Research

Scientists are fascinated by Dupuytren’s, and many of them are trying to unravel the mystery of why patients develop these problems. Here is a list of some of the research projects going on at the moment, it is unlikely to mention all research because we may not have permission to mention ongoing projects or we may not know about them.  The order in which they are presented is arbitrary and does not in any way indicate our support or success in the field.

The Netherlands

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The Team working under Prof Paul Werker in the University of Groningen, the Netherlands has provided us this information about their research. We received this description of their research from Dieuwke Broekstra:

During the past years, the Department of Plastic Surgery of the University Medical Centre Groningen initiated a large study on the genetic background of Dupuytren disease. This study was done in cooperation with medical centres in the Netherlands, England and Germany.  Several genes were identified to be involved in Dupuytren disease, and we found that the Wnt signalling pathway plays an essential role in the disease pathology. This research project has been continued, focussing on cell biology processes, including the Wnt pathway, that form the origin of Dupuytren disease and associated fibromatoses. This leads to a better understanding of the pathology, and provides valuable information on possible starting points for future treatment options.

Additionally, the Department of Plastic Surgery is also involved in research about epidemiological aspects of Dupuytren disease. For instance, we determined the prevalence of Dupuytren disease in the general elderly population in the city of Groningen, which was 22%. Furthermore, we investigated disease patterns and started a study to follow the course of Dupuytren disease. The latter is a longitudinal cohort study including 262 Dupuytren patients with various disease stages. Every 6 months, the hands of the participants are examined to record the disease progression in detail. Eventually, the data of this study will be used to identify factors that predict the course of the disease.

Next to that, our department also focusses on the anatomy of Dupuytren disease. Despite the fact that the condition has first been described in the early 17th century, the patho-anatomy is largely unexplored. This knowledge can contribute to a successful treatment, since many treatment options require a detailed knowledge of the anatomy.

Finally, our department has been involved in various research projects concerning the surgical treatment of Dupuytren disease. It was found that limited fasciectomy (resection of diseased tissue) provides a more durable result than percutaneous needle fasciotomy (dissection of the cord with a needle). However percutaneous needle fasciotomy also demonstrated several advantages compared to limited fasciectomy: quick recovery and a low chance of complications. New innovations in treatment and diagnosis of Dupuytren disease are also subject of research. For instance, we recently started a research project to determine the added value of ultrasonography in prevention of complications that can occur after treatment. In addition, we are investigating whether it is possible to predict Dupuytren disease progression using ultrasonography.

Belgium

 Leuven RU

 

 

 

Dupuytren-Fonds, Leuven University Hospitals, Belgium. Text submitted by Prof Dr Ilse Degreef.

On November 17th 2016, we celebrated the inauguration of the Dupuytren funding organisation, an initiative of Prof Dr Ilse Degreef and Prof Dr  Luc Smet at Leuven University.

With this foundation, both clinical researchers and patient organisations will work together to improve treatment outcome and patient satisfaction in Dupuytren disease. Clinical hand practice at the academic centre is focussed on Dupuytren treatment and the improvement of it. With a multi-disciplinary approach, we aim to inform the patient correctly and completely and offer all available treatment, so the patient can make his or her own decision if interventions are considered in the disease management.

Inspired by the PhD work of Ilse Degreef, presented in 2009, the work and research on Dupuytren disease continued ever since. The PhD was titled ‘Therapy resisting Dupuytren disease: new perspectives in adjuvant treatment’. Epidemiological research was done to estimate the prevalence and identify patients at risk of progression to severe disability. This disability in Dupuytren disease and the influence of the extend of the disease was studied. basic research was focused on myofibroblast activation and its relation to recurrent contractures. The influence of surgical techniques on outcome and recurrence was evaluated and we concluded that recurrence was independent of the technique: ‘the surgeon can cut out the cords but not the disease itself’. Finally, innovative treatment options were introduced in therapy-resisting disease: the use of cellulose implants to isolate the skin and augment the firebreak effect of segmental fasciectomy appeared to improve outcome. The first Level 1 trial on neo-adjuvant pharmacotherapy demonstrated a role for possible disease control in the future.

