of the UCEIS that provides a score from 0 to 8, based on findings of vascular pattern, bleeding, and erosions/ulcers, is the "favored version" but needs to be validated further, they concluded (Gastroenterol. 2013 July 29 [doi: 10.1053/j.gastro.2013.07.024]).

In the Crohn’s disease (CD) study, which used data on 172 patients enrolled in SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease), Dr. Ferrante, of the department of gastroenterology at University Hospitals Leuven, Belgium, and his colleagues identified a cutoff point in two endoscopic response scores after 26 weeks of treatment that was predictive of clinical response at 50 weeks.

At baseline, the patients had endoscopic lesions and CD Activity Index (CDAI) scores of 220-450 points (median, 277). Their median age was 34 years, and they had been diagnosed with CD for a median of 2.5 years.

The patients were dependent on corticosteroids and were randomized to treatment with infliximab (Remicade) infusions and/or oral azathioprine, and were followed to 50 weeks.

The primary endpoint of this study was corticosteroid-free clinical remission (CFREM) at week 26, and one of the secondary endpoints was complete healing of mucosal ulcerations.

The investigators evaluated different cutoff points of endoscopic responses for two methods used to score the severity of endoscopic lesions: SES-CD (Simple Endoscopic Score for CD) and CDEIS (CD Endoscopic Index of Severity).

Almost half of the patients achieved mucosal healing at the 26th week.

A decrease from baseline in the SES-CD of at least 50% at week 26 "appeared to be the best discriminative cutoff value" for predicting patients most likely to be in clinical remission (off steroids at week 50).

This degree of SES-CD response was met by 112 (65%) patients, with 74% sensitivity and 48% specificity for predicting CFREM at week 50.

For the CDEIS values, the best cutoff was at least a 45% drop from baseline at week 26 for predicting patients most likely to achieve CFREM at week 50, with 75% sensitivity and 45% specificity.

Because of the "subtle" difference between the two measures (50% and 45% cutoffs), "we propose a definition of endoscopic response with a decrease in baseline in CDEIS of at least 50% at week 26 for both tests," the authors wrote. (For CDEIS, the 50% cutoff had a sensitivity of 73% and a specificity of 46%.)

"As such, this endoscopic endpoint could serve as a reliable predictor of the midterm clinical outcome of therapies," Dr. Ferrante and his coauthors concluded. A 50% reduction in endoscopic activity from baseline also has potential for use as an endpoint in studies evaluating pharmacotherapy or treatment strategies "to show healing capacity," they wrote.

These cutoff values should be validated in a prospective study, which should also look at correlations between the endoscopic response and "disease-modifying long-term outcomes," such as a sustained clinical response or surgery, they added.

In the study that evaluated the reliability of the UCEIS, 25 investigators from North America and Europe were randomized to assess 28 of 57 sigmoidoscopy videos of patients with UC, which included some duplicates to evaluate intraobserver reliability.

Clinical details such as the number of stools per day were provided for only two of the videos. They were also trained.

The UCEIS provides a score of 0 to 8 based on the sum of three descriptors: vascular pattern (normal, patchy obliteration, or obliterated), bleeding (none, mucosal, luminal mild, luminal moderate, or severe), and erosions and ulcers (none, erosions, superficial ulcer, or deep ulcer). Almost 700 video evaluations were performed.

The results included a satisfactory level of intrainvestigator and interinvestigator reliability, indicating that the UCEIS is simple to use and also "reliably evaluates the overall endoscopic severity of UC and accounts for 88% of the variance between endoscopists," the authors concluded.

The study was the first step in the validation of the UCEIS and has "confirmed the reliability of the UCEIS, even if further validation is needed to establish thresholds for remission, the clinical relevance of different UCEIS scores, and responsiveness of the UCEIS to change in disease status," they noted.

The CD study was partly funded by Janssen Biotech; Dr. Ferrante was supported by the Belgian Society of Gastrointestinal Endoscopy and by Funds for Scientific Research, Belgium.

The authors disclosed serving on advisory committees and review panels of, or serving as consultants and speakers for, multiple pharmaceutical manufacturers, as well as receiving grants or research support from the companies, including Janssen and Abbott. Several authors were employees of Janssen Biotech and Janssen Biologics, the manufacturer of infliximab. One author had no disclosures.

The UCEIS study was funded by Warner Chilcott, and one author was an employee of the company. The authors disclosed serving as consultants, advisers, and/or speakers for, and receiving research grants from, multiple pharmaceutical companies. Several authors had no disclosures.

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Cutoff values are still a moving target

The research field of measurements is fundamental for improving management strategies in inflammatory bowel diseases (IBDs) since the process can progress no faster than its key measured variables.

In recent years, there has been a growing interest in mucosal healing as a goal of treatment in both CD and UC, since it seems to serve as a surrogate marker for long-term well-being and reduced complications (and this is our true ultimate goal of treatment).

However, the paucity of data on how to best measure mucosal healing limits our ability to treat patients to this target. Is mucosal healing best measured by macroscopic appearance of the mucosa?

If so, how can we accurately quantify the degree of inflammation, and what cutoff scores are associated with our ultimate goal? Perhaps other markers of mucosal healing are superior, such as histology, calprotectin (which may be more sensitive for microscopic inflammation), or magnetic resonance (MR) enterography, which measures the entire thickness of the bowel wall and the entire length of the small bowel.

Even after determining the best measurement tool and its cutoff values, change over time (i.e., responsiveness) and reliability must be determined before its implementation in treatment algorithms.

In the November issue of Gastroenterology, Ferrante et al. showed in the robust SONIC data set that a reduction of 50% in the CDEIS (CD Endoscopic Index of Severity) and the simplified SES-CD (Simple Endoscopic Score for CD), or mucosal healing by week 26, predicts to some extent 1-year clinical remission in CD.

In the second study, Travis et al. elegantly report on the reasonable reliability and initial validity of the only validated endoscopic score in UC, the UCEIS (Ulcerative Colitis Endoscopic Index of Severity) score. Both studies present important data that advance our knowledge one step further toward the "treat to target" concept in IBD.

However, the two studies also highlight the shortcomings of our endoscopic definition of mucosal healing and their imperfect reliability, validity, and prediction power. Ferrante et al. should be applauded for reporting diagnostic utility statistics and not only P values in evaluating prediction power. Modest sensitivity/specificity of 74%-75%/45%-48% indicate that mucosal healing can be regarded as another important predictive variable in the decision-making process but not yet alone as the gold standard that mandates treatment escalation.

The studies facilitate significantly our evaluation of endoscopic mucosal healing, but as the authors of both studies rightly indicate, more studies are needed to further define our moving "target" before implementing it in IBD treatment algorithms.

Dr. Dan Turner is head of the pediatric gastroenterology and nutrition unit, Hebrew University of Jerusalem, ShaareZedek Medical Center. He has no relevant conflicts of interest.