Research News Will_Doc Spot Oct 2013 06/05/2014 15:50 Page 1
RESEARCH NEWS SHEET Issue No. 1 May 2014 This newsheet contains general news from centres around the country
Research News Royal Free An overview of current laboratory research into scleroderma at the Royal Free Hospital.
The same medications may be useful in scleroderma but more research is needed.
Scleroderma remains a very challenging disease but there is progress being made in understanding the basic mechanisms that lead to the disease and also in developing Prof Chris Denton treatments that may help patients. Fortunately there is a very strong international and UK research effort that is starting to unravel the secrets of the disease and scientists at the Royal Free are working hard in a number of areas.
Genes and Genetics
The following summarises some of the research that is ongoing and current concepts about the way scleroderma develops. Cells and proteins Cells make up all the tissues of the body such as skin, muscle and bone and some of these cells, called fibroblasts, produce connective tissue that is made up of proteins such as collagen. In scleroderma there is an over-production of proteins such as collagen and this leads to thickening or scarring of the skin, blood vessels and internal organs. Current research is leading to a better understanding of the origins of fibroblasts and the ways in which they are activated in diseases such as scleroderma. In particular it seems that cells can transform or change into fibroblasts and this is part of normal wound healing but is altered in scleroderma and other fibrotic diseases. The immune system Normal good health depends upon the body fighting infection but the immune system can become overactive or start to react to your own cells and then it can cause damage, Scleroderma is one of many diseases in which this occurs and it appears to be one factor that worsens or sustains the disease. More is being understood about the immune system and the precise ways in which it can go wrong in scleroderma. This is important because it can be a target for treatment. There are many drugs that reduce the immune system over activity and these have often been developed for other diseases such as arthritis.
It is now understood that all humans are genetically different but also that some genetic factors are shared and may contribute to the development of disease. In very complex and uncommon diseases such as scleroderma, as it seems likely that very many genetic factors come together in someone that develops the disease. Therefore although there is a genetic component it cannot usually be passed on in the family because the combination of genes that is relevant only occurs rarely and by chance. It explains which features such as Raynaud’s may be inherited even if scleroderma is not. Blood vessels The blood vessel abnormalities are central to scleroderma. They cause Raynaud’s phenomenon and also underlie serious complications of the disease such as kidney disease and pulmonary hypertension. Research is using models of pulmonary disease in the laboratory to better understand the cell types involved and this is leading to better ways of testing treatments that may improve outcomes for scleroderma patients. Cellular networks in scleroderma The result of ongoing research efforts is that it is now possible to develop a network of cells that appear to be functioning abnormally in scleroderma and the way that these cells communicate may underlie the development of the disease. Research is focusing on identifying the signals that allow cells to communicate with each other and with the environment of the cell which is altered in diseases like scleroderma. In this way new treatments are likely to emerge that could modify multiple cell types and so be effective in the clinic. Clinical trials are ongoing to try and work out which of the emerging new possible treatments is the most promising and also safest, so that it can be used in clinical trials in scleroderma. Clinical trials provide the most important way to translate theory into practice in a way that helps patients. Professors Chris Denton and David Abraham, Centre Directors, Royal Free Hospital
Helpline: 07530 810 964
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Research News UCL & Royal Free This is a report carried out by Professor Anton Emmanuel (left) at UCL London together with Dr Charles Murray (right) at the Royal Free Hospital on incontinence in scleroderma (SSc).
publication. This has shown that SNS is not a beneficial intervention for the majority of SSc patients in the longer term. This paper is an important one in as much as it may avoid SSc patients having an un-necessary and invasive option to manage their incontinence. This work has been dependent on the work the RSA have funded in allowing us to review our data and find a group abroad to collaborate with.
Two trials are currently in progress due to generous funding from the RSA. The first is a randomized control trial of posterior tibial nerve stimulation (PTNS) in scleroderma faecal incontinence. This received ethics approval in February 2013 and patients seen in clinic who were keen to participate have been enrolled immediately. Patients continue to be enrolled as they are seen weekly. So far a total of 29 patients are enrolled in this study.
The other study is a randomized controlled trial using Prucalopride, a drug licensed for constipation. It is hoped to show benefit in those scleroderma patients with constipation refractory to conventional treatments. As the study involves investigating the effects of a drug in patients this is still in the process of approval. As things stand important ground has been made with SHIRE, the company responsible for the drug, to provide a placebo product as well as the drug. In addition they have secured us a company providing us with manpower to safely randomize patients at UCL should they need to be admitted to hospital for any reason. Our research and development department together with our designated pharmacist at UCL is currently reviewing the paperwork involved including the protocol and patient information leaflets so that these are to standard for submission to the medicines and healthcare regulatory authority (MHRA) and ethics board. At least 16 patients are currently lined up for the trial and it is hoped to get them enrolled as soon as approved.
