抗黏着斑蛋白抗体检测或可诊断肠易激综合征

圣迭戈——检测血液中的抗黏着斑蛋白抗体——一种参与神经细胞迁移的蛋白——可能使肠易激综合征(IBS)的客观诊断得以实现。一直以来，IBS的诊断都依赖于通过彻底检查排除其他可能性。

洛杉矶Cedars-Sinai医学中心胃肠动力项目主任Mark Pimentel博士领导的团队开展了这项多中心研究，在IBS或炎症性肠病(IBD)患者和健康对照者中检验了这项检查。在美国胃肠病学会(ACG)年会上报告的研究结果表明，抗黏着斑蛋白抗体试验区分IBS和IBD的阳性预测值在90%以上。


Mark Pimentel博士

而且，如果在分析中还考虑到抗细胞致死膨胀毒素B(CdtB，由常引起食物中毒的细菌产生的一种毒素)抗体，阳性预测值可进一步增至≥94%。

“抗黏着斑蛋白抗体水平升高是IBS特有的，抗CdtB抗体水平升高还能进一步增强抗黏着斑蛋抗体检测的特异性。这可能是第一种可区分IBS和IBD的血清诊断性生物标志物，将有助于避免不必要的检查。”

此外，研究结果支持由啮齿动物模型得出的感染后IBS致病机制，即细菌性胃肠炎引起针对消化道黏着斑蛋白的自身免疫。

他指出，这种检测在IBD研究中可能也有用。“IBD研究的一个问题在于，对治疗无应答的患者可能实际上患有IBS而非IBD。也许这项检测可用于在研究开始之前筛选出这类患者。”

一名与会者表示对该研究持保留态度。他指出，一些分析是在IBS患者与健康人之间进行比较的，鉴于这项研究受试人群的组成，阳性预测值可能并不是最佳的统计学参数。“我们不需要做检查就知道谁有症状、谁没有症状。所以这项研究只是验证的开始，而不是结束。我估算了一下，如果你现在就将这种检测投入临床应用，阳性预测值大约会是20%。所以它对临床实践的意义并不是太大……我相信你会继续优化这种检测，但我不认为现在就可以在临床实践中使用它。”


Michael E. Cox博士

Pimentel博士答复称：“首先，你可以使用表示患者所占比例的概率比……我们的概率比介于3~4，希望这个数据能让你更信任这项检查。其次，来到诊室的都不是健康人：假如他们有腹泻症状，就提示患有IBD或IBS或某种其他疾病。”

在新闻发布会上，达特茅斯-希区柯克医学中心的Brian E. Lacy博士评论称：“这是一个非常重要的话题。根据保守估计，有12%~15%的人患有IBS，每年在诊断和治疗IBS方面的花费高达200亿~300亿美元。”

“对于许多患者而言，IBS是一项排除性诊断。他们会经历一连串不必要的检查而往往一无所获，因为这是一种功能性肠病。”他补充道：“假如有一种血液检查能确诊IBS，我认为那将有非常重要的意义。社区医生和家庭医生通常没有信心做出IBS的诊断，而在有了这样的诊断性检查手段后，他们可能会说，‘这项检查太棒了，我们不仅可以做出诊断，而且能排除IBD或者提高我们排除IBD患者的能力’。”

Pimentel博士认为，这项检查对于治疗可能也有启示意义。“另一个问题是，这种抗体试验能否预测谁会对抗生素治疗产生应答，或者能否预测细菌过度生长或其他可治疗的IBS表现？”

最后，这样的检查还有助于证明IBS的确是一种疾病。“IBS是一种非常、非常难应付的疾病，因为我们都不太了解它，而且由于常被认为是一种生活方式紊乱而非疾病，IBS受到了一些‘不公正’待遇。”他评论道：“所以我希望能使大家意识到IBS是一种真正的疾病，不只是一种综合征。”

在这项研究中，研究者前瞻性确定了162例符合罗马Ⅲ IBS诊断标准的患者，测定了这些患者的血清样本。同时还纳入了30例当时未使用生物制剂的活动性IBD患者和26名连续入组的健康人。各组均有约70%的患者为女性，在年龄和性别分布方面无显著差异。

结果表明，IBS患者的抗黏着斑蛋白抗体光密度(OD)读数高于IBD患者(P＜0.01)和健康人(P＜0.01)。同时，IBD患者的抗CdtB抗体OD读数高于IBS患者(P=0.02)。

在区分IBS和IBD方面，抗黏着斑蛋白抗体OD读数超过0.8的敏感性为43%，特异性为73%，阳性预测值为90%。

至于为何要同时检测抗CdtB抗体和抗黏着斑蛋白抗体，Pimentel博士的理由是：在感染后IBS模型中，抗黏着斑蛋白抗体持续存在，而抗CdtB抗体随着时间推移而减少。

事实上，在这项研究中，这两种抗体的OD读数之间的差异(抗黏着斑蛋白抗体-抗CdtB抗体)在IBS患者中更高，与IBD患者相比P＜0.0001，与健康人相比P＜0.001。

在区分IBS和IBD时，差异超过0.2的敏感性为41%，特异性为88%，阳性预测值为94%。

Pimentel博士指出，有一个混杂性问题是，大约10%的IBD患者同时患有IBS。但在考虑这一因素的模型中，抗黏着斑蛋白抗体OD读数超过0.8(92%)、两种抗体OD读数差值超过0.2(97%)仍具有较高的阳性预测值。

Pimentel博士报告称无相关利益冲突。

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By: SUSAN LONDON, Internal Medicine News Digital Network

SAN DIEGO – A blood test for antibodies to vinculin, a protein involved in nerve cell migration, may allow objective diagnosis of irritable bowel syndrome, a condition historically diagnosed clinically, after a thorough workup excludes other possibilities.

