Canadian Scleroderma Research Group
About the CSRG
The Canadian Scleroderma Research Group (CSRG) was established in 2004 with grants from the CIHR, industry and Canadian patient societies. Fifteen rheumatologists across Canada have, at one time or another, recruited patients into the registry. We now have data on 1753 patients, some with up to 13 years of follow up, and we collect 1543 variables. We initially saw all patients, with both new and established disease, yearly.
However, several years ago, we decided to follow patients up to 10 years of disease duration. This plan was meant to save costs and to focus on the disease during earlier, more informative years. Indeed, early disease has become a new focus for our research cohort.
Some sites that participated at the onset of the CSRG have dropped out for various reasons, including the death of a recruiting physician with no one to replace her, retirement, lack of local resources to cover the costs of the nurse needed for the study visits, and change in the focus of the participating physician. On the other hand, we have gained new sites, such as Quebec City.
In 2013, a new set of classification criteria was published on behalf of the American College of Rheumatology and the European League Against Rheumatism. The committee consisted of four North American and four European experts. Drs Murray Baron and Janet Pope, who have recruited the most patients into the CSRG, were two of the four North American experts on the committee, attesting to the Canadian leadership in scleroderma research. Moreover, the CSRG dataset was widely used in the development and validation of these criteria, which have now become the gold standard in the field.
The CSRG has published 135 papers using data from the CSRG database. Our publications in the last 10 years constitute 2.2% of all the world’s scleroderma publications during that period of time. This is a remarkable output for one organization. A booklet with the cover pages of most of our publications has been distributed separately and another copy is available upon request.
The CSRG has become a world leader in scleroderma research. In turn, the reputation of our researchers has soared because of the CSRG. Dr. Baron was president (2015 – 2017), and is currently an active member of the executive committee, of the Scleroderma Clinical Trials Consortium (https://sclerodermaclinicaltrialsconsortium.org/) which represents the majority of researchers and clinicians in the world with an interest and expertise in the care of, and research in, scleroderma. He also serves on the editorial board of the Journal of Scleroderma and Related Disorders and previously served as chair of the American College of Rheumatology Scleroderma Abstract Selection Committee.
In recent years, he created and directs the International Systemic Sclerosis Inception Cohort (INSYNC). This is an international group of researchers that has agreed to use a common dataset and to share data to pursue research specifically in early scleroderma. International collaborations are essential in rare diseases such as scleroderma, even more so when the focus is on new onset cases. To date, INSYNC includes sites in Canada, Australia, Netherlands, Spain, Germany, Brazil, United States, and Sweden.
Of particular note, INSYNC depends entirely on the CSRG infrastructure for administrative and statistical support. Using foundational work generated from the CSRG dataset, Dr Brett Thombs obtained a large CIHR grant to create the Scleroderma Patient-centered Interventional Network (SPIN), an international cohort established to develop and test psychosocial and rehabilitative interventions to improve the health-related quality of life of people living with scleroderma. So far, he has recruited about 2000 patients and has launched studies to investigate …(self-management, hand function, depression).
Dr Marie Hudson, who is the only fulltime academic rheumatologist working on the CSRG data, is now internationally recognized for her scleroderma research. Among other international commitments, she currently directs the Tri-Nation (Canada, Australia, Houston) Scleroderma cohort, leads the Scleroderma Clinical Trials Consortium Working Group on Scleroderma Renal Crisis, is Co-Chair of the American College of Rheumatology Scleroderma Abstract Selection Committee and sits on the editorial board of the Journal of Scleroderma and Related Disorders.
Dr. David Langleben
Senior Investigator, Lady Davis Institute
Dr. David Langleben is a Professor of Medicine at McGill University. He is the Director of the Cardiology Division of the Jewish General Hospital, and founded and directs the Centre for Pulmonary Vascular Disease, an internationally recognized resource for patient care, teaching, and research. He is a Project Director at the Lady Davis Institute for Medical Research.
Dr. Langleben’s research focuses on the vascular biology of pulmonary hypertension. He has studied endothelial dysfunction in the disorder, at the cellular, organ, and whole-body level. He and his colleagues were the first to identify endothelin-1 as a mediator in pulmonary hypertension. Over the following 20 years, this discovery led to the development of several approved therapies that have benefitted thousands of patients. His group has gone on to study the clearance of endothelin-1 in pulmonary hypertension and to examine mechanisms that control its synthesis. Recent work has focused on the effects of bone morphogenic proteins and other members of the transforming growth factor-β family of molecules on the control of endothelin-1 production.
Another major focus has been to measure the degree of loss of lung microvessels in pulmonary hypertension and to assess its impact on prognosis, response to therapy, and exercise capacity. With his colleagues, he has adapted for human use techniques originally developed for animal experiments. These human studies have provided definitive assessments of the restricted pulmonary bed in pulmonary hypertension and have provided the first mechanistic insights for the physiologic abnormalities in the disease. Current studies are examining changes in vascular surface area in response to vasodilators, and studies in exercising patients will begin shortly.
At the Centre for Pulmonary Vascular Disease, Dr. Langleben is the principal investigator in many clinical trials of novel therapies for pulmonary hypertension. He sits on several scientific advisory boards that design and direct major international clinical trials.
Major Research Activities
Langleben D, Orfanos SE, Giovinazzo M, Hirsch A, Baron M, Senecal JL, Armaganidis A, Catravas JD. Pulmonary capillary endothelial dysfunction: Severity in pulmonary arterial hypertension related to connective tissue disease versus idiopathic pulmonary arterial hypertension. Arthr Rheumatism 2008;58:1156-1164.
