Is Skin Disease a Local Manifestation of Systemic Tissue Turnover? Serological Collagen Biomarkers Provide Important Information on Skin Diseases Arising from Mutations in Collagen Genes
Introduction
Collagens are the main constituents of the skin. Genetic mutations in type VI, VII, and XVII collagen cause skin diseases, such as atopic dermatitis, epidermolysis bullosa, and bullous pemphigoid. These are all characterized as systemic diseases, with local manifestations. Novel collagen biomarkers hold the potential to detect skin manifestations, monitor the disease course, as well as improve our understanding of the pathophysiology.
The aim of this study was to develop blood-based biomarkers of type VI, VII, and XVII collagen, and investigate their diagnostic potential for skin pathologies, including systemic sclerosis.
These biomarkers reflect the downstream effect of different genetic mutations leading to skin disease and may be useful to determine skin involvement in rheumatic diseases, including systemic sclerosis and psoriatic arthritis.
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Hi-drad-uh-NIE-tis sup-yoo-ruh-TIE-vuh – also known as hidradenitis suppurutiva (HS) – is a pathologically complicated skin condition, where chronic skin inflammation leads to abscesses and scarring. It is a systemic disease with local manifestations, meaning that the chronic insult to the skin is systemic, but it is physically located where skin rubs against skin, such as the armpits, groins and under the breasts. It is well known that immune cells, such as neutrophils and mast cells are involved, but what do we know about tissue remodeling?
When the beautiful collagens of the skin become a part of disease pathogenesis
Patients with HS not only experience pain from the neutrophil-rich tunnels but also from excessive tissue remodeling that causes scarring of the skin. These patients have an imbalance in tissue formation and tissue repair, partly due to the excessive activity of immune cells, which release enzymes that degrade the skin.
One group of tissue-degrading enzymes are matrix metalloproteinases, abbreviated as MMPs. These are released by macrophages, the most numerous inflammatory cells found in HS patients. MMPs infiltrate and contribute to HS pathology, signaling that increased activity of MMPs degrades the proteins of the skin tissue, such as collagens. This process can be quantified by specific blood-based biomarker assays targeting this pathological process.
Pathological fragments in HS may be used to identify disease types
In HS, biomarkers of tissue remodeling such as type III collagen degraded by MMPs (C3M), are associated with disease severity (Hurley Staging).
Figure 1. Biomarkers of tissue remodeling associate with Hurley Stages
C3M is released upon MMP activation and measures dermal tissue remodeling. This raises the question – can we use C3M to identify subtypes of patients based on their disease activity, and potentially molecular endotypes to help select the right treatment for the patients?
To address this, the levels of C3M are different depending on how active the disease is when divided into the Sartorious Score (HSS).
Finding the patients with high C3M levels reflects high disease activity, and may indicate a different subtype of patients needing a different treatment type.
Figure 2. Type II collagen degradation biomarker C3M as a patient stratification tool
Serum biomarkers of proteolytic tissue destruction, formation and macrophage activity can discern patients with IBD according to infliximab treatment non-response or response
Introduction
Characterized by chronic inflammation, patients with Inflammatory Bowel Disease (IBD) experience detrimental remodeling of their intestinal extracellular matrix (ECM). Treatment with anti-inflammatory drugs can reduce inflammation, leading to remission and tissue healing. However, adequate monitoring of patients is critical to ensure and maintain treatment response.
As potential surrogate markers of ECM remodeling, we investigated blood-based biomarkers of type III and -VII collagen and posttranslational modifications of vimentin in patients with IBD. Our aim was to determine the value of the C3M, PRO-C7, and VICM biomarkers for identifying and monitoring response to infliximab (IFX).
Quantifying a combination of non-invasive biomarkers of ECM remodeling and macrophage activity provided AUCs of 0.684 to 0.797 identifying responders to IFX treatment. Each biomarker provided value at the three different visits (Visit 1, 2, and 3). Combining all three biomarkers measured at each visit resulted in an AUC of 0.797 identifying responders to IFX treatment.
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Immune-cell specific biomarker of early intestinal inflammation: Neutrophil elastase degraded fragment of type III collagen is elevated in patients with inflammatory bowel disease
Introduction
Inflammatory Bowel Disease (IBD) is characterized by epithelial barrier injury of the gastrointestinal (GI) tract and is driven by abnormal immune responses and excessive secretion of proteases from immune cells. Among these, neutrophils are the first to migrate into the inflamed interstitial matrix, where type III collagen is significantly deposited. Early detection of mucosal inflammation is crucial to prevent cumulative clinical damage, as a delayed diagnosis can hinder effective treatment.
