Celebrating the impact of health research

Treatment on a silver platter: the role of platelets in rheumatic diseases

Eric Boilard PhD
Centre de Recherche en Rhumatologie et Immunologie, CHU Research Center, Faculté de Médecine de l'Université Laval

Introduction

We have known about platelets for about 150 years – a tiny, plate–shaped (thus the name) component of blood, nearly a trillion of which patrol our blood, on the ready to repair damage to blood vessels by triggering the formation of a blood clot. What we haven't known, though, is that platelets also play a key immunological function. It is only fairly recently that we have learned about platelets' vast arsenal of immune activators and mediators.1 Since this suggested that platelets may have an immune role, we wondered whether platelets could play a role in rheumatoid arthritis (RA), which is an autoimmune disorder.

Uncovering the role of platelets in rheumatoid arthritis

Our first step was to look for platelets in the synovial fluid (a fluid that acts as a lubricant in joints) in people with RA. We didn't find them – but what we did find, to our surprise, was small microparticles shed from the outside membrane of platelets. These particles were also found in other kinds of arthritis, including psoriatic arthritis, juvenile idiopathic arthritis and gout, but, with few exceptions, were rare in people with osteoarthritis, implying that they play a role in inflammatory arthritis.1, 2

Mice depleted of platelets developed much less intense arthritis than mice with normal platelet counts.

When we looked more closely at the microparticles, we found that they were, indeed, pro–inflammatory. When we looked at a mouse model of arthritis, we found that mice depleted of platelets developed much less intense arthritis than mice with normal platelet counts. And when mice lacked a key receptor involved in producing inflammatory platelet microparticles, they had much less intense arthritis. So we knew one thing – that platelets and their microparticles had an important role to play in the cause of rheumatoid and other inflammatory arthritides, or types of arthritis.1, 2

Platelets, in effect, promote amplification of the inflammation that marks rheumatoid arthritis.

The first focus of our research became figuring out how platelets and their microparticles get out of blood vessels, where they normally are found, and accumulate in the synovial fluid, given that neither generally is migratory. It turns out that arthritic joints have microscopic gaps between endothelial cells, just small enough for the microparticles to find their way into the synovial fluid, though not the platelets.1, 3 Platelets do play a role though. We found that platelets promote the formation of these gaps in joint cells during periods of chronic inflammation, contributing both to joint edema, or the accumulation of fluid, and to the entry of the pro–inflammatory microparticles. Platelets, in effect, promote amplification of the inflammation that marks rheumatoid arthritis.1, 3

Outcomes

This images shows one platelet covered with small buds, which are the microparticles being released from the platelet surface. Around the platelets, I also illustrated five microparticles. This image was taken by electron microscopy, after incubating human platelets with synoviocytes from patients with rheumatoid arthritis. (Image rights: Eric Boilard)

The Faculty of 1000 considered these findings among the top five discoveries in medicine in 2010.

This demonstration of an active contribution of platelets in autoimmune inflammatory arthritis brought colossal enthusiasm from the scientific and medical communities. Indeed, the Faculty of 1000 (F1000) considered these findings among the top five discoveries in medicine in 2010. It is obvious that this research will initiate studies on the role of platelets in other rheumatic disorders and (auto) immune diseases.

Front, left to right: Anne-Claire Duchez (CAN/TAS PhD fellow), Geneviève Marcoux, Tania Lévesque, Valérie Garceau, Eric Boilard
Back, left to right: Luc Boudreau (CAN/TAS postdoctoral fellow), Nathalie Cloutier and Matthieu Rousseau

Research on platelets also provides new targets for arthritis treatment. Treatments currently available target immune cells and, while they can treat inflammatory arthritic diseases such as rheumatoid arthritis, they are, of necessity, also detrimental to the patient's immunity. By focusing on inhibiting the inflammatory functions of platelets, new treatments can be developed that will have little or no impact on the patient's immune system. We are currently, with support from the Canadian Arthritis Network, working to identify platelet receptors whose inhibition could impair arthritis without affecting platelets' ability to stop bleeding by the formation of blood clots.

Acknowledgments

Dr. David M. Lee, Novartis; Dr. Peter A. Nigrovic, Brigham and Women's Hospital, Boston; Dr. Richard Farndale, Cambridge University; Dr. Jerry Ware, U of Arkansas; Dr. Steve Lacroix, CHU de Québec, Université Laval

Funding: Eric Boilard is supported by the Canadian Institutes of Health Research (CIHR), The Arthritis Society, the Canadian Arthritis Network (CAN) and the Fonds de recherche du Québec – Santé.


