Author: Claire Hornung

We recently published an open assess review, where we and our collaborators have investigated the novel concept of “hot” and “cold” fibrosis—published in the Journal of Hepatology.

Fibrosis is a pathological condition characterized by excessive accumulation of extracellular matrix (ECM) components, particularly collagens, leading to tissue scarring and organ dysfunction. The concept of “hot” and “cold” fibrosis has recently emerged to help understanding the immune landscape within fibrotic tissues and how ECM and immune cell interactions could be new targets for future fibrosis treatment.

This review provides a new angle of describing fibrosis as “hot” or “cold”, which refers to the immune status within fibrotic tissues and the nature of fibrogenic signaling. Whereas hot fibrosis is characterized by active immune cell infiltration and inflammation, cold fibrosis is associated with auto- and paracrine myofibroblast activation, immune cell exclusion and quiescence.

We demonstrate that pharmacodynamic biomarkers reflecting ECM remodeling are promising tools to monitor fibrotic and inflammatory processes in hepatic diseases, allowing to identify disease profiles associated either with hot or cold fibrosis. This also enables tailored strategies—such as combining anti-fibrotic drugs with immune-stimulating therapies—to optimize treatment efficacy.

Article: Hot and cold fibrosis: The role of serum biomarkers to assess immune mechanisms and ECM-cell interactions in human fibrosis

September is pulmonary fibrosis (PF) awareness month—a progressive lung disease that affects over 200,000 people in the United States alone. PF causes scarring of lung tissue, leading to severe breathing difficulties and reduced quality of life.

At Nordic Bioscience, we are dedicated to advancing the development of biomarkers that provide deeper insights into disease progression in pulmonary fibrosis.

Together with our collaborators, we contributed to the Lancet publication: Cluster analysis of blood biomarkers to identify molecular patterns in pulmonary fibrosis: assessment of a multicentre, prospective, observational cohort with independent validation.

This research represents a step forward in identifying endotypes that can help improve the monitoring of the disease and guided therapy, ultimately enhancing patient care.

We hope our findings encourage continued research and collaboration, working together to make a lasting impact!

Assessing disease burden and treatment response in ulcerative colitis (UC) remains challenging, often leading to treatment withdrawal and unresolved disease activity. These challenges highlight the need for better, non-invasive biomarkers to monitor disease activity and predict treatment outcomes.

In our recently published paper “Circulating Extracellular Matrix Products as Indicators of Disease Burden and Predictors of Disease Course in Ulcerative Colitis”, we identified C7M (MMP-9/13-degraded type VII collagen α1-chain), nordicPRO-C3™ (type III collagen formation), and PRO-C22 (turnover of type XXII collagen) as biomarkers of endoscopic disease severity and treatment response in UC.

We found that a combination of nordicPRO-C3™ and PRO-C22 predicted endoscopic outcomes at week 24, while lower levels of C7M and the C3M/nordicPRO-C3™ ratio were associated with endoscopic response. Notably, this is the first time that MMP-mediated type VII collagen degradation has been linked to disease severity in UC, highlighting its potential role in epithelial damage and barrier dysfunction.

These biomarkers provide a non-invasive means to assess transmural disease activity and disease extent, addressing a critical gap in disease burden monitoring. Incorporating these biomarkers into clinical practice could improve UC management by refining diagnostic accuracy for predicting endoscopic response prior to treatment adjustment.

Article: Circulating Extracellular Matrix Products as Indicators of Disease Burden and Predictors of Disease Course in Ulcerative Colitis

Pulmonary fibrosis is a condition characterized by progressive lung scarring, resulting in a median survival of 3–5 years after diagnosis. However, the rate of lung function decline varies widely among patients with different aetiologies, posing substantial challenges in clinical management. 

Currently, no cure exists for pulmonary fibrosis, and pirfenidone and nintedanib, approved for idiopathic pulmonary fibrosis treatment, have partial effects in slowing disease progression and variable tolerability.

This study aimed to classify patients with pulmonary fibrosis according to blood biomarkers to differentiate distinct disease patterns, known as endotypes.

Our findings showed that blood biomarker clustering in pulmonary fibrosis identified three distinct blood biomarker signatures associated with lung function and prognosis, suggesting unique pulmonary fibrosis biomarker patterns. These findings support the presence of pulmonary fibrosis endotypes with the potential to guide targeted therapy development.

Article: Cluster analysis of blood biomarkers to identify molecular patterns in pulmonary fibrosis: assessment of a multicentre, prospective, observational cohort with independent validation

Tuesday the 4th of February is World Cancer Day. At Nordic Bioscience, we are dedicated to developing biomarker solutions that provide valuable insights on cancer, enabling drug developers to improve cancer treatment options.

In honor of this day, we would like to share a paper by our ontology team, which unveils a promising avenue for harnessing PRO-C12 as a non-invasive serum biomarker, enabling the quantification of type XII collagen fragments in cancer patients.

With increased stiffness and remodeling often driving tumor growth and metastasis, the extracellular matrix (ECM) plays a crucial role in cancer progression.