In this study we aimed to develop a biomarker that reflects early intestinal inflammation prior to it becoming medically evident; allowing us to distinguish patients that would benefit from an anti-inflammatory treatment.
C3-HNE levels are elevated in patients with IBD compared with HD. This increase is also observed in conditioned media from primary neutrophils activated with lipopolysaccharide (LPS) for six hours. Importantly, C3-HNE reflects the early stages of clinically apparent mucosal damage in experimental models of colitis. As such, this biomarker holds promise for identifying early mucosal injury or acute inflammation in the gastrointestinal tract. Nevertheless, additional studies are needed to evaluate its clinical validity.
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Blood-based biomarkers of type III collagen remodeling as surrogate markers of endoscopic disease activity in patients with ulcerative colitis
Introduction
The chronic inflammation of Ulcerative Colitis (UC) causes excessive extracellular matrix (ECM) remodeling, resulting in clinical complications. Currently, endoscopic evaluation remains the gold standard method for determining disease activity. However, novel methods are wanted due to its invasiveness and accompanying patient discomfort.
As type III collagen is a major component of the intestinal ECM and a target for multiple proteases catalyzing its remodeling in IBD, we sought to investigate two blood-based neoepitope biomarkers of type III collagen degradation, and fibrosis resolution as surrogate markers of disease activity.
C3M was elevated at Week 0 in UC patients with severe endoscopic disease activity according to the Total Mayo Score. The fibrolysis biomarker, nordicCTX-III™, was significantly elevated in patients with moderate endoscopic disease at week 0 and numerically elevated in mild disease compared to severe disease activity.
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Watch this webinar focused on tissue remodeling, inflammation and biomarkers for pulmonary diseases. Our panel of experts will shed light on the tissue changes occurring in pulmonary diseases including idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, and how this is affected by the intricate interplay between fibroblasts, epithelial cells, and immune cells.
Extracellular Matrix is an Active Agent in Lung fibrosis – Dr. Janette Burgess
The Role of the Epithelium in Pulmonary Fibrosis – Dr. Gisli Jenking
Prognostic and Pharmacodynamic Biomarkers for ECM Remodeling, Immune Cell Activity, and Endotyping – Dr. Jannie M. B. Sand
General discussion and questions
Scientific topics and speakers
The speakers will take you on a journey from discovering novel biomarkers to implementing them in clinical trials and clinical practice. They will discuss why blood-based biomarkers are needed for pulmonary diseases, and how biomarkers of ECM remodeling and immune cell activity may aid in the identification of novel endotypes and improvement of drug development.
Here’s a sneak peak of Dr. Janette Burgess’ talking points:
How changes in the composition of the ECM in lung fibrosis impact cellular function
How the ECM organization changes in lung fibrosis, and implications for disease driving processes
How matrix stiffness is altered in fibrosis and the cellular responses to these changes
How the above changes can be incorporated in model systems in vitro to expand our understanding of disease underlying mechanisms
Dr. Janette Burgess
Janette Burgess is a Professor of Extracellular Matrix in Disease Pathogenesis at the University Medical Center Groningen in the Netherlands.
She completed her Bachelor of Science (with honours) at the University of Adelaide, Australia, in 1991, and earned her PhD in Hematology at the University of New South Wales in 1998.
After a post-doctoral position at the University of Sydney focusing on the respiratory system’s structural changes in disease, she developed a keen interest in lung pathology.
In 2015, Janette was awarded a Rosalind Franklin Fellowship to join the University Medical Center Groningen, where she is now a tenured Professor.
Her research centers on understanding the role of the extracellular matrix (ECM) in lung pathology, investigating changes in lung tissue and airway structures during disease development.
Using primary human lung cells, tissue samples, and patient clinical information, her work aims to characterize ECM changes during lung diseases and uncover the underlying mechanisms.
Janette Burgess employs novel in vitro cell models, ex vivo human lung tissue models, and advanced microscopy imaging techniques to unravel the complex regulation of the ECM, exploring its potential as a therapeutic target for lung diseases.
Her research bridges basic science with the practical goals of preventing and treating human lung diseases that affect millions of people worldwide.
Dr. Jannie M. B. Sand
Dr. Jannie M. B. Sand is the head of the respiratory research department at Nordic Bioscience, having joined the company in 2010.
She holds a Master of Science in Molecular Biomedicine and a PhD in Clinical Research from the University of Copenhagen.