Seeing the patient in front of them: addressing physicians' contributions to gender disparity in total joint replacement

Cornelia M. Borkhoff PhD
Department of Health Policy, Management and Evaluation, University of Toronto
Women's College Research Institute, Women's College Hospital

Gillian A. Hawker MD MSc FRCPC
Department of Health Policy, Management and Evaluation, University of Toronto
Department of Medicine, Women's College Hospital

James G. Wright MD MPH FRCSC
Department of Health Policy, Management and Evaluation, University of Toronto
Department of Surgery, The Hospital for Sick Children

Dawn Stacey PhD
School of Nursing, University of Ottawa
Ottawa Hospital Research Institute, Ottawa Hospital

Hans J. Kreder MD MPH FRCSC
Departments of Surgery and Health Policy, Management and Evaluation, University of Toronto
Division of Orthopaedic Surgery, Sunnybrook Health Sciences Centre

Geoff Dervin MD MSc FRCSC
Ottawa Hospital Research Institute, Ottawa Hospital
Department of Surgery, Division of Orthopaedic Surgery, University of Ottawa

Peter Tugwell MD MSc FRCPC
Department of Medicine, University of Ottawa
Ottawa Hospital Research Institute

Introduction

Women are twice as likely as men to suffer from hip and knee osteoarthritis (OA) – yet the "unmet need" for total joint replacement (TJR) (the optimum treatment for relieving pain and restoring joint function when medical treatment fails) is higher in women than men. In fact, women are less likely than men to have discussed TJR with a physician or to be on a TJR waiting list, much less have the actual surgery. Now, new research is focusing on the (unconscious) role of the physician in this gender disparity.

We broke new ground by examining the role of the physician and by doing so in a novel way. Now the results of our study are guiding further research to reduce gender disparities by focusing on the physician rather than solely on the patient.

The original findings come from a study conducted in the 1990s by Dr. Gillian Hawker and her colleagues.4 To paraphrase Isaac Newton, "if we can see further, it is by standing on the shoulders of giants". Theirs was the first research to establish the presence of gender disparity in rates of use of total hip and knee replacements in Canada. The study found that, while there is underuse of TJR in both genders, the degree of underuse among willing and appropriate candidates for surgery is more than three times as great in women as in men. Their paper was published in the New England Journal of Medicine, received a Gold Medal from the Royal College of Physicians and Surgeons of Canada and continues to be cited by authors throughout the world.

Subsequent research investigating potential explanations for the observed gender disparity in TJR has focused on the patient. We broke new ground by examining the role of the physician and by doing so in a novel way. Now, the results of our study are guiding further research to reduce gender disparities by focusing on the physician rather than solely on the patient.

"Operation Knee"

"Operation Knee" was a methodologically and logistically challenging study that used standardized, or "mystery", patients to assess whether physicians responded differently to patients identical in every way but gender. The patients – one man and one woman, both with moderate knee OA – were trained to present themselves with identical clinical scenarios.

We found that physicians did, indeed, respond differently. When the patient was a woman, physicians were less likely to recommend total knee replacement (TKR). They also provided the woman with less medical information and less encouragement to participate in the decision to undergo TKR.5, 6 Physicians also seldom discussed her role in decision making, explored whether she understood the decision, elicited her preferences or discussed post–surgery recovery,6 which we know to be a specific concern for women7.

Our findings suggest that physicians may be at least partially responsible for the gender disparity in the rates of use of TJR. Our study was the first to demonstrate that patient gender affected physicians' treatment recommendations and interpersonal behaviour in actual clinical practice and provides some of the most conclusive evidence to date of a significant provider contribution to gender disparity in health care.

The approach we used to investigate gender bias as a possible explanation for the gender disparity in TJR, using standardized patients, was rigorous and original and is an important methodological contribution to the field. Using standardized patients enabled us to design a study that comes closest to controlling for patients' countless clinical, social and personal characteristics that might influence physicians' clinical decision making.

It took three years to recruit and extensively train a man and woman with comparable levels of knee OA severity as standardized patients and subsequently arrange 142 physician visits for them. The process was complex, involving everything from recruiting family physicians to provide mock referral letters to the participating orthopaedic surgeons, to involving a radiologist to regularly provide up–to–date bilateral standing knee x–rays with a fictitious hospital file number and the patient's pseudonym for each standardized patient.

Outcomes and impacts: extending the research

We do not think that physicians are deliberately withholding treatment from women; rather they are just not recognizing the seriousness of women's symptoms.

Our research has led to increased attention to patient–physician communication, both at a primary care and surgeon level, as a source for gender disparities in TJR.

We do not think that physicians are deliberately withholding treatment from women; rather they are just not recognizing the seriousness of women's symptoms. Attributing women's symptoms to emotional rather than physical causes or holding inappropriate preconceptions that women don't receive the same benefit from TJA as men are some possible implicit or unconscious stereotypes based on gender that may be influencing physicians' treatment decisions.

We are currently examining the extent to which an unconscious gender bias explains physicians' treatment decisions, using a customized implicit association test (IAT). We are evaluating whether this test could also be used to measure the effectiveness of a skills course that focuses on increasing physicians' awareness of the unconscious biases that may be influencing their decision making and provides them with the capacity to overcome such biases.