Preliminary results from this trial are very promising and an abstract for the Digestive Diseases Week (DDW) conference has recently been submitted. The trial has been successful in showing a significant improvement in faecal incontinence symptoms in 13 scleroderma patients who completed 12 weeks of PTNS therapy by September 2013. As this trial is on going it is hoped to enroll at least 50 participants in total to make this trial statistically significant, thus proving that PTNS is a beneficial treatment for scleroderma patients. A review of 7 SSc patients who have undergone SNS has also been completed and the data has been added to that of a group in Denmark and generated a paper being sent in for
Professor Anton Emmanuel UCL London
Research News Bath Dr John Pauling was appointed as a consultant rheumatologist in September 2012 after completing a doctoral fellowship under the supervision of Professor McHugh at the Royal National Hospital for Rheumatic Diseases in Bath studying Raynaud’s and scleroderma. His fellowship was part funded by the Raynaud’s & Scleroderma Association. He set up a dedicated Raynaud’s and Scleroderma Clinic, which he continues to lead and develop. He works as part of a team of clinicians interested in connective tissue diseases in Bath where combined clinics are run with respiratory clinicians, cardiologists and dermatologists to meet the complex needs of patients with scleroderma. They are happy to meet patients with Raynaud’s and scleroderma for diagnosis and to provide patient education regarding their condition and advice on management. The Royal National Hospital for Rheumatic Diseases has longstanding interests in autoimmunity in scleroderma and noninvasive microvascular imaging. The unit has an international reference laboratory for rare autoantibodies in connective tissue diseases and is currently planning work to look for new antibodies in scleroderma, which will shed further light on the causes of the disease and provide new methods to assist in
the early diagnosis of scleroderma. Dr Pauling is developing their interest in microvascular imaging and multicentre studies are in the pipeline to study laser Doppler imaging alongside other scleroderma centres within the UK (Manchester, London, Leeds and others) and laser contrast speckle imaging with scleroderma centres from the USA (Utah, Pittsburgh, California). This work is designed to better understand the Dr John Pauling relationship between blood vessel abnormalities and fibrosis (scar tissue formation) in scleroderma, and to help to develop new methods for assessing disease severity and response to treatments in scleroderma. The team members of the UK Scleroderma Study Group and International Scleroderma Clinical Trials Consortium and have recently supported multicentre clinical trial initiatives in scleroderma such as the ESOS, DUO and CAP studies. Dr John Pauling Royal National Hospital for Rheumatic Diseases
Helpline: 07530 810 964
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Research News The Brompton Hospital Investigation into the role of gastro-esophageal reflux in pulmonary fibrosis in scleroderma. Lay summary Scarring of the lungs is common in patients with scleroderma and is one of the main cause of death. Patients Dr Elizabeth Renzoni with scleroderma frequently have problems with their esophagus, the food pipe that leads into the stomach. Normally, a small circular muscle at the base of the esophagus opens to allow food to pass into the stomach and closes to keep the digestive fluids from flowing back up into the esophagus. In patients with scleroderma, the muscle may become weak and no longer close properly. Gastroesophageal reflux (GER) is the medical term for reflux of stomach contents into the esophagus. Our hypothesis is that small amounts of GER can move back up into the esophagus and get inhaled into the lungs, and may be one of the triggers for lung scarring. We propose to look for certain substances normally only found in the stomach in the “exhaled breath condensate” which is collected by breathing comfortably into a cooled cylinder, allowing the breath to condensate.
Professor Athol Wells
In a smaller group of patients, we also plan to perform a bronchoalveolar lavage, a more widely studied test in which a small amount of fluid is introduced into a small part of the lungs through a fine tube, and then removed for examination, to evaluate whether the two tests provide similar measurements. We will also evaluate the correlation between these molecules and other tests, including lung function, and markers of lung scarring activity, and tests to look at how the esophagus is working so that we can get a clearer picture of how this affects patients’ daily lives. Finally, we will be following up patients over time with lung function to see whether evidence of GER into the lungs is linked with a greater likelihood of worsening of lung scarring in the future. This is an RSA funded project (prospective observational study). Dr Elizabeth Renzoni is consultant respiratory physician at the Royal Brompton Hospital and honorary senior lecturer at Imperial College, London.