Dr. Sand’s research is dedicated to biomarker development and understanding lung tissue changes in chronic lung diseases, with a specific focus on pulmonary fibrosis and chronic obstructive pulmonary disease (COPD).
With over a decade of experience in biomarkers of lung tissue remodeling, she has authored over 50 articles, abstracts, and book chapters.
Her team at Nordic Bioscience focuses on developing non-invasive tools for specific lung disease processes, aiming to enhance understanding of pathologies and therapeutic effects.
The tools developed by Dr. Sand’s team include biomarkers for fibrogenesis, lung tissue destruction, basement membrane repair, and immune cell activity.
Their work spans both clinical and preclinical research, with a translational approach to bring tools to the broader community.
The team’s research has successfully identified prognostic and pharmacodynamic biomarkers and explores the identification of novel endotypes in chronic lung diseases.
Dr. Gisli Jenkins
Professor Gisli Jenkins is an NIHR Research Professor and holds the Margaret Turner-Warwick Chair of Thoracic Medicine at Imperial College London.
He serves as the Head of the Margaret Turner-Warwick Centre for Fibrosing Lung Diseases at the National Heart and Lung Institute, located at the Guy Scadding Building at the Brompton Campus.
Dr. Jenkins has honorary contracts with both the Royal Brompton and Harefield NHS Foundation Trust and the Imperial College Healthcare NHS Trust.
His primary research focus is on Interstitial Lung Diseases, with a particular emphasis on Pulmonary Fibrosis.
Prof Jenkins and his team strive to comprehend the biological foundations of pulmonary fibrosis, aiming to translate this understanding into improved outcomes for patients.
He is the Principal Investigator of several longitudinal observational studies, including the PROFILE study, the INJUSTIS Study, the UKILD Post COVID ILD study, and the DEMISTIFI Multi-Morbidity consortium.
Prof Jenkins serves as the pulmonary fibrosis working group lead for the Genomics England Clinical Interpretation Partnership in Respiratory Medicine, the PHOSP-COVID study, and the HEAL COVID platform study.
Recognitions include the ERS Gold Medal in Interstitial Lung Disease in 2020, Fellowship of the European Respiratory Society in 2022, and the role of President of Action for Pulmonary Fibrosis. He was also awarded the BTS Meritorious Service Award for 2022.
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Liver fibrosis is a progressive condition characterized by the excessive accumulation of scar tissue in the liver, often resulting from chronic liver diseases. Fibroblast activity plays a critical role in the progression of fibrosis, leading to organ function loss and liver-related complications. Liver fibrosis accounts for approximately 2 million deaths worldwide, while alcohol-related liver disease (ArLD) causes over 330,000 cirrhosis deaths globally every year.
In two recent studies, we investigated the fibrogenesis biomarker nordicPRO-C3™ in the context of advanced liver disease and full-spectrum fibrosis in alcohol-related liver disease. Our goal was to assess the nordicPRO-C3™ biomarker’s potential prognostic value and clinical utility as a predictor of outcome, and our results are very promising.
The nordicPRO-C3™ biomarker is capable of identifying advanced liver fibrosis and alcohol-related liver disease, providing a new clinical utility tool
In the first paper, published in JHEP Reports, we conducted investigations using two distinct cohorts of patients with compensated cirrhosis of mixed etiologies. In both cohorts, a 2-fold increase in nordicPRO-C3™ at baseline was associated with a significant hazard increase for liver-related events. Notably, nordicPRO-C3™ exhibited prognostic significance.
The identification of nordicPRO-C3™ as an independent prognostic factor for liver-related clinical outcomes has important implications for both drug development and clinical practice. By understanding the dynamic range of nordicPRO-C3™, researchers can improve its utility as a predictive marker in drug trials, enabling the development of targeted therapies to mitigate fibrosis progression and improve patient outcomes.
In a clinical setting, the integration of nordicPRO-C3™ measurement alongside established markers such as fibrosis-4 index (FIB-4) or transient elastography (TE) may enhance risk stratification and inform treatment decisions. Early identification of patients at higher risk for liver-related events can facilitate timely interventions, such as disease monitoring, lifestyle modifications, and appropriate therapeutic interventions.
In the second paper, published in Liver International, we assessed nordicPRO-C3™ models to predict liver-related events in patients with a history of excessive alcohol use but without a confirmed diagnosis of chronic liver disease. Our findings our promising for improving risk stratification and clinical outcomes in alcohol-related liver disease.