We are also evaluating whether a knee OA patient decision aid (PtDA) with a one–page "patient preference report" (considered the first published knowledge translation tool to communicate a patient's clinical severity and individual concerns in clinical practice) developed by our group8 is a viable clinic–based intervention to overcome these biases. There is good evidence that PtDAs improve patients' decision quality, knowledge and expectations, but few studies have evaluated their effect on patient–physician interaction. As well, no studies have examined the impact of PtDAs in reducing disparities in the utilization of any medical or surgical procedure. And whether the use of PtDAs improves shared decision making between physician and patient overall and as effectively with female patients has been virtually unexplored. Nonetheless, PtDAs do prepare patients for participating in an informed discussion about treatment options with their physician and help physicians to be more aware of patients' individual concerns and preferences. We therefore believe that their use will result in physicians recognizing the seriousness of women's symptoms, and seeing the patient in front of them, thus "neutralizing" any unconscious stereotypes physicians might hold.

Our achievement advances the field of health services research, with an explicit focus on reducing inequities in access to musculoskeletal care for disadvantaged populations. Our further research will provide effective tools to overcome these inequities.

Acknowledgments

The authors thank the physicians who participated in this research. We also acknowledge the invaluable contributions made by all members of the "Operation Knee" research team, especially Dorothy Aungier, Marylyn Peringer, Murray Nisker, Len Berk, Mindy Green, Lois MacKenzie, Werner Thom, Gaby Thom, Sam Osak and Harold Weston for their work as standardized patients or mock family members. We are also especially grateful to Jennifer Ionson and Sara Karlsson for their work in recruiting participants, data entry and an unwavering commitment to this research.

Funding: Past projects were funded by the Canadian Institutes of Health Research (CIHR) and the Arthritis Society of Canada. Ongoing projects are funded by CIHR and the Foundation for Informed Medical Decision Making. Cornelia Borkhoff was supported by a Canadian Arthritis Network (CAN) Graduate Student Award, and a CIHR Postdoctoral Fellowship Award.


It's all relative: early detection of rheumatoid arthritis in First Nations

Hani El–Gabalawy MD FRCPC
Professor of Medicine and Immunology and Endowed Rheumatology Research Chair, University of Manitoba

Introduction

Aboriginal people in Canada, particularly the Cree/Ojibway First Nations (FN), bear a disproportionate burden from rheumatoid arthritis (RA). This chronic progressive autoimmune inflammatory disease affects just 1% of Canadians in general, but 2% or more of First Nations People. If not detected and treated at an early stage, this painful disease can cause catastrophic functional loss and progressive lifelong disability, leading to substantial loss of earning power, social stature and quality of life. It also results in enormous costs to society, both in direct health–care costs and indirect costs from lost productivity.

Rheumatoid arthritis affects just 1% of Canadians in general, but 2% or more of First Nations People.

Not only is RA highly prevalent and severe in Cree/Ojibway FN, the disease also exhibits a strong tendency towards familial clustering in this population. We are taking advantage of this tendency to learn how to detect – and possibly prevent – RA at its earliest stages, by studying the first–degree relatives of FN people with RA, including parents, children and siblings, who may be at highest risk for future development of the disease.

Working with communities to uncover clues to RA

In Manitoba, the study has recruited RA patients and their first–degree relatives from the Winnipeg area, and we have worked closely with members of two remote Manitoba FN communities, Norway House and St Theresa Point, to identify and recruit RA patients and their relatives in these communities. Drs. Janet Markland and Elizabeth Ferucci have recruited RA patients and their first–degree relatives into the study from urban and rural settings in Saskatchewan and Alaska, respectively. In total, we recruited 300 people with RA and more than 500 of their first–degree relatives, as well as 300 geographically matched people with no family history of RA as a comparison group. We have followed the first–degree relatives for several years to understand more about who will develop the disease. Our work with these cohorts has allowed us to assemble a clearer picture of the risk factors for disease development.

Specifically, we defined genes associated with RA and with RA–associated autoantibodies to RA in the FN population. Since the major genetic risk for RA, called the "shared epitope", is very common in the FN population, present in 60–70% of healthy individuals, only a small proportion of whom will develop RA, we have found several other genes that further affect this risk of disease development. We have also found that about one–third of first–degree relatives of people with RA have the RA–associated autoantibodies to the disease, compared to about 1–3% in people with no family history, suggesting that many first–degree relatives, despite having no signs of RA, are more predisposed to developing it.

We also explored the association between having these autoantibodies and smoking and periodontitis (gum disease), to learn more about the link between genetic susceptibility and environmental risk factors. We found a strong association between bacteria that cause gum disease and the presence of RA autoantibodies. This suggests an important link between gum disease and RA, and implies that reducing gum disease may affect the future risk of RA development. Our studies in the two FN communities indicate that gum disease is common, which may increase RA in these communities. Smoking, another well–known risk factor for RA, is also very common in the FN population, thus further increasing risk.

