Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, Georgia.
Department of Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.
Clin Gastroenterol Hepatol. 2019 Aug;17(9):1799-1806. doi: 10.1016/j.cgh.2018.09.008. Epub 2018 Sep 10.
BACKGROUND & AIMS: There are few serum biomarkers to identify patients with Crohn's disease (CD) who are at risk for stricture development. The extracellular matrix components, collagen type III alpha 1 chain (COL3A1) and cartilage oligomeric matrix protein (COMP), could contribute to intestinal fibrosis. We investigated whether children with inflammatory CD (B1) who later develop strictures (B2) have increased plasma levels of COL3A1 or COMP at diagnosis, compared with children who remain B1. We compared results with previously studied biomarkers, including autoantibodies against colony-stimulating factor 2 (CSF2).
We selected 161 subjects (mean age, 12.2 y; 62% male) from the Risk Stratification and Identification of Immunogenic and Microbial Markers of Rapid Disease Progression in Children with Crohn's cohort, completed at 28 sites in the United States and Canada from 2008 through 2012. The children underwent colonoscopy and upper endoscopy at diagnosis and were followed up every 6 months for 36 months; plasma samples were collected at baseline. Based on CD phenotype, children were separated to group 1 (B1 phenotype at diagnosis and follow-up evaluation), group 2 (B2 phenotype at diagnosis), or group 3 (B1 phenotype at diagnosis who developed strictures during follow-up evaluation). Plasma samples were collected from patients and 40 children without inflammatory bowel disease (controls) at baseline and analyzed by enzyme-linked immunosorbent assay to measure COL3A1 and COMP. These results were compared with those from a previous biomarker study. The Kruskal-Wallis test and the pairwise Dunn test with Bonferroni correction were used to compare differences among groups.
The median baseline concentration of COL3A1 was significantly higher in plasma from group 3 vs group 1 (P < .01) and controls (P = .01). Median baseline plasma concentrations of COMP did not differ significantly among groups. A model comprising baseline concentrations of COL3A1 and anti-CSF2 identified patients with B2 vs B1 CD with an area under the curve of 0.80 (95% CI, 0.71-0.89); the combined concentration identified patients with strictures with a sensitivity value of 0.70 (95% CI, 0.55-0.83) and a specificity value of 0.83 (95% CI, 0.67-0.93).
We found median plasma concentrations of COL3A1, measured by enzyme-linked immunosorbent assay at diagnosis, to be significantly higher in patients with CD who later developed strictures than in patients without strictures. The combination of concentrations of COL3A1 and anti-CSF2 might be used to identify pediatric patients at CD diagnosis who are at risk for future strictures.
ClinicalTrials.gov identifier: NCT00790543.
目前，用于识别有狭窄发展风险的克罗恩病（CD）患者的血清生物标志物较少。细胞外基质成分，III 型胶原α 1 链（COL3A1）和软骨寡聚基质蛋白（COMP），可能有助于肠道纤维化。我们研究了炎症性 CD（B1）患儿在诊断时是否存在 COL3A1 或 COMP 血浆水平升高，与仍为 B1 的患儿相比。我们将结果与先前研究的生物标志物进行了比较，包括对集落刺激因子 2（CSF2）的自身抗体。
我们从 2008 年至 2012 年在美国和加拿大的 28 个地点完成的儿童克罗恩病免疫原性和微生物标志物快速疾病进展风险分层和识别研究中选择了 161 名受试者（平均年龄 12.2 岁；62%为男性）。这些儿童在诊断时接受了结肠镜检查和上消化道内镜检查，并在接下来的 36 个月中每 6 个月进行一次随访；在基线时收集了血浆样本。根据 CD 表型，将儿童分为第 1 组（诊断和随访评估时为 B1 表型）、第 2 组（诊断时为 B2 表型）或第 3 组（诊断时为 B1 表型，但在随访评估期间发展为狭窄）。从患者和 40 名无炎症性肠病（对照组）的患者中采集基线时的血浆样本，通过酶联免疫吸附测定法测量 COL3A1 和 COMP。将这些结果与先前的生物标志物研究进行了比较。使用 Kruskal-Wallis 检验和配对 Dunn 检验（带有 Bonferroni 校正）比较组间差异。
第 3 组与第 1 组（P<.01）和对照组（P=0.01）相比，COL3A1 血浆基线浓度中位数明显更高。COMP 的基线血浆浓度在各组之间无显著差异。包含基线 COL3A1 和抗 CSF2 浓度的模型，可识别出 B2 与 B1 CD 患者，曲线下面积为 0.80（95%CI，0.71-0.89）；联合浓度可识别出有狭窄的患者，其灵敏度值为 0.70（95%CI，0.55-0.83），特异性值为 0.83（95%CI，0.67-0.93）。
我们发现，通过酶联免疫吸附测定法测量的 COL3A1 血浆浓度在以后发生狭窄的 CD 患者中明显高于无狭窄的患者。COL3A1 和抗 CSF2 浓度的组合可能用于识别 CD 诊断时存在未来狭窄风险的儿科患者。
ClinicalTrials.gov 标识符：NCT00790543。