A prospective cohort study involving patients with alcohol-related Liver Disease (ArLD), was conducted and divided into a derivation cohort of secondary care patients and a validation cohort of primary care patients. Baseline variables, including nordicPRO-C3™, were utilized to develop a prediction model known as the ALPACA score. The prognostic accuracy of the ALPACA score was compared to existing tools such as the enhanced liver fibrosis (ELF) test, FIB-4, TE, and the ADAPT score (developed for fatty liver disease).
The ALPACA score demonstrated excellent discriminative accuracy in both the derivation and validation cohorts, comparable to TE and the ELF test, and superior to FIB-4, nordicPRO-C3™ alone, and the ADAPT score. Importantly, the ALPACA score provided reliable prognostic performance independent of the baseline fibrosis stage. This breakthrough has the potential to revolutionize risk stratification and patient management in primary and secondary care settings.
NordicPRO-C3™ has recently become available on the Roche-COBAS high-precision platform, paving the way for its commercial availability worldwide in the near future. This accessibility will enable widespread adoption of nordicPRO-C3™-based scores, leading to improved risk prediction and better outcomes for individuals.
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This webinar focuses on the intricate interplay between fibroblasts and arthritic diseases. Our panel of experts will unravel mechanisms behind tissue damage and repair, discussing fibroblast activation, collagen overproduction, and scar tissue formation.
Discover how blood-based biomarkers of extracellular matrix destruction offer insights into treatment effectiveness and patient well-being. Our speakers will also give insights into PRIME cells’ role in heralding rheumatoid arthritis flare-ups and delve into the molecular underpinnings of symptoms like pain and morning stiffness.
Agenda
Fibroblast Activation in Arthritis – Dr. Adam Croft
PRIME cells in Rheumatoid Arthritis Flares – Dr. Dana Orange
Identification of Fibrotic and Fibrolytic Endotypes in Rheumatic Disease Cohorts – Dr. Anne Bay-Jensen
We will explore how measuring tissue damage through blood markers can offer insights into treatment effectiveness and patient experiences. A segment is dedicated to PRIME cells, fibroblast-like entities in blood that signal rheumatoid arthritis flares. We will also delve into the molecular basis of symptoms like pain, morning stiffness, and flares in rheumatoid arthritis.
This webinar spotlights the buzz around developing fresh therapies targeting fibroblasts and fibrosis in arthritic diseases. By sharing the latest research, we aim to shed light on the specific roles and types of fibroblasts driving disease progression and outcomes.
Scientific topics and speakers
In this edition of the ECM Pharmacology Symposium Series, we’re diving into the realm of fibroblasts and their relevance in arthritic diseases. These cells are key players in disease progression, responsible for crafting collagen and extracellular matrix proteins that build the foundation of tissues. In arthritic conditions, activated fibroblasts kick into overdrive, generating excess matrix components, leading to the formation of scar tissue, or fibrosis, with potential impact on joints and tissues.
We will explore how measuring tissue damage through blood markers can offer insights into treatment effectiveness and patient experiences. A segment is dedicated to PRIME cells, fibroblast-like entities in blood that signal rheumatoid arthritis flares. We will also delve into the molecular basis of symptoms like pain, morning stiffness, and flares in rheumatoid arthritis.
This webinar spotlights the buzz around developing fresh therapies targeting fibroblasts and fibrosis in arthritic diseases. By sharing the latest research, we aim to shed light on the specific roles and types of fibroblasts driving disease progression and outcomes.
Dr. Adam Croft
Dr. Adam Croft is a Professor of Translational Rheumatology at the University of Birmingham and also serves as a Consultant Rheumatologist at University Hospitals Birmingham.
He holds a senior research fellowship from the Kennedy Trust for Rheumatology Research.
Dr. Croft’s research program encompasses the entire spectrum of inflammatory arthritis, spanning from children to adults.
His goal is to establish connections between synovial tissue pathology and specific disease outcomes and treatment responses.
He places a strong emphasis on the discovery of novel and actionable therapeutic targets, leveraging cutting-edge single-cell profiling technologies.
Dr. Croft’s research is particularly focused on understanding the role of tissue resident fibroblasts in perpetuating inflammation in immune-mediated inflammatory diseases and finding therapeutic strategies to target these cells effectively.
Dr. Dana Orange
Dr. Dana Orange, MD, MSc, holds the position of Associate Professor of Clinical Investigation at Rockefeller University and serves as an Assistant Attending of Rheumatology at the Hospital for Special Surgery.