We also monitored the evolution of autoantibodies and serum cytokines (which regulate immune–system functioning) in people who had autoantibodies but had not yet started to manifest symptoms of RA. We found that high levels of cytokines in first–degree relatives may be another risk factor for future RA development.

We have been able to generate a clinically meaningful model, incorporating both symptoms and biomarker signatures, to help predict the onset of RA in a high–risk FN population.

Finally, in following the high–risk relatives over several years, we have seen the RA autoantibody profile in individuals developing the first symptoms of RA become expanded and amplified in the period immediately preceding disease onset, thus giving us valuable biomarkers for predicting imminent RA. We have now, as a result, been able to generate a clinically meaningful model, incorporating both symptoms and biomarker signatures, to help predict the onset of RA in a high–risk FN population. Early detection means treatment can begin early, thus minimizing or slowing its progression.

Even more exciting, we are now designing clinical trials aimed at preventing RA before it even starts.

Outcomes

Dr. Hani El-Gabalawy examining a patient in St. Theresa Point, a remote community in northern Manitoba.

The most obvious impact of our research is a way to detect RA and begin treatment early – and work toward a way to prevent it altogether.

Our research has also had important impacts for the participating communities. We have trained local community members to undertake clinical research, thereby increasing capacity for research in these communities. The people we have trained now serve as research assistants, as well as advocates for early RA detection and treatment. We were also able, through a partnership with the Centre for Aboriginal Health Research at the University of Manitoba, to provide an indigenous student an opportunity to take on one aspect of the project. She presented her work at a meeting, and has since started medical school in another country.

Through the use of radio "call in" programs regularly held in the communities during the study visits, we have substantially increased knowledge about RA, its early symptoms, and the value of early detection and treatment among the communities at large. We have also enhanced local access to rheumatology services through regular outreach clinics held during study visits.

We have held focus groups in the community with RA patients and their first–degree relatives that explored individual perceptions of RA risk and the willingness of individuals to undertake prevention strategies, both pharmacologic and non–pharmacologic. These will be helpful in planning future prevention studies.

Finally, we have held two major international symposia in Winnipeg, in 2009 and 2012, the first funded by the Canadian Arthritis Network (CAN) and the Canadian Institutes of Health Research (CIHR) and the second funded by CIHR, to advance the research agenda for RA and rheumatic diseases in FN. These symposia have brought together Canadian researchers who are undertaking various RA projects in First Nations communities and helped to integrate our RA research project with international initiatives designed to develop risk models and prevention strategies for RA.

We are now exploring the possibility of developing appropriate surveillance mechanisms for detecting imminent RA in remote FN communities. This will allow us to undertake unprecedented RA prevention studies in conjunction with the international community.

Acknowledgments

We are particularly indebted to the Chief and Band Council, and the people of Norway House and St Theresa Point, Manitoba for their support of the project. We are also indebted to the Assembly of Manitoba Chiefs for supporting the project.

Co–Investigators: Brenda Elias PhD, Kiem Oen MD FRCPC, Christine Peschken MD FRCPC, David Robinson MD FRCPC, Carol Hitchon MD FRCPC, University of Manitoba; Elizabeth Ferucci MD MPH, Alaska Native Tribal Council, Anchorage, Alaska

Primary Collaborators: Marvin Fritzler PhD MD, University of Calgary; Janet Markland, MD FRCPC, University of Saskatchewan; Marianna Newkirk PhD and Henri Menard MD FRCPC, McGill University; Katherine Siminovitch MD FRCPC, University of Toronto; Tom Huizinga MD PhD, Leiden University; William Robinson MD PhD, Stanford University; Charles Bernstein MD FRCPC, University of Manitoba

Funding: Canadian Institutes of Health Research (CIHR), Canadian Arthritis Network (CAN)


A better way to restore knee cartilage

Caroline D. Hoemann PhD
Department of Chemical Engineering and Institute of Biomedical Engineering, École Polytechnique

Georges–Etienne Rivard MD
Division of Hematology and Oncology, Hôpital Sainte-Justine, Montreal

Hani El–Gabalawy MD
Rheumatic Diseases Research Laboratory, University of Manitoba

Mark Hurtig DVM
Department of Clinical Studies, University of Guelph

Michael Buschmann PhD
Department of Chemical Engineering and Institute of Biomedical Engineering, École Polytechnique

Introduction

We subject our knees to a lot of abuse over the years – and all that stands between a healthy knee joint and an arthritic one is a thin and smooth layer of elastic tissue called cartilage, which covers the ends of bones that form the knee joint. In fact, the most serious and irreversible damage to the knee involves the loss of cartilage.

Our work has built the science behind an entirely new way to repair articular cartilage, allowing patients to return to daily activities with less pain and better quality of life.