Star GP, Giovinazzo M, Langleben D. Bone morphogenic protein-9 stimulates endothelin-1 release from human pulmonary microvascular endothelial cells. A potential mechanism for elevated ET-1 levels in pulmonary arterial hypertension. Microvasc Res 2010;80:349-354.
Fox BD, Shimony A, Langleben D. Meta-analysis of monotherapy vs. combination therapy for pulmonary arterial hypertension. Am J Cardiol 2011; in press.
Dr. Russell J. Steele
Senior Investigator and Biostatistician, Centre for Clinical Epidemiology, Lady Davis Institute
Dr. Russell J. Steele is an Associate Professor in the Department of Mathematics and Statistics at McGill University and a Research Investigator in the Centre for Clinical Epidemiology at the Jewish General Hospital. He received his PhD in statistics from the University of Washington in 2002 and began collaborating with researchers at the Jewish General Hospital soon after arriving to McGill.
Dr. Steele has not only published papers in statistics journals, but also made important contributions to research in rheumatology, sports medicine, cancer, cardiovascular treatments, and epidemiology. He has a deep interest in applied statistics, in particular collaborating with researchers in other disciplines to improve the state of statistical methods in their areas and to develop new approaches to analyzing data.
Major Research Activities
Dr. Steele’s primary statistical research interests are in the analysis of missing data and model selection using computationally intensive Bayesian approaches. Dr. Steele also has worked on problems in applying statisics to other fields, particularly applications in medical and population health research. He is a member of the Canadian Scleroderma Research Group (CSRG) and has collaborated closely with several physicians on problems related to analyzing data from the CSRG patient registry. He has also worked on epidemiology methodological problems relating to meta-analysis and the analysis of sports injury data.
Steele, R.J., Wang, N., and Raftery, A.E. Inference from Multiple Imputation for Missing Data Using Mixtures of Normals, Statistical Methodology (7) 351–365 (2010).
Hudson, M., Impens, A., Baron, M., Siebold, J.R., Thombs, B.D., Walker, J.G., CSRG, and Steele, R. Discordance between Patient and Physician Assessments of Disease Severity in Systemic Sclerosis, Journal of Rheumatology. To appear. (2010).
Shrier, I., Steele, R.J., Hanley, J., Rich, B. Analyses of injury count data: some dos and some donts, American Journal of Epidemiology (170) pp. 1307–15 (2009).
Dr. Mervyn Gornitsky
|Research Director, Department of Dentistry, Jewish General Hospital
Chief Emeritus, Department of Dentistry, Jewish General Hospital
Professor Emeritus, Faculty of Dentistry, McGill University
Dr. Mervyn Gornitsky is Research Director of the Department of Dentistry at the Jewish General Hospital. He is a Professor Emeritus at McGill University, Faculty of Dentistry, and Chief Emeritus of the Department of Dentistry at the Jewish General Hospital. Dr. Gornitsky’s distinguished careers in academic dentistry and oral and maxillofacial surgery have spanned over 50 years. He has contributed more than anyone in Canada to the development of departments of dentistry in Canadian hospitals. He was chair of the Hospital Dental Services Committee for Quebec for 15 years and Chair of the Council on Hospital Dental Services for the Canadian Dental Association for six years.
Dr. Gornitsky was granted a fellowship at the inception of the examination by the Royal College of Dentists of Canada in Oral and Maxillofacial Surgery in 1967. He is a fellow of the American College of Dentists, the International College of Dentists, L’Academie dentaire du Quebec, and a member of the Pierre Fauchard Academy.
Major Research Activities
Dr. Gornitsky is the director of the JGH Databank for Saliva Specimens, located at the LDI. Currently his research themes focus on the discovery of salivary biomarkers in Parkinson’s disease and other neurological conditions, and the biomarkers and treatment of painful temporomandibular disorders and sleep apnea.
In the past, Dr. Gornitsky’s team has completed epidemiologic studies associated with facial pain and bruxism, periodontal diseases in HIV positive and AIDS patients, xerostomia in patients undergoing radiotherapy for head and neck cancer, as well as the effects of oxidative stress on saliva. The latter focused on oxidative damage to lipids, proteins and DNA, in addition to total oxidative capacity as markers for various diseases, such as periodontitis, scleroderma, diabetes, Alzheimer’s disease, and breast cancer.
Song W, Kothari V, Velly A, Cressati M, Liberman A, Gornitsky M, Schipper HM. Evaluation of Salivary Heme Oxygenase-1 as a Potential Biomarker of Early Parkinson’s Disease. Movement Disorders. Accepted December 22, 2017.
Baron M, Hudson M, Dagenais M, Macdonald D, Gyger G, El SayeghT, Pope J, Fontaine A, Masetto A, Matthews D, Sutton E, Thie N, Jones N, Copete M, Kolbinson D, Markland J, Nogueira-Filho G, Robinson D, Fritzler M, Wang M, Gornitsky M. Relationship Between Disease Characteristics and Oral Radiologic Findings in Systemic Sclerosis: Results From a Canadian Oral Health Study. Arthritis Care & Research. 2016 May:68(5):673-680.
Gornitsky M, Velly AM, Mohit S, Almajed M, Su H, Panasci L, Schipper HM. Altered Levels of Salivary 8-oxo-7-hydrodeoxyguanosine in Breast Cancer. JDR Clinical & Translational Research. 2016 April;1:171-177. doi: 10.1177/2380084416642197.
Wang J, Schipper HM, Velly AM, Mohit S, Gornitsky M. Salivary Biomarkers of Oxidative Stress: a Critical Review. Free Radical Biology and Medicine 2015; 85:95–104 (Corresponding author).