She earned her medical degree from Weill Cornell Medical College, Cornell University, and obtained her MSc from Rockefeller University.
Dr. Orange completed her Internal Medicine Residency at New York Presbyterian Hospital and her Rheumatology Fellowship at the Hospital for Special Surgery.
Her research is dedicated to unraveling the molecular mechanisms behind symptoms associated with rheumatoid arthritis, including pain, morning stiffness, and flares.
Dr. Anne Bay-Jensen
Dr. Anna Bay-Jensen serves as the Chief Technology Officer (CTO) and Director of ImmunoScience at Nordic Bioscience, where she has been part of the team since 2008, starting as a post-doc and advancing to leadership roles.
She is recognized for her hard work, innovative thinking, and leadership in the development of novel biomarkers that support precision medicine, an ongoing journey.
Dr. Bay-Jensen’s research primarily focuses on biomarkers related to rheumatic diseases, with a particular emphasis on joints and rheumatoid arthritis, a field she has dedicated two decades to.
She has an impressive academic record with 10,459 citations, an h-index of 60, and an i10-index of 191, reflecting her significant contributions to the field.
Her research has highlighted the importance of extracellular matrix remodeling as a common denominator in connective tissue diseases and the development of novel combinations of post-translational modification (PTM) neo-epitopes as tissue-specific biochemical markers.
We have collected some of our best publications that we and our collaborators worked on in the second quarter of 2023—in no particular order. We invite you to browse and read according to your interests!
Hepatology
Alcohol-related liver disease (ArLD) leads to progressive liver-related outcomes and death, necessitating vigilant monitoring. Examining patients with ArLD over an average of 5.2 years, the PRO-C3-based score known as ALPACA (PRO-C3/AST/ALT, Platelets) demonstrated remarkable prognostic capability for liver-related events.
Comparatively, FIB-4, single markers like PRO-C3, ADAPT, ELF, and liver stiffness measures were all surpassed by the predictive efficacy of the ALPACA score in assessing outcomes for ArLD patients.
Fibronectin is a key protein for matrix organization and has been described as the glue of the extracellular matrix. The novel biomarker FN-EDB targets a degradation fragment of cellular fibronectin and showed to be elevated in patients with idiopathic pulmonary fibrosis.
This new biomarker enables quantification of a vital matrix embedded protein – laying the groundwork for important future studies.
In this study, we explored three collagen type III markers in the kidney’s interstitial matrix. These markers exhibited varied expressions and associations with inflammation, kidney function, and fibrosis in IgA nephropathy patients.
These findings emphasize the significance of selecting appropriate epitopes for distinct organs and diseases. Notably, urinary C3M emerges as a potential non-invasive fibrosis biomarker, complementing kidney biopsies in IgA nephropathy.
In our second renal publication, We examined whether collagen type III fragment C3M relates to inflammation markers and endothelial dysfunction, predicting chronic kidney disease (CKD) progression in type 2 diabetes patients with microalbuminuria.
Inflammatory markers and select endothelial indicators correlated with baseline serum C3M. Doubling serum C3M predicted CKD progression (accounting for mortality risk) post-conventional factor adjustment. These findings highlight serum C3M’s dual role as a CKD risk predictor and inflammation marker in type 2 diabetes.
Biomarkers aren’t just confined to different omics categories; various classes are referring to the types of serological measurements.
Consider cytokines, growth factors, receptors, kinases, transcription factors, intracellular proteins, extracellular proteins, and a subset within that—Extracellular Matrix (ECM) proteins. The common denominator in most pathologies is a loss of balance between different ECM proteins, especially collagens.
Biomarkers are more than just omics categories
This excessive destruction and deposition of proteins significantly propel the progression of end-stage diseases, culminating in organ dysfunction, failure, and, ultimately, death.
Diverse cytokines and growth factors orchestrating via specific receptors and kinases lead to ECM destruction and deposition, making ECM the converging pathway for multiple stimuli.
By the end of the day, what matters is to reverse ECM deterioration, or even undo, organ damage and function decline. Reversing organ damage can be achieved by stopping ECM deterioration. To truly reverse organ damage and restore organ functionality in patients, we need to repair the ECM to its normal balance.
We at Nordic Bioscience believe that the answer lies in effecting change at the tissue level—the key to reversing organ damage and, in turn, revitalizing organ function.
Have you considered if your treatment or pathway is affecting tissue formation or degradation? If so, feel free to browse our unique ECM biomarker portfolio.
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