Investigators led by Dr. Mark Pimentel, director of the GI Motility Program at the Cedars-Sinai Medical Center in Los Angeles, performed a multicenter validation study of the test among patients with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), and healthy individuals.

Study results, reported at the annual meeting of the American College of Gastroenterology, showed that the anti-vinculin antibody test had a positive predictive value of at least 90% for distinguishing IBS from IBD.

And when analyses also took into account antibodies to cytolethal distending toxin B (CdtB) – a toxin produced by bacteria commonly associated with food poisoning – the positive predictive value was at least 94%.

"Elevated anti-vinculin antibodies are specific for IBS compared to IBD, and an increase in anti-vinculin antibodies with respect to anti-CdtB increases that specificity," Dr. Pimentel said, summing up the findings. "This may be the first serum diagnostic biomarker that can discriminate IBS from IBD, and it would help avoid unnecessary tests."

Additionally, the findings lend support to a pathogenic mechanism for postinfectious IBS suggested by a rodent model, whereby bacterial gastroenteritis gives rise to autoimmunity against vinculin in the digestive tract.

The assay may be useful in IBD research too, he noted. "One of the problems with IBD studies is those patients who don’t respond to therapies, and maybe they have IBS and they don’t have IBD. Maybe this test could be used to screen those patients out before the study begins."

A session attendee expressed reservations about the study, noting that some analyses compared IBS patients with healthy individuals, and that positive predictive values may not be the best statistic given the composition of the study population.

"We don’t need a test to tell us someone that has no symptoms versus someone that does. So this is the start of your validation, not the end of it," he said. "If you apply this to the population right now, I’ve done some calculations, your positive predictive value would be about 20%. So it’s not that great in clinical practice. ... I’m sure you will develop this more and it will get better, but right now, I don’t think this is ready for prime time."

"First, you can use a likelihood ratio, which accounts for the volumes of patients. ... Our likelihood ratio is between 3 and 4, which I hope gives you more confidence in it," Dr. Pimentel replied. "The second thing is that the patients who arrive in a doctor’s office are not healthy: They are going to have IBD or IBS or something else if they have diarrhea in the clinic."

In a related press briefing, Dr. Brian E. Lacy, of the Dartmouth-Hitchcock Medical Center, Lebanon, N.H., commented, "This is an incredibly important topic, when we are talking about prevalence rates of IBS – a conservative rate is 12% to 15% – and when you are talking about spending $20 billion to $30 billion a year diagnosing and treating IBS."

"For many patients, IBS is a diagnosis of exclusion; they undergo a battery of unnecessary tests which are usually fruitless because this is a functional bowel disorder," he added. "To possibly have a diagnostic test – a blood test – that could confidently make the diagnosis of IBS to me would be incredibly important. And I think for the community primary care providers, family practice doctors, who are not confident at diagnosing IBS, to have somebody say, ‘This is a great test, and we can not only make the diagnosis, but exclude or maybe improve our ability to exclude the patients with IBD,’ that would be incredibly important."

The test may also have implications for treatment, according to Dr. Pimentel. "Another question is, could this antibody test predict who will respond to antibiotics, or does it predict bacterial overgrowth or other treatable aspects of IBS?" he explained.

Finally, such a test would help validate IBS as a legitimate medical condition. "IBS is a very, very difficult illness because nobody understands it, and it kind of gets the short end of the stick because it is viewed as a lifestyle disorder instead of a legitimate disease," he commented. "So what I’d like to do in my career is to make IBS a real disease, not just a syndrome as it’s been for at least the last 2 decades."

Press briefing moderator Dr. Michael E. Cox of the Mercy Medical Center in Baltimore, said, "The $64,000 question is, when would this possibly be ready for prime time?"

"We are validating this antibody every day," Dr. Pimentel replied, although as yet, no companies are collaborating in developing the assay. "When it will be ready for prime time, I’m not sure."

In the study, the investigators assayed serum samples from 162 prospectively identified patients who met Rome III criteria for IBS, 30 patients with active IBD who were not receiving biologic agents, and 26 consecutive healthy individuals.

Across groups, about 70% of patients were female, with no significant differences in the sex and age distributions.

Results showed that the anti-vinculin antibody optical density (OD) reading was higher in patients with IBS than in patients with IBD (P less than .01) and healthy individuals (P less than .01), reported Dr. Pimentel.

Meanwhile, the anti-CdtB antibody OD reading was higher in the patients with IBD than in the patients with IBS (P = .02).

For distinguishing IBS from IBD, an anti-vinculin antibody OD reading exceeding 0.8 had a sensitivity of 43%, a specificity of 73%, and a positive predictive value of 90%.

There is a good rationale for simultaneously looking at anti-CdtB and anti-vinculin, according to Dr. Pimentel: In the model of postinfectious IBS, anti-vinculin antibodies persist over time, whereas anti-CdtB antibodies decline.

And indeed, in the study, the difference between the two OD readings (anti-vinculin minus anti-CdtB) was higher in the patients with IBS than in both the patients with IBD (P less than .0001) and the healthy individuals (P less than .001).

For distinguishing IBS from IBD, a difference exceeding 0.2 had a sensitivity of 41%, a specificity of 88%, and a positive predictive value of 94%.

A confounding issue is that about 10% of patients with IBD also have IBS, Dr. Pimentel noted. But a model taking this into account showed high positive predictive values for an anti-vinculin antibody OD reading exceeding 0.8 (92%) and for a difference between the OD readings of anti-vinculin and anti-CdtB exceeding 0.2 (97%).

Dr. Pimentel disclosed no relevant conflicts of interest.