Baron M, Hudson M, Gyger G, El Sayegh T, Pope J, Fontaine A, Masseto A, Matthews D, Sutton E, Thie N, Jones N, Copete M, Kolbinson D, Markland J, Nogueira-Filho G, Robinson D, Fritzler M., Gornitsky M. The Canadian Systemic Sclerosis Oral Health Study V: Relationship Between Disease Characteristics and Oral Radiologic Findings in Systemic Sclerosis. In preparation, April 2015.
Dagenais M, MacDonald D, Baron M, Hudson M, Tatibouet S, Steele R, Gravel S, Mohit S, El Sayegh T, Pope J, Fontaine A, Masseto A, Matthews D, Sutton E, Thie N, Jones N, Copete M, Kolbinson D, Markland J, Nogueira-Filho G, Robinson D, Gornitsky M. The Canadian Systemic Sclerosis Oral Health Study IV: Oral radiographic manifestations in systemic sclerosis compared with the general population. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology. Epub April 17, 2015 (Corresponding author).
Baron M, Hudson M, Tatibouet S, Steele R, Lo E, Gravel S, Gyger G, El Sayegh T, Pope J, Fontaine A, Masseto A, Matthews D, Sutton E, Thie N, Jones N, Copete M, Kolbinson D, Markland J, Nogueira-Filho G, Robinson D, Gornitsky M. The Canadian systemic sclerosis oral health study II: The Relationship Between Oral and Global Health-Related Quality of Life in Systemic Sclerosis. Rheumatology April 2015: 54(4): 692-6.
Baron M, Hudson M, Tatibouet S, Steele R, Lo E, Gravel S, Gyger G, El Sayegh T, Pope J, Fontaine A, Masseto A, Matthews D, Sutton E, Thie N, Jones N, Copete M, Kolbinson D, Markland J, Nogueira-Filho G, Robinson D, Gornitsky M. The Canadian Systemic Sclerosis Oral Health Study III: Relationship Between Disease Characteristics and Oro-facial Manifestations in Systemic Sclerosis. Arthritis Care & Research Epub Oct. 9, 2014
Baron M, Hudson M, Tatibouet S, Steele R, Lo E, Gravel S, Gyger G, El Sayegh T, Pope J, Fontaine A, Masseto A, Matthews D, Sutton E, Thie N, Jones N, Copete M, Kolbinson D, Markland J, Nogueira-Filho G, Robinson D, Gornitsky M. The Canadian systemic sclerosis oral health study: orofacial manifestations and oral health-related quality of life in systemic sclerosis compared with the general population. Rheumatology August 2014;53:1386-1394. (Corresponding author).
Su H, Baron M, Benarroch M, Velly AM, Gravel S, Schipper HM, Gornitsky M. Altered salivary redox homeostasis in patients with systemic sclerosis. J Rheumatol. 2010; 37(9):1858-63.
Baron M, Bernier P, Côté LF, Delegge MH, Falovitch G, Friedman G, Gornitsky M, Hoffer J, Hudson M, Khanna D, Paterson WG, Schafer D, Toskes PP, Wykes L Screening and therapy for malnutrition and related gastro-intestinal disorders in systemic sclerosis: recommendations of a North American expert panel. Clin Exp Rheumatol. 2010 Mar-Apr;28(2 Suppl 58):S42-6.
Dr. Murray Baron
|Senior Investigator, Lady Davis Institute
Chief, Division of Rheumatology, Jewish General Hospital
Director of the Canadian Scleroderma Research Group
Associate Professor of Medicine, McGill University
Dr. Murray Baron is the chief of the Division of Rheumatology at the Jewish General Hospital, where he has practiced since 1981. He graduated from McGill University’s Faculty of Medicine and, after stints as a family doctor in Newfoundland and British Columbia, trained in internal medicine at the University of British Columbia and rheumatology at the University of Toronto. He is an Associate Professor of Medicine at McGill University.
He runs a division with five full-time academic rheumatologists and one part-time rheumatologist, which is similar to the numbers at the McGill University Health Centre, McGill’s other teaching hospital. In the last three years, three new rheumatologists have been hired, including Dr. Marie Hudson who is a full-time academic. Among the other rheumatologists, one has a strong interest in medical education, another in the use of musculoskeletal ultrasound as a diagnostic tool, and a third in the use of videocapillaroscopy as a clinical and research tool in the rheumatic diseases. In addition, Dr. Brett Thombs, an academic psychologist from the department of psychiatry, has a cross appointment in rheumatology.
Major Research Activities
Dr. Baron’s primary research interest is in an uncommon rheumatic disease called scleroderma. In this disease, there is fibrosis of multiple organs leading to severe morbidity and increased mortality. Because the disease is rare, Dr. Baron has established the Canadian Scleroderma Research Group (CSRG). Over 15 rheumatologists from across Canada see patients once a year and enter a large amount of data into a central database. Biological specimens, such as blood and skin, are also collected. Research is performed on the data by clinical researchers at McGill and elsewhere, and on the bio-specimens at multiple laboratories that Dr. Baron has brought into his group.
Since its inception in 2004, over $4.5 million dollars has been brought in from peer review agencies by Dr. Baron and his colleagues in the CSRG. More than 60 articles have been published in the scientific literature since the CSRG was formed. The CSRG, under Dr. Baron’s direction, has become a well recognized leader in scleroderma research in the world.
In addition, Dr. Baron has established the McGill Early Arthritis Registry that has performed research on recent onset inflammatory arthritis. Much of the work in this area will be turned over to one of the new rheumatology recruits, Dr. Sabrina Fallavollita.
He has also created CANCoRC, the Canadian Consortium of Rheumatology Cohorts, in an attempt to strengthen Canadian rheumatology research by seeking common funding and identifying commonalities across rheumatic disease research teams.