Produced by cancer-associated fibroblasts (CAFs), type XII collagen is a key regulator of ECM organization, stabilizing type I collagen fibrils, contributing to ECM stiffening, and facilitating a pro-invasive tumor microenvironment (TME). In our study, we developed the PRO-C12 ELISA, a non-invasive tool to monitor type XII collagen fragments in serum that is related to ECM stiffening and CAF activity, providing critical insights into tumor biology and metastasis risk.

By quantifying type XII collagen fragments in serum, clinicians and drug developers gain a powerful tool to non-invasively assess CAF-driven mechanisms. PRO-C12 is relevant for diverse cancer types and stages, paving the way for its integration into diagnostic workflows and clinical trials.

Article: Type XII collagen is elevated in serum from patients with solid tumors: a non-invasive biomarker of activated fibroblasts

Today is Rheumatoid Awareness Day, which we would like to honor by sharing one of our rheumatology teams’ publications from 2024.

Rheumatoid arthritis is a chronic autoimmune disease characterized by inflammation in multiple articular joints, causing pain, joint damage, and loss in joint function. Despite the successful development of disease-modifying therapies, the heterogeneity of RA means that a significant proportion of patients respond poorly to treatment. Utilizing personalized and predictive biomarkers can optimize treatment efficacy, safety, and cost.

This study explored the link between type VI collagen breakdown and the effectiveness of Tocilizumab (toci), a drug used to treat rheumatoid arthritis (RA). By measuring a specific fragment of degraded type VI collagen (C6M), researchers found that toci treatment reduced C6M levels compared to placebo and that patients who responded well to TCZ showed a greater reduction in C6M. Additionally, lower initial decreases in C6M were associated with a lower likelihood of a good treatment response.

These findings suggest that quantifying type VI collagen turnover could help predict which RA patients will benefit most from TCZ therapy, potentially leading to more personalized treatment approaches.

Article: Changes in type VI collagen degradation reflect clinical response to treatment in rheumatoid arthritis patients treated with tocilizumab

Primary sclerosing cholangitis (PSC) is a chronic liver disease that leads to a damage of the bile duct, inflammation and fibrosis.

As there is a need for non-invasive biomarkers that can accurately assess the disease severity and prognosis, this study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events.

Our findings in this study showed that nordicPRO-C3™ correlated with fibrosis stage, and nordicPRO-C3™ and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. Therefore, nordicPRO-C3™ and ELF may be utilized for staging and can act as prognostic markers in PSC, contributing to improving current screening and treatment of immune-mediated liver diseases.

Article: Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis

There are more than 500 million people worldwide who are affected by osteoarthritis (OA) and left without effective treatment options. Despite significantly different etiologies, clinical trial designs for evaluation of novel treatments still do not typically involve patient selection based on pheno- or endotypic traits.

This has likely contributed to the lack of approved disease-modifying OA drugs (DMOADs) and the high risk of unsuccessful intervention trials in the field.

In recent years, various factors indicating diverse patient subpopulations of OA have been described, such as phenotypes driven by cartilage, metabolic syndrome, subchondral bone, inflammation, and trauma injury. However, their underlying pathobiological mechanisms have not been fully elucidated nor have they been validated by differential treatment response.

In our recent publication we found that tissue turnover biomarkers can reliably identify knee OA endotypes across different OA populations, and these endotypes remain stable over time. This breakthrough takes us one step closer to developing a biomarker-based tool for prognostic enrichment in clinical trials, paving the way for more precise and effective OA treatments.

Article: Longitudinal stability of molecular endotypes of knee osteoarthritis patients

In this paper from our cardiovascular research team the aim was to investigate type III collagen (COL III) turnover with the help of pharmacodynamic biomarkers in participants from the CANVAS Program.

The biomarkers of COL III formation (PRO-C3/nordicPRO-C3™) and COL III degradation fragments (C3M/nordicC3M™ and CTX-III/nordicCTX-III™) were assessed in baseline and year 3 plasma from patients enrolled in CANVAS, investigating the effect of canagliflozin in participants with type 2 diabetes. The clinical outcomes explored in this study were hospitalization for heart failure, cardiovascular death and all-cause mortality.

The study showed that higher levels of nordicPRO-C3™ and C3M at baseline were associated with a greater incidence of all investigated outcomes, whereas levels of nordicCTX-III™ at baseline were not associated with any of the investigated outcomes.

After treatment with canagliflozin, the levels of nordicPRO-C3™ decreased and levels of CTX-III increased. An increase from baseline to year 3 in nordicPRO-C3™ in the placebo arm was associated with an increased incidence of cardiovascular outcomes, and in all participants was associated with an increased risk of all-cause mortality.

Reflecting a shift in the dynamics of COL3 turnover after the treatment with canagliflozin, nordicPRO-C3™ and nordicCTX-III™ are promising pharmacodynamic tools. In future interventional trials, they can be used to monitor the impact of the canagliflozin treatment and possibly other sodium-glucose co-transporter-2 inhibitors on tissue remodeling.

Article: Association of type III collagen turnover with cardiovascular outcomes and impact with canagliflozin in the CANVAS Program: A post hoc analysis