Inflammatory bowel disease (IBD) is a chronic intestinal disease caused by a dysfunctional immune system when fighting foreign pathogens mistakenly attacking the intestinal tissue resulting destruction of the mucosal tissue and increased extracellular matrix (ECM) remodeling. IBD is commonly divided into Crohn’s disease (CD) and ulcerative colitis (UC). CD and UC are characterized by mucosal inflammation with elevated protease activity leading to increased ECM remodeling and increased deposition of collagen in lamina propria and submucosa. Excessive collagen deposition into the intestinal mucosal tissue and unresolved inflammation is the leading cause of surgery for IBD patients due to inadequate response to treatment. Therefore ECM markers to monitor mucosal healing/intestinal healing and predicting of treatment response are important.

How many have Inflammatory Bowel Disease?
More than 7 million people are currently diagnosed with IBD, with a prevalence of around 0.3% worldwide. Risk factors also include age, genetics, smoking status, obesity, and environmental factors.

How is Inflammatory Bowel Disease treated?
There is no cure for IBD, but symptoms and inflammation can be treated using immunosuppressants, steroids, or synthetic or biologic treatment. The type of treatment will depend on the severity of symptoms, location of disease and the number of years with IBD.

How is Inflammatory Bowel Disease diagnosed?
A single reference standard for the diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC) does not exist. The diagnosis of CD or UC is based on a combination of clinical, biochemical (CRP and faecal calprotectin), stool, endoscopic, cross-sectional imaging, and histological investigations.

The medical need for biomarkers in IBD today is two-fold. First, diagnosis of IBD remains a challenge because the signs and symptoms mimic those of many other diseases including CD and UC, therefore distinguishing between UC and CD is challenging. Current biomarker techniques are imprecise and struggle to determine future prognosis of the patients.

Next, then despite great progress in the availability of new and efficacious drugs in the last decades, there is still a significant proportion of patients who fail to respond to treatment or lose treatment effect over time. Diagnostic and prognostic biomarkers have the potential to greatly benefit patients, by aiding in early diagnosis of disease and directing the most appropriate treatment at the right time and to monitor mucosal healing.

Tissue remodeling as a predictor of treatment response

  • Biomarkers of the mucosal basement membrane may be predictors of response.

Monitoring of treatment response

  • Biomarkers for monitoring structural effect.

Collagen fragments as surrogate markers for endoscopic remission

  • Biomarkers for mucosal healing.

Disease complication

  • Biomarkers for intestinal fibrosis and fistula development

Furthermore, the use of predictive or prognostic biomarkers to enrich or stratify patients that are more likely to achieve mucosal healing and treatment response in drug development trials, may reduce trial length, and size required to determine therapeutic efficacy.

Inflammatory bowel disease is characterized by chronic recurrent inflammation resulting in increased mucosal destruction and ECM remodeling. The Protein Fingerprint Biomarker technology can be applied to quantify the degree of Inflammation, Mucosal damage and  Intestinal Fibrogenesis  by quantifying fragments of protease mediated degradation essential mucosal tissue proteins including a novel serum calprotectin biomarker (CPa9-HNE) and collagen derived biomarkers (e.g. C3M, PRO-C3, C4M), which is released into the circulation

The ECM of the intestinal mucosa consist mainly of collagen, laminin and elastin. The intestinal tissue is a high turnover tissue, which means that the epithelium is replaced once a week. ECM remodeling is essential for the intestinal tissue homeostasis. However, if the ECM remodeling is constantly altered and out of balance, the tissue homeostasis will be affected causing severe tissue destruction and ineffective healing.

In IBD, the ECM remodeling equilibrium is imbalanced due to high protease activity and increased ECM deposition, leading to increased mucosal destruction and initiation of repair processes which in turn will result in intestinal mucosal scarring and intestinal fibrosis.

CPa9-HNE is suppresed in IBD patients in remissions compared to IBD patients with active disease. Thus high serum levels of CPa9-HNE reflects disease activity. 

While faecal calprotectin remains one of the best diagnostic biomarkers to differentiate IBD from IBS, faecal calprotectin’s and CRP’s capacity for predicting treatment response is limited. There is therefore still a medical and drug development need for biomarkers that are able to characterize and quantify structural mucosal changes and predict disease progression and treatment response. 

Protein Fingerprint biomarkers measured in serum are generally increased in UC and CD patients compared to healthy subjects (HS).

Reference: Mortensen et al 2015 JCC. 

Fragment of calprotectin degraded by human neutrophil elastase (CPa9-HNE) and  type III collagen turnover (C3M/PRO-C3) are both increased in UC and CD patients compared to healthy subjects

Protein Fingerprint biomarkers measured in serum are associated with established disease activity parameters, including SES-CD (CD endoscopic score) and mMES (UC endoscopic score), generally increased in UC and CD patients compared to healthy subjects.

Correlations between baseline biomarkers concentrations and clinical disease activity parameters. 

Protein Fingerprint biomarkers measured in serum demonstrates to be associated with different CD phenotypes e.g. fistula (C3M/PRO-C3) and fibrostenotic strictures (PRO-C16).

(to the left) Reference: Haaften et al 2016 AP&T
(to the right) Reference: Mortensen et al 2018 JCC.

Association of the biomarkers C3M/PRO-C3 and PRO-C16 with fistula and fibrostenotic phenotypes for Crohn's disease.

Protein Fingerprint biomarkers allow pharmacodynamic profiling of novel treatments by measuring protein degradation fragments directly in a serum sample.

Reference: Mortensen et al 2020 JCG.

Asterisks (*) depictssigficant difference from baseline. Squares (#) depictssignificant difference betweenresponders and non-responders

Early suppression in the Protein Fingerprint biomarker VICM provides and information on target engagement and monitoring of treatment response.

Low baseline serum levels of the Protein Fingerprint biomarker, C4M, predicts response to efficacious treatment. The response is defined as being in clinical remission assessed with the HBI (CD clinical disease activity score).

Reference: Haaften et al 2020 CTG.

Baseline prediction of anti-TNFα (IFX and ADA)  clinical response with Protein Fingerprint biomarker C4M

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