This cartilage, also known as articular cartilage, has a poor capacity to heal by itself; small lesions, if left untreated, can progress to generalized knee degeneration, which generates considerable pain during simple daily activities. Surgical methods developed in the 1950s, and still used today, help "resurface" exposed bone and restore knee function, using marrow stimulation therapy. In these procedures, called microfracture surgery, the surgeon creates small wounds in the bone below the cartilage lesion to induce bleeding, which in turn stimulates cells from the underlying bone marrow to migrate into the lesion and rebuild new tissue. This approach can alleviate symptoms in most patients, but the effects frequently don't last. Repaired tissue often lacks the resilient qualities of cartilage and breaks down with use, often within two–to–three years after the surgery.

Developing new, affordable therapies that create a durable cartilage repair tissue is a major challenge. Our work has built the science behind an entirely new way to repair articular cartilage, allowing patients to return to daily activities with less pain and better quality of life.

Engineering a solution

Around 12 years ago, we came up with a completely new idea of how to repair damaged articular cartilage, by amplifying the natural response to marrow stimulation using a bio–engineered blood clot.

The novel blood clot was formed by incorporating a biomaterial called chitosan into whole blood. The resulting bio–engineered blood clot is more adhesive and more voluminous than normal blood clots. The liquid implant can coagulate just like whole blood in a cartilage lesion with microfracture holes, and was found to improve cartilage–repair tissue quality in several preclinical models.

Our research revealed that biodegradable chitosan has a number of unique abilities and features that make it ideal for repairing cartilage.

We set out to understand how chitosan–stabilized blood clots guide inflammatory cells to recruit more stem cells from the bone marrow to the cartilage defect. Our research revealed that that biodegradable chitosan has a number of unique abilities and features that make it ideal for repairing cartilage.

First, chitosan has a unique ability, not shared by other polymers, to attract more neutrophils, alternatively activated macrophages and blood vessels to healing bone defects. In addition, chitosan has a "calming" effect on inflammatory cells, stimulating these cells to release molecules that delay fibrosis and remodel the bone lesions, which allows more blood flow and helps rebuild and integrate new bone tissue. Chitosan also stimulates macrophages, a specialized type of white blood cell that helps heal all wounds, to release specific stem cell chemotactic factors. In addition to these findings, we also discovered that coagulation factors currently used in the clinic to stop bleeding can be used to help hybrid clot implants solidify in the surgical defect, and to promote new blood vessels to grow into the bone channels created by marrow stimulation.

To translate our findings to other scientists, we carried out traditional knowledge translation activities, including publishing our findings in scientific journals and presenting them at a variety of international and national conferences. We also used more non–traditional avenues, such as interviews for newsletters and on–line blogs, to make our research accessible to the public.

Most importantly, the therapy we developed was successfully translated to the clinic thanks to a partnership with BioSyntech Inc., now Piramal Healthcare Canada. Following encouraging results from the treatment of 33 patients with the chitosan implant, through a Canadian humanitarian–based special access program, a randomized controlled clinical trial was carried out in Canada and Europe with 80 patients recruited. A superior outcome was obtained for patients who received the BST–CarGel® treatment compared to those who received only microfracture surgery.

Outcomes

Professor Caroline Hoemann and her research team: Front: Caroline Hoemann; second row, left-to-right: Jessica Guzmán-Morales (research associate), Genevieve Picard (technician), Xian Li (post-doc); back row, from left-to-right: Charles-Hubert Lafantaisie-Favreau (PhD student), David Fong (PhD student), Gaoping Chen (Research associate)

The clinical trial has led to product approval of the BST–CarGel® for clinical use in Europe. Approval for clinical use in Canada is currently pending. Thus, our research has led to a new treatment for patients with degenerating knee cartilage; we continue to make important advances in understanding how to heal cartilage lesions from bone marrow responses.

Our research program, by allowing us to build the science behind an entirely new and affordable therapy for articular cartilage repair, has also paved the way for further advances in scaffold–guided bone and cartilage repair. Results from this program, initiated in 2005, demonstrated, in preclinical models, that a more hyaline and integrated cartilage repair tissue can be obtained when marrow stimulation defects are treated with a chitosan–blood implant, compared to marrow stimulation surgery alone.

Our data also show, however, that in patients with chronic cartilage lesions, there are important alterations in the subchondral bone that could create a more challenging repair environment. One of the persisting challenges is the heterogeneity of the repair tissues, which is most probably related to the pre–existing subchondral bone environment. Future research will focus on advancing our knowledge of the subchondral reactions to biomaterial implants and how white blood cells and the surgical environment can be fine–tuned to stimulate a reproducible and optimal stem cell influx. Continuing research will allow us to further improve this therapeutic approach in middle–aged patients and patients with chronic lesions, who represent a large share of those needing treatment. The next steps will also involve creating new implants that can be delivered by arthroscopy, a minimally–invasive procedure for orthopaedic repair therapies.