Schieir O, Thombs BD, Hudson M, Boivin JF, Steele R, Bernatsky S, Hanley J, Baron M. Prevalence, severity, and clinical correlates of pain in patients with systemic sclerosis. Arthritis Care Res (Hoboken) 2010;62:409-17.
Fan X, Pope J, Baron M. What is the relationship between disease activity, severity and damage in a large Canadian systemic sclerosis cohort? Results from the Canadian Scleroderma Research Group (CSRG). Rheumatol Int 2010;Sep 24. 2009 [Epub ahead of print].
Baron M, Bernier P, Côté L, DeLegge M, Falovitch G, Friedman G, Gornitsky M, Hoffer J, Hudson M, Khanna D, Paterson W, Schafer D, Toskes P. Screening and Therapy for Malnutrition and Related Gastro-Intestinal Disorders in Systemic Sclerosis: Recommendations of a North American Expert Panel. Clin Exp Rheumatol 2010;In Press.
Dr. Celia M. T. Greenwood
|Senior Investigator, Centre for Clinical Epidemiology, Lady Davis Institute
Associate Professor, Department of Oncology, Department of Epidemiology, Biostatistics and Occupational Health, and Division of Cancer Epidemiology, McGill University
Dr. Greenwood joined the LDI from the Hospital for Sick Children and the Dalla Lana School of Public Health in Toronto. She is a statistician with an interest in methodology for the analysis of genetic and genomic data. Her methodological work spans family studies looking for patterns of inheritance of disease-causing genes, case-control studies looking for associations between anonymous markers and disease status, gene expression studies examining differences between patient groups or tissues, and estimation of copy number variation in the genome. Some of the theoretical work developed by her students includes: a haplotype estimation algorithm using hidden Markov models, a flexible method for estimating disease-gene relationships in sparse data using Dirichlet process mixtures, and tree-based models for estimating the evidence for linkage in the presence of heterogeneity.
She led the statistical analysis team in a genome-wide association study of colorectal cancer, where a new locus was identified conferring increased risk. In the context of that study, the team proposed, and used, a novel stratified method for assessing false discovery rates, and developed a computationally-efficient method for empirically estimating large numbers of p-values for haplotype-disease associations.
Major Research Activities
For many years, Dr. Greenwood has been working on issues of data quality and measurement in genomic data, and how measures of quality can be developed and used to improve the detection of important signals in high-throughput genomic data. In particular, one focus of this research has been in data integration, where information from different experiments is combined to improve prediction performance or signal detection.
Pingzhao Hu, Celia MT Greenwood, Joseph Beyene. Using the ratio of means as the effect size measure in combining results of microarray experiments. BMC Systems Biology 2009, 3:106. doi:10.1186/1752-0509-3-106.
Babak Shahbaba, Andrew J Gentles. Joseph Beyene, Sylvia K. Plevritis, Celia M.T. Greenwood (2009). A Bayesian nonparametric method for model evaluation. Journal of Nonparametric Statistics, 21(2): 379-396.
Celia MT Greenwood, Shuying Sun, Justin Veenstra, Nancy Hamel, Bethany Niell, Stephen Gruber, William D Foulkes (2010). How old is this mutation? A study of three Ashkenazi Jewish founder mutations. BMC Genetics 11:39.
Dr. Marie Hudson
Dr. Marie Hudson, M.D. MPH FRCPC, is a rheumatologist, epidemiologist, and Assistant Professor in the Department of Medicine at McGill University.
She is a physician-scientist and member of the Center for Clinical Epidemiology and Community Studies at the Jewish General Hospital.
Dr. Hudson is a fellow of the Royal College of Physicians of Canada and is funded as a New Investigator by the Canadian Institutes of Health Research (CIHR).
Major Research Activities
Dr. Hudson pursues research in systemic autoimmune rheumatic diseases. In particular, she is one of the founding members of the Canadian Scleroderma Research Group (CSRG), a CIHR-funded, multi-centre group of researchers that follows a cohort of over 1000 SSc patients across Canada. She has published landmark studies documenting the magnitude of impairment in health-related quality of life (HRQoL) with scleroderma. She is particularly interested in scleroderma lung disease, its natural history, its optimal treatment, and its impact on HRQoL.
Dr. Hudson is also involved in a number of studies in other rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, and inflammatory myositis. In particular, she is a co-investigator on a large Canada Foundation for Innovation (CFI) funded study to develop a new integrated database and biospecimen tracking system for systemic autoimmune rheumatic diseases in order to support future cross-disease studies.
She is the recipient of the 2011 Canadian Rheumatology Association Young Investigator Award.
Hudson M, Baron M, Lo E, Weinfeld J, Furst D, Khanna D. An international, web-based, prospective cohort study to determine if the use of ACE inhibitors prior to the onset of scleroderma renal crisis is associated with worse outcome – methodology and preliminary results. International J Rheumatol 2010; doi:10.1155/2010/347402.
Hudson M, Fritzler MJ, Baron M. Systemic sclerosis: Establishing diagnostic criteria. Medicine (Baltimore) 2010; 89(3): 159-65.
Hudson M, Thombs BD, Steele R, Panopalis P, Newton E, Baron M, Canadian Scleroderma Research Group. Health-related quality of life in Systemic Sclerosis: A systematic review. Arthritis Rheum 2009; 61(8): 1112-20.
Current research project summaries
Precision Medicine in Cellular Epigenomics
Competition: 2017 Bioinformatics and Computational Biology Competition
Genome Centre(s): Génome Québec
Project Leader(s): Celia Greenwood (Lady Davis Institute for Medical Research), Karim Oualkacha (Université du Québec à Montréal)
DNA methylation refers to the attachment of a methyl molecule to our DNA. This chemical binding makes the DNA inaccessible, and provides a mechanism to influence which parts of the DNA are active or inactive. Since DNA methylation can vary across cell types, with disease, with exposures to contaminants, and with other factors such as genetic factors and age, many clinicians and researchers are excited to identify which parts of the genome are associated with certain diseases or exposures. This could be used to understand mechanisms of disease and to provide potential targets of intervention. for these reasons, there is increasing interest to study DNA methylation in scleroderma.
