IBD与某些癌症风险增加有关

根据《临床胃肠病学与肝病学》2月刊发表的一项大型数据库分析和一项meta分析的结果，用于炎症性肠病(IBD)的免疫抑制疗法似乎与这些患者的黑色素瘤和血液恶性肿瘤风险增加无关。

第一项研究是基于丹麦的一项全国人群队列分析，结果显示IBD患者的癌症风险增加，尤其是血液恶性肿瘤和黑色素瘤，标化发病率分别为1.9和1.4。

第二项研究是基于对医学文献的系统综述和meta分析，结果显示诊断为克罗恩病或溃疡性结肠炎与罹患黑色素瘤的风险增加37%有关。在1998年引入生物治疗之前开展的研究中黑色素瘤风险增高，而在1998年之后开展的研究中不增高。

在第一项研究中，北卡罗来纳大学小儿消化科的Michael D. Kappelman医生利用医疗数据库确定了丹麦1978~2010年期间诊断为克罗恩病或溃疡性结肠炎的患者(doi: 10.1016/j.cgh.2013.03.034)。对患者进行随访，直至首次发生癌症、死亡或移民。并采用标化发病率(SIR)比较IBD患者与一般人群的癌症发病率。

研究者表示：“假如免疫抑制药物可通过抑制肠道炎症降低胃肠恶性肿瘤风险而增加肠外恶性肿瘤风险，IBD患者的这两类风险就可能相互平衡。因此，我们试图在丹麦的全国IBD患者队列中综合评价肠道和肠外恶性肿瘤风险。”

这项分析纳入了13,756例克罗恩病患者和35,152例溃疡性结肠炎患者，平均随访近8年。排除诊断IBD后1年内诊断癌症的患者后，克罗恩病患者中发生了772例侵袭性癌症(SIR 1.3)，在溃疡性结肠炎患者中发生了2,331例侵袭性癌症(SIR 1.1)。诊断克罗恩病与胃肠癌症(SIR 1.2)和肠外癌症(SIR 1.3)之间呈弱相关性，与血液恶性肿瘤(SIR 1.9)、吸烟相关癌症(SIR 1.5)和黑色素瘤(SIR 1.4)之间呈强相关性。溃疡性结肠炎与胃肠和肠外癌症的相关性均较弱(均SIR 1.1)。

研究者总结称，克罗恩病患者的额外癌症风险“在很大程度上来自肠外癌症，尤其是血液恶性肿瘤、黑色素瘤(这两类癌症均可能与免疫抑制有关)和吸烟相关癌症”。他们补充道：“这项研究提供了令人放心的数据，表明观察到的胃肠恶性肿瘤风险降低并未被肠外或血液恶性肿瘤风险增加所抵消。这些发现提示，IBD的内科和外科治疗和/或其他长期趋势尚未在人群水平上对癌症相对风险产生实质影响。”

这项研究得到了国立糖尿病、消化病和肾病研究所、Karen Elise Jensen基金会和临床流行病学研究基金会的支持。

在第二项研究中，罗切斯特梅奥医院胃肠与肝病科的Suddharth Singh医生等人系统检索了2013年3月之前的描述诊断IBD后偶发性黑色素瘤的队列研究，并估算了发病率比率或标化发病率。排除病例报告或病例系列(doi: 10.1016/j.cgh.2013.04.033)。

在找出的838项研究中，包含172,837例IBD患者的12项研究被纳入最终分析。在这12项研究中，汇总的黑色素瘤粗发病率为27.7/10万人-年，相当于黑色素瘤风险增加37%(RR 1.37)。研究者单独观察了克罗恩病患者(RR 1.51)和溃疡性结肠炎患者(RR 1.23)中的发病率。此外，1998年之前开展的研究中的黑色素瘤风险更高(RR 1.52)，而在1998年引入生物治疗之后风险并未明显升高(RR 1.08)。

“我们已知道，免疫抑制患者的黑色素瘤风险增高，包括曾接受实体器官移植、罹患淋巴瘤和人类免疫缺陷病毒感染/获得性免疫缺陷综合征的患者。可能的原因是，观察到的IBD患者黑色素瘤风险升高与其潜在的免疫功能障碍有关。”

研究者猜测，免疫抑制药物可能通过“下调”肿瘤监视机制、增加对致癌性病毒(例如黑色素瘤相关性逆转录病毒)感染的易感性，或通过直接作用于DNA代谢而增加黑色素瘤风险。尽管巯基嘌呤类似物已被证实与非黑色素瘤皮肤癌风险增加有关，但我们的汇总分析并未提示黑色素瘤风险增加，虽然研究数量有限。

Singh医生及其同事承认这项分析存在某些局限性，包括所纳入的研究可能存在误分类偏倚，以及这些研究“并未校正已知的黑色素瘤危险因素，包括非黑色素瘤皮肤癌病史、黑色素瘤家族史或日光暴露”。

这项meta分析的作者Edward V. Loftus医生披露称为杨森生物技术、雅培和UCB制药提供了咨询服务和获得这些公司提供的研究支持。其他作者无相关利益冲突披露。

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By: DOUG BRUNK, Internal Medicine News Digital Network

Immunosuppressive therapies for inflammatory bowel disease do not appear to be implicated in the increased risk for melanomas and hematologic malignancies seen in these patients, based on the results of a large database analysis and a separate meta-analysis published in the February edition of Clinical Gastroenterology and Hepatology.