Acknowledgments

Individuals, communities/cities/regions and organizations involved: Patrice Poubelle, Maria Fernandes, William D Stanish, Marc McKee, Matthew Shive, Alberto Restrepo, Bob McCormack, Michael Centola, Isabelle Villemure, Gregory De Crescenzo, Mario Jolicoeur, Janet Henderson, Pierre Ranger, Amine Selmani, Nicolas Duval, Abdellatif Chenite, Jun Sun, Gaoping Chen, Anik Chevrier, Jessica Guzmán–Morales, Julie Tremblay, Hongmei Chen, Viorica Lascau–Coman, Genevieve Picard, Nicolas Tran–Khanh, Marc Thibault, Evgeny Rossomacha, Francine Dérome, Angélique Hoeffer, Michelle Brydges, Deb McWade, Catherine Marchand, Charles–Hubert Lafantaisie–Favreau, David Fong, Marianne Ariganello, Colleen Mathieu, Angela Bell, Angel Contreras–Garcia, Adam Harris, T Duncan Smith, Pascal Simard, Yoann Gosselin, Sam Osseiran, Myriam Lamarre, Jessy Bachand, Jessica Jonker, Maxime Desgagné, Simon Bolduc–Beaudoin, Joel Girard–Lauziere

Funding: Natural Sciences and Engineering Research Council of Canada (NSERC), BioSyntech Ltée, Piramal Healthcare Canada, Canadian Foundation for Innovation (CFI), Fonds de Recherche du Québec–Santé (FRQ–S), Groupe de Recherche en Sciences et Technologies Biomédicales (GRSTB–FRQ–S), Canadian Arthritis Network (CAN)


A randomized trial of arthroscopic surgery for osteoarthritis of the knee

Alexandra Kirkley MD
Fowler Kennedy Sport Medicine Clinic and Department of Surgery, University of Western Ontario

Trevor B. Birmingham PhD
Fowler Kennedy Sport Medicine Clinic and Faculty of Health Sciences, University of Western Ontario

Robert B. Litchfield MD
Fowler Kennedy Sport Medicine Clinic and Department of Surgery, University of Western Ontario

J. Robert Giffin MD
Fowler Kennedy Sport Medicine Clinic and Department of Surgery, University of Western Ontario

Kevin R. Willits MD
Fowler Kennedy Sport Medicine Clinic and Department of Surgery, University of Western Ontario

Cindy J. Wong MSc
Robarts Clinical Trials, Robarts Research Institute, University of Western Ontario

Brian G. Feagan MD
Robarts Clinical Trials, Robarts Research Institute, Department of Medicine, and Department of Epidemiology and Biostatistics, University of Western Ontario

Allan Donner PhD
Robarts Clinical Trials, Robarts Research Institute and Department of Epidemiology and Biostatistics, University of Western Ontario

Sharon H. Griffin CSS
Fowler Kennedy Sport Medicine Clinic, University of Western Ontario

Linda M. D'Ascanio BScN
Fowler Kennedy Sport Medicine Clinic, University of Western Ontario

Janet E. Pope MD
Department of Medicine, University of Western Ontario
St. Joseph's Health Care

Peter J. Fowler MD
Fowler Kennedy Sport Medicine Clinic and Department of Surgery, University of Western Ontario

Introduction

In a perfect world, all surgical or medical treatments would have strong evidence supporting their effectiveness. As our research demonstrated, however, sometimes the strong evidence actually refutes accepted practice.

Our focus was osteoarthritis of the knee. Extremely common, this degenerative disease represents a major source of pain and disability for Canadians, and a huge cost to the Canadian economy. There are several treatments for osteoarthritis of the knee, including physical therapy, medication, and surgery. One of the most common surgical techniques for osteoarthritis is arthroscopic debridement, in which a device is inserted into the knee joint, allowing the surgeon to see the structures in the knee, remove unwanted tissue, and smooth the cartilage surface. The theory is that the surgical intervention will allow for smoother mechanical operation of the knee and a better outcome for patients. In practice, though, despite its widespread use, there has been surprisingly little high–level evidence to support its use. Due to this lack of evidence, our research team (led by Dr. Alexandra Kirkley) carried out a clinical trial between January 1999 and August 2007, to compare the outcome for patients who received surgical versus non–surgical therapy – and were surprised at just how ineffective this common surgery proved to be.

Gathering needed evidence

"Patients assigned to arthroscopic surgery were no more likely to report improvement with respect to physical function, pain, or health–related quality of life than were those assigned to the control group."

Our study, a single–centre, randomized controlled trial, randomly assigned 192 patients with moderate–to–severe osteoarthritis of the knee to one of two study groups. One group received arthroscopic debridement surgery together with optimized physical and medical therapy, while the other received solely optimized physical and medical therapy, without surgery. All patients were followed for two years, and their outcome was measured using a number of generic and disease–specific heath status questionnaires (such as the Western Ontario and McMaster Universities Osteoarthritis Index) to evaluate pain, stiffness, physical functioning and other factors important to patients. Scores were obtained at baseline (i.e., before treatment) and at 3, 6, 12, 18, and 24 months after treatment.

A surgical treatment that was part of the normal process of care for osteoarthritis of the knee failed to show any benefit for patients.