It has recently become technically and financially feasible to perform single nucleotide-resolution measurement of DNA methylation on a large scale across the genome, using a method called bisulfite sequencing. However, the data are noisy and many measures can be missing. Appropriate methods of analysis for this voluminous and highly correlated data are currently unsatisfactory.
We have assembled a team of experts including leading methodological statisticians, scientific researchers in several domains such as scleroderma, as well as asthma and behavioural development, and experienced bioinformaticians. Together we will develop an algorithm and software package to analyze large scale, high dimensional DNA methylation data so that we can profit from the potential hidden in the messy data. We have already a prototype method in place that shows excellent performance.
Strong support for the ideas in our study have been obtained from patient-led associations including Scleroderma Quebec, and also from two Montreal companies, one that develops machine learning methods and the other that provides a high-performance computational platform. Leading epigenetic researchers and consortia have also expressed their interest in our research. Understanding of epigenetic contributions to disease will be revolutionized through this project.
Current Ongoing and Future Studies
The following is a list and descriptions of 30 ongoing and future studies, as well as four laboratory projects. This list is ever expanding as the findings of these projects often lead researchers to new and more nuanced questions. The limitations to this research- into better ways to diagnose and treat scleroderma, and improve patient quality of life- are related entirely to the scarcity of funding. Many of these projects are unfunded which in reality means researchers, physicians, and support staff, carry them out without being compensated and on their own time.
Do immunosuppressive drugs prevent the development of lung disease in scleroderma? Dr Sabrina Hoa, Master in Epidemiology (McGill), funded by The Arthritis Society Post-doctoral award, is trying to answer this question in her thesis. Her results look very promising.
Pulmonary Function Tests as Surrogate Markers for Interstitial Lung Disease Progression in Systemic Sclerosis. Funded by a CIHR doctoral award, Melissa Caron from McGill is examining the trajectories of lung disease in scleroderma, how should we measure them best and what predicts them. It is important to understand this to be able to decide who should be treated and when.
The risk of HRCT scans on the development of lung cancer in scleroderma
Lung cancer occurs more often in scleroderma than in the general population. Does frequent use of lung scans contribute to this? Mohamed Mansour, a McGill medical student, has been funded by a Faculty of Medicine bursary to pursue this project.
Treatment of interstitial lung disease in subjects excluded by clinical trials. To date, there have been 3 randomized clinical trials for SSc subjects with interstitial lung disease. All 3 have selected patients with early disease with at least moderate lung disease (FVC < 85%). However, the vast majority of patients with interstitial lung disease in the CSRG cohort have more longstanding and/or milder lung impairment.
There is no data available on the benefits of treatment in these 2 subsets of patients. Dr Sabrina Hoa, Master in Epidemiology (McGill), funded by The Arthritis Society Post-doctoral award, will also address this question in her thesis.
Can Small Intestinal Bacterial Overgrowth (SIBO) be diagnosed and treated more efficiently? SIBO is a frequent and serious complication of scleroderma where bacteria grow in the bowel because the bowel slows down in scleroderma. We have been funded by the CIHR to do an international study to test if a very strict protocol to treat this will help our patients more than usual care. The funds awarded are actually small (about $200,000) and we need to find additional financial resources to complete the study successfully.
Do immunosuppressive drugs prevent the development of severe gastrointestinal disease? This is another project we are leading with other INSYNC sites.
Is severe gastrointestinal disease in early scleroderma associated with an increased risk of mortality? We are leading this project and working in collaboration with other INSYNC sites including Australia, Spain, the Netherlands, and the United States.
The role of WNT signaling in the pathophysiology of calcinosis.
Treatment of calcinosis is one of the most serious unmet needs in scleroderma. We have developed a new collaboration with Drs Adel Schwertani (McGill) and Louis-Georges Ste-Marie (University of Montreal) to study samples of calcinosis to understand what metabolic pathways are involved. This could give us important clues on how to treat this.
Calcinosis. In addition to understanding mechanisms contributing to calcinosis, we must also be able to measure this problem so that the efficacy of potential treatments can be tested. We developed a way to use xrays of the hands to score the amount of calcium deposited there and are now participating in an international study of the course of calcinosis. We will be testing a new patient reported questionnaire assessing the effect of calcinosis on their lives and will also test the ability of the xray score to detect changes over time.
The predictive value of skin involvement. Does the extent of skin involvement allow us to predict future organ damage and quality of life in early diffuse cutaneous systemic sclerosis? Drug approval agencies want to know if drug studies that use the changes in skin as the main outcome of the trial can expect that internal organ changes mirror the skin changes. We are doing a large study using our data to look at this.
Systematic review of the role of ultrasound to measure skin fibrosis in scleroderma. Skin is usually scored based on a physical exam by the doctor.
Could there be a better way to do this? We are reviewing the world literature to see if ultrasound would be a more objective measure. Dr Meriem Kerbachi, PGY5 (McGill), is involved in this project.
Development of classification criteria for scleroderma renal crisis.
Funded by the Scleroderma Clinical Trials Consortium ($12,000 USD), Dr Marie Hudson is leading an international group of experts to develop consensus- and data-driven classification criteria for scleroderma renal crisis. This should facilitate future research into this rare but life-threatening complication of SSc, for which there is an urgent need to identify novel therapeutic options.