Today, this work is continued. At the university, 2 PhD student, a clinical fellow, 3 residents and many medicine, physiotherapy and orthopaedic technician students work together in our team in a multi-disciplinary clinical and lab research project. We focus on translational research: putting bench into practice.

At Leuven University, today we focus on:

– The genetic background of Dupuytren disease in collaboration with the Laboratory of Complex Genetics

– The development of a lab animal model and research on the cellular function of the myofibroblast, in collaboration with both The research centre for Skeletal Biology & Engineering, and Molecular Digestive Oncology

– The influence of stem cells in collaboration  with the Peyronie Research Group

– Radiotherapy in therapy-resisting Dupuytren in collaboration with the Centre for Experimental Radiotherapy

– Clinical research on orthesiology, splinting and external fixation in collaboration with the Faculty of Kinesiology and Rehabilitation Sciences, IORT and the VIGO group

– Clinical outcome translational research on surgery and collagenase treatment in the Hand Unit at Leuven University Hospitals, Orthopedic Department.

DeGreef1Official inauguration of the Dupuytren Fonds at leuven University with Rector Rik Torfs (left) and Prof Dr Luc De Smet and Prof Dr Ilse Degreef (right)

 

 

 

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(left to right) Prof Dr Luc De Smet, Prof Dr Ilse Degreef, Francois Mathys of the Belgian Patient Society and Rector Rik Torfs of Leuven University

 

 

 

 

 

 

Canada

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A team led by Prof David O’Gorman in Canada has given us this explanation of what they are working on:

The Cellular and Molecular Research Laboratory at the Roth McFarlane Hand and Upper Limb centre in London, Canada was originally established by Dr Robert McFarlane, one of the pioneers of Dupuytren’s disease research. Our current research program is focussed on modelling Dupuytren’s disease development using human cells in bio-artificial “tissues” in the laboratory, and the use of these models to identify new avenues of therapeutic intervention. Our research is currently funded by the Canadian Institutes of Heath Research  (CIHR), the Canadian equivalent of the National Institute of Health (NIH).

Our current research interests include molecules that reside in the “matrix ” secreted by the cells that cause Dupuytren’s disease. Some of these molecules supply “positive feedback” to promote Dupuytren’s disease progression and recurrence, and may have utility as novel therapeutic targets. We are also assessing the feasibility of immunizing patients against disease promoting molecules with the aim of minimizing the rate of Dupuytren’s disease recurrence after surgical or other treatments.

From Mr James J Armstrong, an MD/PhD student in the Roth MacFarlane Centre we received this description of his research:

Further efforts in our lab have been focussed around creating artificial tissues that mimic real world Dupuytren’s disease affected human tissues. As there is not yet a widely accepted animal model for Dupuytren’s disease, it is our hope that through recent advances made in tissue engineering, a robust artificial fibrosis model can be created. Such a model could greatly aid in not only the study of Dupuytren’s disease, but also many other fibrotic diseases and avoid many of the practical and ethical issues that are inherent to animal models.


 United States

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Dr Charles Eaton provided us with this summary of their goals and activities.

The Dupuytren Foundation is conducting research to develop a blood test for Dupuytren disease. A blood test is the missing piece of the puzzle needed to develop and test medical treatments for Dupuytren disease and related conditions. Right now, the ruler, protractor and camera are the only non surgical tools to measure a persons Dupuytren/Ledderhose disease. These only show what has already happened, not what is happening right now. A blood test could show what is happening right now, including the biologic response to medical treatment or to changes in diet, physical activity, or other lifestyle changes – before any changes in lumps or angles. A blood test could be used to test medical treatments for Dupuytren disease more quickly and accurately than has ever been possible.

