Collagen Factors Into Stricturing of Crohn’s Disease

Arno R. Bourgonje, MD

Collagen degradation could factor into disease phenotype of Crohn’s disease, according to new research based in the Netherlands.

A team, led by Arno R. Bourgonje, MD, Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, identified the associations between serological biomarkers of collagen turnover and disease behavior according to the Montreal classification in patients with Crohn’s disease.

Stricturing and penetrating disease phenotypes are prevalent in 30-50% of patients with Crohn’s disease at the time of diagnosis.

Collagen

Collagens are important to maintain epithelial integrity and structure and tensile strength of intestinal tissue. Type IV is the most abundant collagen of the basement membrane, while type I and III collagens are the most abundant collagens of the interstitial matrix, which are directly associated with the intestinal epithelium.

In the study, the investigators measured the serological biomarkers of type III and IV collagen formation (PRO-C3, PRO-C4) and matrix metalloproteinase (MMP) or granzyme-B (GrzB)-mediated type I, III, IV and VI collagen degradation (C1M, C3M, C4M, C4G, C6Ma3) using neo-epitope protein fingerprint assays.

Overall, the study included 101 patients with Crohn’s disease (Montreal B1: n = 37; B2: n = 27; B3: n = 37) and 96 control participants. Each patient was followed up with until their last outpatient visit, allowing the investigators to monitor structuring or penetrating disease progression and recurrence, as well as the occurrence of surgical interventions.

Each patient included in the study was identified from the IBD center database and biobank of the University Medical Center Groningen in the Netherlands.

Data Collection

The investigators collected detailed phenotypic data for all participants, including age, sex, body-mass index (BMI), smoking status, Montreal disease classification, medication use, history of bowel surgery, disease activity, and standard laboratory parameters. Each of these was assessed at the time of serum sampling.

The team sought primary outcomes of disease behavior according to the Montreal classification. This was classified for B1 as non-stricturing, non-penetrating disease, representing inflammatory Crohn's disease without any prior stricturing or penetrating disease complications.

For B2, it was classified as stricturing disease, representing the presence of stenosis, either asymptomatic or symptomatic, and either previous or current, as well as previous surgery because of stenosis, or postoperative stenosis in anastomosis.

Finally, for B3, it was classified as penetrating disease, representing the history or current presence of fistulizing disease, including intra-abdominal fistulae, perforations, and abscesses.

Results

The team found C1M, C3M, and C4M were significantly reduced in patients with structuring disease (Montreal B2). This was accurately differentiated these patients from patients with either non-stricturing, non-penetrating (B1), or penetrating (B3) disease (all P < 0.001, multivariable analysis).

The investigators also saw the type IV collagen formation/degradation (PRO-C4/C4M) ratio demonstrated high discriminative capacity (B1/B2: AUC = 0.90; B1/B3: AUC = 0.87, both P < 0.001, multivariable analysis).

In addition, higher baseline levels of C1M and C4G was linked to an increased risk of penetrating disease progression (C4G: HR, 1.71; 95% CI, 1.05–2.81; P <0.05).

“Elevated degradation of type I, III and IV collagen and excessive (relative) formation of type IV collagen strongly associates with stricturing [Crohn’s disease],” the authors wrote. “Type I and IV collagen fragments show predictive potential for the risk of penetrating disease progression. These biomarkers may become valuable tools for detection and prediction of stricturing and penetrating [Crohn’s disease].”

The study, “Serological biomarkers of type I, III and IV collagen turnover are associated with the presence and future progression of stricturing and penetrating Crohnʼs disease,” was published online in Alimentary Pharmacology & Therapeutics.