Genetics of scleroderma renal crisis (SRC)– The CSRG has been asked to participate in an international study led by Dr John Varga of Northwestern University (Chicago) to identify genetic markers that are associated with SRC.
This may help us understand the pathophysiology of this complication as well as identify novel therapeutic targets. The CSRG will contribute approximately 40 cases and 80 controls.
Activation of mammalian target of rapamycin in renal tissue of patients with scleroderma renal crisis: a hypothesis-testing study. Scleroderma patients can develop severe high blood pressure and kidney failure. We want to better understand why this happens. This could also help us find new treatments for this serious complication. Dr Jessica Salturi, PGY2 at McGill, submitted an abstract summarizing preliminary results for the 2018 Canadian Rheumatology Association annual meeting.
Electrocardiograms in scleroderma. How do we know if the heart is involved in scleroderma? This is a very difficult question. We have examined 1000 electrocardiograms (ECGs) from our patients and another 1000 from controls to see what abnormalities may be specific to scleroderma. Dr Sophie Wojcik, PGY5 (McGill), submitted an abstract summarizing some of this work for the 2018 Canadian Rheumatology Association annual meeting.
How to define heart disease in scleroderma? We initiated and are part of a working group of the Scleroderma Clinical Trials Consortium created to define heart involvement in scleroderma. CSRG data will be used extensively for this project.
Systematic review of EKG abnormalities in Scleroderma
Dr Stephanie Kelly, PGY1 (Northwestern University, Chicago) has undertaken this project. A systematic review is a very rigorous way of reviewing the world’s scientific literature. It is very time consuming but is the best way to put together a lot of different studies together and to make robust conclusions. This is being done as part of our interest in finding out what ECG abnormalities really are associated with the disease.
Evidence-based guidelines for screening for pulmonary arterial hypertension in SSc. Guidelines recommend yearly cardiac echocardiography to screen SSc patients for pulmonary arterial hypertension. However, there is little evidence to support this and in fact this is probably not needed in patients at very low risk.
We are in the process of developing an algorithm using symptoms and pulmonary function tests to identify patients at very low risk who may not need yearly echocardiography. This has the potential to save precious resources and reduce health care costs by eliminating unnecessary testing.
This project involved Teresa Semalulu, a medical student from the University of Northern Ontario, who was funded by a Canadian Rheumatology Association summer studentship. In addition, Roche Inc has provided in-kind funding worth approximately $40,000 to test whether a blood test, NT-proBNP, adds to the predictive ability of the algorithm.
Trigeminal neuralgia in scleroderma – clinical and serological associations. One of the facial nerves is sometimes affected by scleroderma. We are looking at how this relates to the rest of the disease. Dr Nancy Maltez, PGY5 (University of Ottawa), will be presenting an abstract on our findings at the American College of Rheumatology meeting in San Diego in November 2017.
The spectrum of myopathy in scleroderma– clinical and serological associations. Inflammation in muscle occurs in scleroderma. We want to describe this more carefully to help determine why this happens and how to treat it. Dr Teresa Carfaro, PGY4 (McGill), presented preliminary results at the 2017 Canadian Rheumatology Association annual meeting, and is now preparing a more detailed manuscript.
Biomarkers, Assessment Tools, and Scales
Do immunosuppressive drugs affect the CRISS?
The American College of Rheumatology Provisional Composite Response Index for Clinical Trials (CRISS) is a new way of measuring patient outcomes in drug trials. We participated in its development and are now doing a study using the CSRG database to see if we can tell if the use of drugs that suppress the immune system lead to patient improvement based on the CRISS.
Validation of the Scleroderma Clinical Trials Consortium Damage Index
With members of INSYNC, we led a team that developed a totally new way to measure scleroderma. The disease leads to damage in many organs but there has not been a way to measure that overall damage.
We have developed the Scleroderma Damage Index, which does just that. This can be used in drug trials to see if a drug prevents the accumulation of damage. We are now testing this in our database to see how well it performs.
Disease Activity Index
The same group that developed a damage index is now just starting to work n a disease activity index. We assume that the disease process may have times when it is active and others when it is quiet. We do not know how to tell when it is active. That is important because that may be the time to use medications that may do nothing when the disease is quiet.
PRESCIENCE - PREcision medicine in SCleroderma using Cellular Epigenomics
There is an urgent need to accurately predict disease progression in SSc,to avoid exposing patients to drugs with possible toxicity if their risk of progression is low and to optimize the use of new, expensive treatments. Dr Marie Hudson recently submitted a grant to CIHR to studythemethylomes of a suite of disease-relevant cell typesin aprospective, treatment-naïve cohort of SSc patients followed longitudinally, to identify biomarkers of disease progression andthereby personalize treatment decision-making in SSc.A funding decision is expected for early 2018.
Tri-nation Scleroderma Cohort
This cohort is composed of the CSRG, GENISOS, an NIH-funded study based in Houston, Texas, and the Australian Scleroderma Interest Group. This collaboration was undertaken to study the clinical correlates of some of the less frequent autoantibodies found in systemic sclerosis.
The harmonized dataset includes over 1500 subjects with detailed serologies using a common platform. We have already published 2 papers in high-impact journals using this dataset. We have 3 more studies underway. This work is unfunded but is highly dependent on the CSRG infrastructure (research coordination and statistical support).
Novel antibodies associated with cancer in scleroderma
A link between scleroderma and cancer has been identified in many studies, in particular in patients with anti-RNA polymerase III antibody positive patients. However, 2 fascinating papers published in the last year have also identified a higher risk in “triple negative” patients (those without anti-centromere, anti-topoisomerase and anti-RNA polymerase III antibodies). In those patients, about 25% had a novel antibody, anti-RNPC3.