Research News Leeds Scleroderma update The Leeds Scleroderma (SSc) Clinical and Research Programme overseen by Drs. Buch and Del Galdo respectively, is growing exponentially, with development in wide-ranging clinical, translational and basic research initiatives. On the clinical front, we deliver a Dr Maya Buch weekly nailfold capillaroscopy service run by Dr. Buch with clinical research fellows, Dr. Bissell and Dr Abignano – this allows alignment of an effective clinical service for early diagnosis of SSc with research aims towards identifying predictive factors for the development of SSc. To facilitate this, we are also routinely assessing patients with 2 imaging techniques, called thermography (to assess heat distribution reflecting blood flow) in the fingers and optical coherence tomography (a technique like ultrasound, but using light instead of sound) to obtain highly detailed images of the skin that can serve like a biopsy. Dr. Buch is also developing a programme on cardiovascular involvement in autoimmune conditions; with Dr Bissell’s PhD including an initial project that aims to understand and identify early signs of cardiovascular involvement in Scleroderma, partly funded by a Raynauds & Scleroderma Association grant. We are also increasing our involvement in clinical trials of new drugs, drawing from our vast experience in other rheumatological conditions such as rheumatoid arthritis. Prof. Redmond oversees research related to foot and ankle (biomechanical) problems associated with SSc – podiatrists and research fellows, Ms. Alcacer-Pitarch and Ms. Loughrey are currently undertaking PhDs to investigate foot health in SSc and the basis for development of calcinotic deposits in SSc, respectively. Biomarker research to identify blood markers that can predict development of SSc as well as identify patients at risk of poorer outcome is one of the main focuses of the Research programme. This research, conducted by Dr Abignano (alongside the imaging methods described above) is now supported by the Department of Health (NIHR)-funded research platform called Diagnostic Evidence Cooperatives (DEC). Through this initiative Dr Del Galdo, with the help of biostatisticians and health economic experts is promoting the adoption of the research findings, by the NHS. Furthermore, within the Scleroderma Research programme, Dr. Del Galdo is developing several lines of basic research work that aim to understand the processes that lead to fibrosis (scarring) and to the defective circulation characteristic of SSc, with the aim of identifying potential targets for future drug development. Dr Maya Buch Leeds
www.raynaudsandscleroderma.co.uk
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Research News Salford and Manchester Salford Royal Hospital, a University of Manchester teaching hospital, has for many years been a referral centre for patients with scleroderma and/or Raynaud’s phenomenon. Over 300 patients with scleroderma are under regular review, and many of those who attend have very kindly agreed to participate in research projects. We have an active research Professor Ariane Herrick programme which investigates different aspects of pathogenesis (causation), measurement, and treatment of scleroderma and of Raynaud’s phenomenon. This involves collaborations with clinicians and scientists across Manchester, as well as from elsewhere in the UK and abroad. We also encourage undergraduate and postgraduate students, Allied Health Professionals, and specialist registrars to become involved in research. Our research is dependant upon the goodwill of the patient volunteers who participate in clinical studies and who donate blood samples and skin biopsies for research. We have a particular interest in vascular (blood vessel) physiology, and we have two well-equipped temperature-controlled vascular laboratories. The methods we use include thermography (which measures surface temperature), nailfold videocapillaroscopy (which assesses the small blood vessels of the finger, which are very abnormal in scleroderma) and laser Doppler imaging (which measures blood flow). Ongoing studies include:
2. Development and application of novel optical techniques to examine the inter-relationships between microvascular abnormality and skin thickening, and to measure disease progression and treatment response. 3. Studies of digital ulceration. Digital ulcers are painful and disabling, and we are investigating how best to measure them, and possible new types of treatment. 4. Studies of calcinosis. We are trying to find out more about what causes calcinosis: this isthe first step in finding an effective treatment. 5. Studies of nutritional issues. Many patients with scleroderma have gastrointestinal problems, which can lead to weight loss. 6. ESOS (European Scleroderma Observational Study), investigating different immunosuppressant drugs in early diffuse cutaneous scleroderma. This study is being coordinated from Manchester and involves over 50 centres worldwide. 7. A study examining the use of wax-baths for treating the hands in patients with scleroderma. The scleroderma team in Salford/Manchester is indebted to all those funding our research, in particular to the Raynaud’s & Scleroderma Association and to the Scleroderma Society, who have funded a variety of projects and individuals over many years. We are also very grateful to the other organisations who have funded our research: Arthritis Research UK, the British Skin Foundation, the European League Against Rheumatism (EULAR) and the Wellcome Trust. Professor Ariane Herrick Salford Royal Hospital
1. Nailfold videocapillaroscopy studies. We are investigating the potential of this technique as an outcome measure of microvascular (small blood vessel) disease.
Research News Aintree The Merseyside Raynaud's and Systemic Sclerosis service is centred at Aintree University Hospital and is led by Dr Marina Anderson, Honorary Consultant in Rheumatology and Senior Lecturer at the University of Liverpool. The clinical service established by Dr Anderson has a weekly Raynaud's and Systemic Sclerosis Clinic, with dedicated clinical nurse specialist and helpline. There is a supporting vascular service, with a vascular nurse technician. In addition to the clinical service, the unit participates in an active research programme: in addition to taking part in a number of pharmaceutical clinical trials, the Liverpool Raynaud's and Systemic Sclerosis unit is working on grant-funded collaborative studies to find better ways to examine blood flow and blood vessels in these disorders, and has discovered important cell interactions in laboratory studies of systemic sclerosis.
With a growing number of local and national collaborations, the Liverpool Raynaud's and Systemic Sclerosis unit continues to search for answers as to why these disorders happen, how we can better measure, diagnose and monitor these disorders and how we can improve treatment. future. Dr Marina Anderson Aintree University Hospital
Dr Marina Anderson
Published by Raynaud’s & Scleroderma - Care and Support www.raynaudsandscleroderma.co.uk email: anne@raynaudsandscleroderma.co.uk Helpline 07530 810 964