The first goal of the  Dupuytren Foundation’s International Dupuytren Data Bank (IDDB) is to develop a Dupuytren blood test. This research is organised in three stages. Stage one is a large online survey of people with Dupuytren/Ledderhose disease – severity, how it impacts their life, and how other medical factors relate to their disease. Stage two is collecting blood samples from stage one participants and analysing these samples for genetic, immune, inflammation, dietary and other factors. Stage three is comparing blood test finding with the severity of Dupuytren disease. Stage one launched in 2015 and is growing daily. Stage two and three will be repeated in competitive cycles. Each cycle will select groups based on disease severity, collect their blood samples, and identify the best blood tests to repeat in the next cycle. Following cycles will do the same with more people and fewer tests until the best tests are confirmed. This strategy is designed to reduce overall costs. This strategy of repeated testing is also the fastest way to confirm the accuracy and reliability of a test available to all researchers to develop a cure for Dupuytren disease and related conditions. IDDB online enrolment is http://Dupstudy.com. 

 

Pittsburgh University

 

 

In Pittsburgh, USA a team led by Dr Latha Satish MSc, PhD and Dr Sanjeep Kathju MD, PhD are working towards developing an animal model for studying the behaviour of Dupuytren’s tissue and understanding the differences between Dupuytren’s and non-Dupuytren’s cells, especially the expressions of genes and how the process could be influenced by medication.

Dr Satish kindly provided us with this explanation of the research:

Drs Latha Satish MSc, PhD and Dr Sandeep Kathju MD, PhD at the Department of Plastic Surgery, University of Pittsburgh, USA have been collaborating for many years now to understand the pathophysiology and the gene expression changes that contribute to the progression and/or recurrence of Dupuytren’s contracture. Our previous data examining the global gene expression patterns of DD-derived fibroblasts versus control carpal tunnel (CT)-derived fibroblasts confirms that there are numerous differences in their transcriptomes (mRNA expression) even in in vitro culture, indicating a stable intrinsically distinct disease pathology for DD-cells. Recently, for the first time, we have described an animal model for Dupuytren’s disease at the physiologically relevant orthotopic location. We also showed that gene expression differences seen between CT- and DD-derived fibroblasts persisted even in in-vivo. Using the animal model that we have developed which shows increased evidence of fibrosis in the forepaw that received the DD cells compared to CT cells we are currently pursuing with novel therapeutic interventions to diminish the DD-dependent fibrosis. We are also in the process of refining the animal model to recapitulate the disease completely. Our research is being funded by Private Donor Donation, Department of Plastic Surgery and the Pittsburgh Foundation.


United Kingdom

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At the Kennedy Institute of Rheumatology of the Oxford University, UK, a team led by Professor Jagdeep Nanchahal BSc, PhD, MBBS, FRCS, FRSC(plast) has started clinical trials for a revolutionary type of treatment. Ms J Swettenham Phd and RIDD trial manager provided us with this explanation:

  The RIDD trial is investigating whether injections of anti-TNF can help early stage Dupuytren’s disease. The trial has two parts- the first part is a dose response study in which patients with moderately advanced disease with finger contracture, who are due to have surgery to removed the diseases tissue, are given an injection of either anti-TNF or a placebo. The removed tissue is then examines at the labs in Oxford to see the effects of anti-TNF at different doses on the Dupuytren’s cells. The second part of the trial is looking at whether anti-TNF slows or prevents the progression of Dupuytren’s in patients with early stage disease. The progression of the disease will be followed for 18 months and the trial team will be looking to see if people who have received anti-TNF therapy show regression of the nodules and whether they are less likely to need surgery. Anti-TNF therapies have a well-established safety profile and have been used worldwide for around twenty years to treat disorders such as rheumatoid arthritis and Crohn’s disease.