Other novel antibodies in “triple negative” patients therefore remain to be identified. In collaboration with Dr Marvin Fritzler, a world leader in antibody discovery at the University of Calgary, we are trying to identify some of these in the sera of CSRG patients who have and have not had cancer. These novel antibodies will allow us to identify patients at high risk of underlying malignancy, as well as shed new insights into mechanisms of disease.
Stem Cell Transplants
In a quick informal survey we found that about 16 stem cell transplants have been performed in Canada as treatment for SSc. Recent studies show marked improvement after transplants in certain patients. We expect the requests for this therapy to increase.
We wish to develop a Canadian transplant agenda by bringing together patients, hematologists, rheumatologists and the authors of the large studies stem cell transplant studies with the aim of developing a national Scleroderma transplant network. We will develop a research program around it to study ways to make transplants safer for patients.
We plan to study the cost-effectiveness of transplant in collaboration with Professor Mark Harrison, UBC. We also will study the changes in Health-related quality of life pre-post transplant (collaboration with Professor Dominique Farge, Paris.
We submitted an application for funding mid-November 2017 to the CIHR ($40 000) with matched pledged funding from various provincial patient Scleroderma societies (including Ontario, British Columbia, Saskatchewan, and Nova Scotia) and FondsFrance-Canada pour la Recherche to fund trainees ($15,000).
In the past 2 years alone we have 26 publications, including many collaborations between the CSRG and other groups in the world. A comprehensive booklet of our publications has been provided to you in the past year. Additional copies can be provided if required.
- Wu M, Baron M, Pedroza C, Salazar GA, Ying J, Charles J, Agarwal SK, Hudson M, Pope J, Zhou X, Reveille JD, Fritzler MJ, Mayes MD, Assassi S. CCL2 in the Circulation Predicts Long-Term Progression of Interstitial Lung Disease in Patients With Early Systemic Sclerosis: Data From Two Independent Cohorts. Arthritis & rheumatology (Hoboken, NJ) 2017;69:1871-8.
- Terao C, Kawaguchi T, Dieude P, Varga J, Kuwana M, Hudson M, Kawaguchi Y, Matucci-Cerinic M, Ohmura K, Riemekasten G, Kawasaki A, Airo P, Horita T, Oka A, Hachulla E, Yoshifuji H, Caramaschi P, Hunzelmann N, Baron M, Atsumi T, Hassoun P, Torii T, Takahashi M, Tabara Y, Shimizu M, Tochimoto A, Ayuzawa N, Yanagida H, Furukawa H, Tohma S, Hasegawa M, Fujimoto M, Ishikawa O, Yamamoto T, Goto D, Asano Y, Jinnin M, Endo H, Takahashi H, Takehara K, Sato S, Ihn H, Raychaudhuri S, Liao K, Gregersen P, Tsuchiya N, Riccieri V, Melchers I, Valentini G, Cauvet A, Martinez M, Mimori T, Matsuda F, Allanore Y. Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis. Annals of the rheumatic diseases 2017;76:1150-8.
- Richard N, Hudson M, Gyger G, Baron M, Sutton E, Khalidi N, Pope JE, Carrier N, Larche M, Albert A, Fortin PR, Thorne C, Masetto A. Clinical correlates of faecal incontinence in systemic sclerosis: identifying therapeutic avenues. Rheumatology (Oxford, England) 2017;56:581-8.
- Nevskaya T, Baron M, Pope JE. Predictive value of European Scleroderma Group Activity Index in an early scleroderma cohort. Rheumatology (Oxford, England) 2017;56:1111-22.
- Mejia Otero C, Assassi S, Hudson M, Mayes MD, Estrada YMR, Pedroza C, Mills TW, Walker J, Baron M, Stevens W, Proudman SM, Nikpour M, Mehra S, Wang M, Fritzler MJ. Antifibrillarin Antibodies Are Associated with Native North American Ethnicity and Poorer Survival in Systemic Sclerosis. The Journal of rheumatology 2017;44:799-805.
- Li G, Adachi JD, Cheng J, Thabane L, Hudson M, Fritzler MJ, Lorenzi S, Baron M, Larche M. Relationship between calcium channel blockers and skin fibrosis in patients with systemic sclerosis. Clinical and experimental rheumatology 2017.
- Levis B, Kwakkenbos L, Hudson M, Baron M, Thombs BD. The association of sociodemographic and objectively-assessed disease variables with fatigue in systemic sclerosis: an analysis of 785 Canadian Scleroderma Research Group Registry patients. Clinical rheumatology 2017;36:373-9.
- Jewett LR, Kwakkenbos L, Hudson M, Baron M, Thombs BD. Assessment of English-French differential item functioning of the Satisfaction with Appearance Scale (SWAP) in systemic sclerosis. Body image 2017;22:97-102.
- Hao Y, Hudson M, Baron M, Carreira P, Stevens W, Rabusa C, Tatibouet S, Carmona L, Joven BE, Huq M, Proudman S, Nikpour M. Early Mortality in a Multinational Systemic Sclerosis Inception Cohort. Arthritis & rheumatology (Hoboken, NJ) 2017;69:1067-77.
- Baron M. Pros and cons of echocardiography in the screening, diagnosis and follow-up of patients with systemic sclerosis pulmonary arterial hypertension – a rheumatologist’s perspective. J scleroderma relatdisord 2017.
- Wu M, Assassi S, Salazar GA, Pedroza C, Gorlova OY, Chen WV, Charles J, Taing ML, Liao K, Wigley FM, Hummers LK, Shah AA, Hinchcliff M, Khanna D, Schiopu E, Phillips K, Furst DE, Steen V, Baron M, Hudson M, Zhou X, Pope J, Jones N, Docherty P, Khalidi NA, Robinson D, Simms RW, Silver RM, Frech TM, Fessler BJ, Fritzler MJ, Molitor JA, Segal BM, Movahedian M, Martin J, Varga J, Mayes MD. Genetic susceptibility loci of idiopathic interstitial pneumonia do not represent risk for systemic sclerosis: a case control study in Caucasian patients. Arthritis research & therapy 2016;18:20.