The first study, based on a nationwide population-based cohort analysis conducted in Denmark, found that patients with inflammatory bowel disease (IBD) are at increased risk for cancer, in particular hematologic malignancies and melanoma at standardized incidence ratios of 1.9 and 1.4, respectively.

The second study, based on a systematic review and meta-analysis of the medical literature, found a diagnosis of Crohn’s disease or ulcerative colitis was associated with a 37% increase in the risk of developing melanoma. Melanoma risk was higher in studies performed before the introduction of biologic therapies in 1998, but not in those studies performed after 1998.

For the first study, researchers led by Dr. Michael D. Kappelman of the division of pediatric gastroenterology at the University of North Carolina at Chapel Hill used health care databases to identify patients in Denmark with a diagnosis of Crohn’s disease or ulcerative colitis from 1978 through 2010 (doi: 10.1016/j.cgh.2013.03.034). They followed the patients until the first occurrence of cancer, death, or emigration and used standardized incidence ratios (SIRs) to compare cancer incidence in patients with IBD with that expected in the general population.

"If immunosuppressive medications reduce the risk of gastrointestinal malignancy by suppressing intestinal inflammation but increase the risk of extraintestinal malignancies, IBD patients may be trading off one set of risks for another," the researchers wrote. "We therefore sought to evaluate both intestinal and extraintestinal malignancies comprehensively, as well as the occurrence of any invasive cancer, in a nationwide cohort of patients with IBD in Denmark."

The analysis included 13,756 patients with Crohn’s disease and 35,152 patients with ulcerative colitis who were followed up for a mean of nearly 8 years. After the exclusion of cancers diagnosed within 1 year of IBD diagnosis, 772 cases of invasive cancer occurred among patients with Crohn’s disease (SIR 1.3) and 2,331 occurred among patients with ulcerative colitis (SIR 1.1). Diagnosis of Crohn’s disease was weakly associated with gastrointestinal cancers (SIR 1.2) and extraintestinal cancers (SIR 1.3), with the strongest associations for hematologic malignancies (SIR 1.9), smoking-related cancers (SIR 1.5), and melanoma (SIR 1.4). Associations between ulcerative colitis and gastrointestinal and extraintestinal cancers were weaker (SIR of 1.1 for both).

The excess risk of cancer in patients with Crohn’s disease "largely is owing to extraintestinal cancers, particularly hematologic malignancies and melanoma, both of which may be related to immune suppression, and smoking-related cancers," the researchers concluded. They added that their study "provides reassuring data that the decreasing risk for gastrointestinal malignancy observed here ... has not been offset by a concomitant increase in the risk of extraintestinal or hematologic malignancies. These findings suggest that changes in the medical and surgical treatment of IBD and/or other secular trends have not substantially impacted cancer relative risk on a population basis."

The study was supported in part by grants from the National Institute for Diabetes and Digestive and Kidney Diseases, the Karen Elise Jensen Foundation, and the Clinical Epidemiological Research Foundation.

In the second study from the journal, researchers led by Dr. Suddharth Singh of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn., conducted a systematic literature search through March 2013 for cohort studies showing incident melanoma after IBD diagnosis and an estimate of incident rate ratio or standardized incidence rate. Case reports or case series were excluded (doi: 10.1016/j.cgh.2013.04.033).

Of the 838 studies identified, 12 that comprised 172,837 patients with IBD were included in the final analysis. The pooled crude incidence rate of melanoma among patients in the 12 studies was 27.7/100,000 person-years. This translated into a 37% increase in the risk of melanoma (risk ratio of 1.37). The increase was observed independently in the patients with Crohn’s disease (RR 1.51) and in those with ulcerative colitis (RR 1.23). In addition, the risk of melanoma was higher in studies conducted prior to 1998, when biologic therapies were introduced (RR 1.52), but not in those conducted after 1998 (RR 1.08).

"The risk of melanoma has been shown to be increased in immunosuppressed patients, including patients with a prior solid organ transplant, lymphoma, and patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. It is possible that the increased risk of melanoma observed in patients with IBD may be related to underlying immune dysfunction in these patients, resulting in altered tumor surveillance" the researchers wrote.

They hypothesized that immunosuppressive medications may increase the risk of melanoma by "down-regulation of the tumor surveillance mechanisms, increased susceptibility to infection with oncogenic viruses such as melanoma-associated retroviruses, or through direct pharmacologic effects of medications on DNA metabolism. Although thiopurine analogs have been associated with an increased risk of nonmelanoma skin cancers, our pooled analysis did not suggest an increased risk of melanoma, albeit there were a limited number of studies."

Dr. Singh and his associates acknowledged certain limitations of the analysis, including the potential for misclassification bias in the included studies and the fact that studies "did not adjust for known risk factors for melanoma, including personal history of nonmelanoma skin cancers, family history of melanoma, or sun exposure."

For the meta-analysis, one author, Dr. Edward V. Loftus, disclosed that he has consulted for and has received research support from Janssen Biotech, Abbott Laboratories, and UCB Pharma. The others had no relevant conflicts to disclose.