The RIDD trial is a translational study, meaning that it has been developed using knowledge gained from lab-based experiments. These experiments have shown that Dupuytren’s nodules contain high numbers of cells called myofibroblasts, which normally help repair wounds by producing proteins that bridge the would and then contracting to pull the wound together. In Dupuytren’s disease these scaffolding proteins develop into fibrous cords just under the skin of the palm. The contractions of the myofibroblast cells then pull on the cords and curl the finger irreversibly towards the palm. Using tissue samples collected during surgery, Professor Nanchahal’s group have shown that TNF (tumour necrosis factor) produced by inflammatory cells causes precursor cells to change into myofibroblasts – but only in people with Dupuytren’s disease. They have also found that drugs which block TNF reduce the activity of the myofibroblast cells. These results led to the development of the RIDD trial and the lab work is continuing to further explore the mechanisms of the disease. All of the lab work is made possible by the donation of Dupuytren’s tissue by patients having surgery.

The group is also starting a study called Dupuytren’s in Society Outcomes (DISCO) to find out more about Dupuytren’s disease in the community. People with Dupuytren’s disease at any stage are invited to complete a short questionnaire so the researchers can find out more about the impact of the disease and its progression. The GP records of some practices will also be screened to find out the prevalence of Dupuytren’s disease.

You can find out more about the research group on their website: www.dupuytrenstrial.com.  The RIDD trial is registered on the European Clinical Trials Database (EudraCT: 2015-001780-40)

UEA

In Norwich, UK a team led by Prof Ian Clark is working on gene expression in Dupuytren’s, tissue markers called MMP’s and other small biochemical molecules that influence the pathway for collagen production. 

They have used excised Dupuytren’s tissues and blood samples taken at the time of surgery to extract RNA and measure gene expression, and proteins (MMP’s) in the blood. This was correlated to pre-and post operative scores for extension deficit (contracture) of the fingers and grip strength. For control tissue they used carpal tunnel fascia removed from patients who did not have Dupuytren’s.

Circulating MMP14 proteins correlated to extension deficit measurements. This may be used as indicator to predict surgical outcome. Similar measurements at 1 year follow up will be taken.

 

Nottingham

 

 

 

Mr Jeremy Rodrigues BSc(Hons), MBChB(Hons), MSc, PhD, MRCS has written a thesis called ‘Assessing the outcome of surgery for Dupuytren’s Disease of the Hand’ at the University of Nottingham, ROD, under Profs Davis, Scammell and Zhang.

The project was made possible by competitive awards from the British Society for Surgery of the Hand (BSSH) and Nottingham Orthopaedic Walk charity, and by participation from the following hand surgery centres:

– Derriford Hospital, Plymouth

– Pulvertaft Hand Centre, Royal Derby Hospital, Derby

– Queen’s Medical Centre, Nottingham

– Rotherham General Hospital

– St Johns Hospital at Howden. Livingston, Scotland

It was supported by a NICE Scholarship. The aim was to assess the outcome of Dupuytren’s surgery, and to look at the outcome measures to do this, as a service evaluation of standard NHS surgery.

Mr Rodrigues collected evidence from previously reported trials and studies and also measured people before and after planned NHS surgery at five hand centre across the UK. He compared different outcome measures that are used in Dupuytren’s disease (such as finger joint angles and questionnaires about the hand like the DASH and URAM).

The main findings include the following:

– There have not been enough trials comparing treatments or outcomes in Dupuytren’s disease.

– Joint angle measurements can be influenced and so may not be as reliable as we think.

– Patients have unique goals for surgery that are not necessarily well represented when measuring joint finger angles.

– Neither the DASH nor the URAM may be ideal questionnaires when measuring Dupuytren’s disease.

– Open surgery, where the disease is removed by cutting it out is more likely to cause problems, or complications, such as stiffness in the hand, compared to needle aponeurotomy (needle fasciotomy).