- Leclair Valérie, MH, Susanna M. Proudman, Wendy M. Stevens, Marvin J. Fritzler, Mianbo Wang, Mandana Nikpour, Murray Baron Subsets in systemic sclerosis: one size does not fit all. J scleroderma relatdisord 2016;1:298 – 306
- Valenzuela A, Baron M, Herrick AL, Proudman S, Stevens W, Rodriguez-Reyna TS, Vacca A, Medsger TA, Jr., Hinchcliff M, Hsu V, Wu JY, Fiorentino D, Chung L. Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study. Seminars in arthritis and rheumatism 2016;46:344-9.
- Levis B, Rice DB, Kwakkenbos L, Steele RJ, Hagedoorn M, Hudson M, Baron M, Thombs BD. Using Marital Status and Continuous Marital Satisfaction Ratings to Predict Depressive Symptoms in Married and Unmarried Women With Systemic Sclerosis: A Canadian Scleroderma Research Group Study. Arthritis care & research 2016;68:1143-9.
- Khanna D, Berrocal VJ, Giannini EH, Seibold JR, Merkel PA, Mayes MD, Baron M, Clements PJ, Steen V, Assassi S, Schiopu E, Phillips K, Simms RW, Allanore Y, Denton CP, Distler O, Johnson SR, Matucci-Cerinic M, Pope JE, Proudman SM, Siegel J, Wong WK, Wells AU, Furst DE. The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis. Arthritis & rheumatology (Hoboken, NJ) 2016;68:299-311.
- Jewett LR, Malcarne VL, Kwakkenbos L, Harcourt D, Rumsey N, Korner A, Steele RJ, Hudson M, Baron M, Haythornthwaite JA, Heinberg L, Wigley FM, Thombs BD. Development and Validation of the Body Concealment Scale for Scleroderma. Arthritis care & research 2016;68:1158-65.
- Hudson M, Luck Y, Stephenson M, Choi MY, Wang M, Baron M, Fritzler MJ. Anti-HMGCR antibodies in systemic sclerosis. Medicine 2016;95:e5280.
- Hoa S, Hudson M, Troyanov Y, Proudman S, Walker J, Stevens W, Nikpour M, Assassi S, Mayes MD, Wang M, Baron M, Fritzler MJ. Single-specificity anti-Ku antibodies in an international cohort of 2140 systemic sclerosis subjects: clinical associations. Medicine 2016;95:e4713.
- Harel D, Hudson M, Iliescu A, Baron M, Steele R. Summed and Weighted Summary Scores for the Medsger Disease Severity Scale Compared with the Physician’s Global Assessment of Disease Severity in Systemic Sclerosis. The Journal of rheumatology 2016;43:1510-8.
- Baron M, Pope J, Robinson D, Jones N, Khalidi N, Docherty P, Kaminska E, Masetto A, Sutton E, Mathieu JP, Ligier S, Grodzicky T, LeClercq S, Thorne C, Gyger G, Smith D, Fortin PR, Larche M, Abu-Hakima M, Rodriguez-Reyna TS, Cabral-Castaneda AR, Fritzler MJ, Wang M, Hudson M. Calcinosis is associated with digital ischaemiain systemic sclerosis-a longitudinal study. Rheumatology (Oxford, England) 2016;55:2148-55.
- Baron M, Hudson M, Dagenais M, Macdonald D, Gyger G, El Sayegh T, Pope J, Fontaine A, Masetto A, Matthews D, Sutton E, Thie N, Jones N, Copete M, Kolbinson D, Markland J, Nogueira-Filho G, Robinson D, Fritzler M, Wang M, Gornitsky M. Relationship Between Disease Characteristics and Oral Radiologic Findings in Systemic Sclerosis: Results From a Canadian Oral Health Study. Arthritis care & research 2016;68:673-80.
- Adina Coroiu LK, Brooke Levis, Marie Hudson, Murray Baron, David Cella, Brett D. Thombs The comparability of Functional Assessment of Chronic Illness Therapy – Fatigue scores between cancer and systemic sclerosis. Journal of scleroderma and related disorders 2017.
- Greenfield J, Hudson M, Vinet E, Fortin PR, Bykerk V, Pineau CA, Wang M, Bernatsky S, Baron M. A comparison of health-related quality of life (HRQoL) across four systemic autoimmune rheumatic diseases (SARDs). PloS one 2017;12:e0189840.
- Hudson M, Bernatsky S, Colmegna I, Lora M, Pastinen T, Klein Oros K, Greenwood CMT. Novel insights into systemic autoimmune rheumatic diseases using shared molecular signatures and an integrative analysis. Epigenetics 2017;12:433-40.
- Lagares D, Ghassemi-Kakroodi P, Tremblay C, Santos A, Probst CK, Franklin A, Santos DM, Grasberger P, Ahluwalia N, Montesi SB, Shea BS, Black KE, Knipe R, Blati M, Baron M, Wu B, Fahmi H, Gandhi R, Pardo A, Selman M, Wu J, Pelletier JP, Martel-Pelletier J, Tager AM, Kapoor M. ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis. Nature medicine 2017;23:1405-15.
- Lagares D, Santos A, Grasberger PE, Liu F, Probst CK, Rahimi RA, Sakai N, Kuehl T, Ryan J, Bhola P, Montero J, Kapoor M, Baron M, Varelas X, Tschumperlin DJ, Letai A, Tager AM. Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Science translational medicine 2017;9.