The findings were clear – there were no significant differences between the surgical and control treatment groups at any point after three months. "Patients assigned to arthroscopic surgery were no more likely to report improvement with respect to physical function, pain, or health–related quality of life than were those assigned to the control group."9 A surgical treatment that was part of the normal process of care for osteoarthritis of the knee failed to show any benefit for patients. These results were in general agreement with those of an earlier study carried out by Moseley et al.10 that compared arthroscopic surgery to sham surgery in a group of older men at a Veterans Affairs hospital.

When they were published in the New England Journal of Medicine in September, 2008, our study results immediately generated considerable interest and discussion. In an editorial published in the same issue, Marx concluded by stating "Surgeons must practice evidence–based care and use sound clinical judgment to make the best decisions for individual patients."11 The study was also featured in a 2009 article in the Journal of the American Medical Association, describing evidence–based advice for treating osteoarthritis of the knee.12 Media coverage related to this study was extensive, with feature stories in the New York Times and Globe and Mail. Time Magazine featured the study in its annual review of medicine in 2008.

Outcomes

This CIHR–funded study has had a significant impact, with 90 citations in the past four years. This study, together with the results of Moseley et al., is changing clinical practice around the world. In 2009, Mounsey and Ewigman concluded – based on the results of these two high–quality randomized controlled trials – that surgeons should "not recommend arthroscopic surgery to adults with osteoarthritis of the knee", but should "treat knee pain with medical and physical therapy instead."13 In 2012, Felson referred to the Kirkley study in an article in Best Practice & Research Clinical Rheumatology, stating that "large randomized trials have suggested that arthroscopy has a limited role as a treatment of osteoarthritis."14

The total reduction in this surgery translates into national savings (in the US) of between $82 million and $138 million annually.

The clearest impact of this type of study is in the area of knowledge translation; specifically, the impact of research on health services and clinical practice. Although there is still room for improvement,15 faced with objective evidence of the limited efficacy of arthroscopy for knee osteoarthritis, surgeons across North America have significantly reduced the rates for this procedure. In 2012, Howard et al. published the results of a study entitled "Evidence of no benefit from knee surgery for osteoarthritis led to coverage changes and is linked to decline in procedures."16 They set out to determine if the results of clinical trials were associated with changes in practice patterns, and concluded that arthroscopic knee surgery declined in Florida by 47 percent between 2001 and 2010, and specifically found that "rates also declined following publication of the results of Kirkley and colleagues' trial in 2008." They estimate that the total reduction in this surgery translates into national savings (in the US) of between $82 million and $138 million annually, indicating clearly that "clinical trials of widely used therapies can lead to cost–saving changes in practice patterns."16

Acknowledgments

Individuals, communities/cities/ regions and organizations involved: Dr. Alexandra (Sandy) Kirkley was a founding member of the Canadian Arthritis Network (CAN) and an active participant until her tragic death in an airplane accident in September, 2002.

Funding: Supported over the period 1998–2007 entirely by operating grants from the Canadian Institutes of Health Research (CIHR), entitled "Arthroscopic surgery versus non–surgical treatment of osteoarthritis of the knee."


Peer to peer mentoring in early inflammatory arthritis

Dawn Richards PhD
Canadian Arthritis Network Consumer Advisory Council

Jennifer Boyle PhD
The Arthritis Society – Ontario Division

Paula Veinot
Sunnybrook Health Sciences Centre, Rheumatology

Dr. Mary Bell
Sunnybrook Health Sciences Centre, Rheumatology and University of Toronto, Medicine

Introduction

Receiving a diagnosis of inflammatory arthritis (IA) – arthritis caused by the body's own immune system – can be difficult. The medical resources to treat such arthritis are greatly improved today, with relatively new drugs able to treat and slow the progress of the disease. Other non–medical support is often lacking, or dependant on the patient being resourceful enough to find it on his or her own.

Our research focuses on the potential benefit of peer support on the health and quality of life of individuals with early inflammatory arthritis (EIA), using both qualitative and quantitative evaluation methods. Peer–support models have been successfully used for persons with various chronic conditions, including HIV/AIDS,17 cancer18 and diabetes.19 Our research is a feasibility study exploring the value of expanding such models into the field of arthritis. In this context, peer support consists of the provision of emotional, appraisal and informational assistance20 by a peer – a person who shares common characteristics and who is able to relate to and empathize with the person being supported on a level that would not be possible for a non–peer.21

Our multidisciplinary research team importantly includes two individuals who live with IA (i.e., consumers), one of whom feels very strongly, based on personal experience, that this type of resource is sorely lacking as a patient supplementary healthcare resource. These consumers are integrated into every aspect of this research and provide an important patient perspective to our project.

The importance of someone to talk to

The intervention we developed is based on the work we did in the first phase of the project, a needs assessment. This assessment phase featured one–on–one interviews with IA patients, family/friends and health care providers to explore their needs and perspectives on peer support and was augmented by a literature review (i.e., a meta–ethnography) to explore the perceived impact and experience of participating in peer–support interventions. We held working groups and research team meetings to discuss various aspects of intervention development (i.e., peer–mentor training, peer–mentoring program, evaluation).