– Although Dupuytren’s disease tends to come back more following less aggressive treatment, it still seemed to achieve  similar hand function to more aggressive surgery, possibly because of less damage to the hand from the treatment itself.

– People may need to see bigger improvement in how their hand works before they think surgery has been ‘worthwhile’ (for fasciectomy or dermofasciectomy) compared to after a needle aponeurotomy.

– The characteristics of people that are more likely to have poor outcomes from surgery for Dupuytren’s disease are different from the characteristics of people who are more likely to have their Dupuytren’s disease come back, or recur.

A better understanding of the outcome of treating Dupuytren’s Disease and how it should be measured was achieved. Further work should examine the validity of other outcome measures, offer a qualitative investigation of patients’ experiences and patient-centred high quality randomised controlled trials.

More of his work can be found here.

 

New Zealand

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Recent discoveries give hope for more effective treatment of Dupuytren’s disease.

People suffering from Dupuytren’s disease could ultimately regain the function of their hands and quality of life, thanks to the work of the Gillies McIndoe Research Institute  in New Zealand.

Dupuytren’s disease causes one or more fingers to curl into the palm due to the contracting and toughening of connective tissue under the skin of the palm. While surgery is commonly used to remove the contracted tissue, ultimately it can lead to hand deformity and impaired function, and not uncommonly it leads to amputation.

The Gillies McIndoe Research Institute’s discovery of aberrant stem cells, thought to be the origin of this challenging condition, has recently been published in a paper titled ‘Embryonic Stem Cell-like Population in Dupuytren’s Disease’ in Plastic and Reconstructive Surgery, widely regarded as the world’s most prestigious plastic surgery journal. The research team, led by Dr Swee Tan, has gone on to discover an in-built regulatory system that controls the aberrant stem cells in Dupuytren’s disease. Their findings, contained in a separate paper titled ‘ Embryonic Stem Cell-like Population in Dupuytren’s Disease Expresses Components of the Renin-Angiotensin System’, has been accepted for publication in the same journal.

The findings are especially significant to the medical research field and to many people throughout the world as the discoveries may be fundamental to the development of a novel and effective treatment for this unsolved medical problem.

 


Australia

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In Australia a group of scientists, notably Swaminathan Iyer, PhD and colleagues from The University of Western Australia, the Fiona Wood Foundation and Royal Perth Hospital Burns Unit, and Pharmaxis Ltd are working on a LOX (lysyl oxidase) inhibitor, that has the potential to prevent crosslinking between collagen fibres (LOX promotes this crosslinking). The product has been tested in vitro, and now they are at a stage to start trials in Dupuytren specific settings, animal models and eventually in patients. It is hoped a topical application will be possible, also for burns and keloid patients.


 Iraq

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In the Biotechnology Research Centre of Al-Nahrein University in Baghdad, Dr Niyaf Alkadhem and colleagues have examined the effect of caffeine on Dupuytren’s fibroblasts. Since caffeine was proven to reduce fibrosis in rodents, they cultured fibroblasts in experimental models, and stimulated them with TGF-b to transform into myofibroblasts. Then some cultures were treated with caffeine which resulted in less proliferation and less alpha-smooth muscle actin than the untreated ones. However when the cells were grown under tension caffeine failed to have an effect on contraction. Therefore the conclusion was that caffeine affects cellular pathways relating to migration rather than contraction or tension generation. Treating existing fibrotic conditions with caffeine may prove challenging for this reason.

 
Israel

Rubin and colleague Rinott 

In Afula, Israel a team of scientist led by G Rubin, MD has performed a trial using bromelain injections (found in pineapple juice (NexoBrid®)) into Dupuytren’s cords, to ascertain if the enzyme is capable of disrupting the collagen strands and breaking the cord. The study was done in a laboratory on cords that were removed from patients, and the results were promising. The next step will be safety studies to make sure injecting the solution into people is well tolerated. A publication on the study can be found here.  2016 Rubin et al. Bromelain for enzymatic fasciotomy