The feasibility study itself (see Figure 1) consisted of a peer–mentor training model with thorough accompanying support resource material. Experts external to the project, including four consumers, reviewed all training materials, which we modified based on their feedback. We trained nine peer mentors, using both didactic and interactive sessions to ensure they were knowledgeable and comfortable with their proposed role of mentoring a newly diagnosed IA patient. We also recruited nine individuals with EIA (mentees) and paired them with a peer mentor to receive one–on–one support (face–to–face or telephone) approximately once a week for 12 weeks.

Figure 1. Flow diagram of the peer support intervention design

Figure 1 long description

When we collected and analyzed evaluation data, we found the peer–mentor training process, peer–support program and outcome measures were feasible with modifications. For instance, we found that peer mentors' self efficacy significantly increased after training, followed by a decline immediately post–program and subsequent recovery after three months. Mentees experienced improvement in terms of overall arthritis impact on health–related quality of life, coping, and social support.

We also conducted qualitative interviews with nine peer mentors and eight mentees. The peer–mentor training was positively received: "It will help me problem–solve in my own life and has given me additional resources," said one mentor. Mentors reported that training increased their knowledge, inspired ideas for new self–management techniques and coping strategies, and made them realize how far they had come in their disease experience.

"It's different, I guess, in a clinical setting with a therapist versus having other people that you can talk to from life experience...please don't stop."

Most importantly, mentees appreciated the emotional, informational, appraisal and instrumental support they received. As one of them said, "It's different I guess in a clinical setting with a therapist versus having other people that you can talk to from life experience. I've been saying that all the way through the program, as soon as I heard what they were doing, that this is 100% needed for the arthritis community... I just know when I was given the binder and this kind of information, it's like if somebody had handed me this on the day of diagnosis, that would have been critical for me, because this is as important as medication, because this is all your information and resources... please don't stop."

Peer mentors similarly reported benefits and learned from mentees' fortitude and self–management skills. Both mentors' and mentees' experience of peer support was informed by the unique relationship with their peer partner. A "connection" was facilitated by similarities in personality, age, gender, interests, life stage, positions of responsibility at work, diagnosis, disease severity and limbs affected. Participants were unequivocal about the need for peer support for individuals with IA.

Outcomes

Peer mentors gathering at one of the training sessions at Sunnybrook Health Sciences Centre, September 28, 2011.

Our study has clearly demonstrated that early peer support may augment current care in rheumatology. We thought these findings would be important, so adopted an integrated knowledge translation approach from the start, as evidenced by our multidisciplinary team, consisting of consumers, researchers and partners from The Arthritis Society. We delivered many interim presentations, including at international venues. Manuscripts on the needs assessment and the evaluation phases of the pilot feasibility study have been submitted for publication.22, 23

We have now expanded this research to a small pilot randomized controlled trial, partially funded by the Canadian Initiative for Outcomes in Rheumatology Care. We hope to demonstrate the effectiveness of peer support in EIA management, which we believe will positively and measurably affect health outcomes. The research team feels strongly that the development of a peer–support intervention, in which program materials have been well thought out and peer mentors have been well–prepared to work with their newly diagnosed mentees, is a much–needed patient resource. Ultimately this program will better prepare EIA patients to deal with their intimidating diagnosis and the new daily challenges they face living with arthritis for the rest of their lives.

Acknowledgments

Research Team: Gayathri Embuldeniya, Sunnybrook Health Sciences Centre; Joyce Nyhof–Young, University of Toronto, University Health Network; Joanna Sale, University of Toronto, St. Michael's Hospital; Joan Sargeant, Dalhousie University; Peter Tugwell, University of Ottawa, Ottawa General Hospital; Sydney Brooks, The Arthritis Society – Ontario Division; Laure Perrier, University of Toronto; Susan Ross, The Arthritis Society – Ontario Division; Ruth Tonon, The Arthritis Society – Ontario Division; Kerry Knickle, University of Toronto; SharronSandhu, Sunnybrook Health Sciences Centre; Nicky Britten, University of Exeter, UK; Emma Bell, Sunnybrook Health Sciences Centre; Fiona Webster, University of Toronto; Mary Cox–Dublanski, St. Mary's General Hospital, Kitchener

Funding: The needs assessment, meta–ethnography and feasibility pilot of this research received funding from the Canadian Arthritis Network (CAN), Canadian Institutes of Health Research (CIHR), and Ontario Rehabilitation Research Advisory Network.


Exercise is fun? You're kidding – right?

Dr. Tony Szturm
Associate Professor, Department of Physical Therapy, University of Manitoba

Dr. Barbara Shay
Associate Professor, Department of Physical Therapy, University of Manitoba

Dr. James F. Peters
Professor, Computational Intelligence Laboratory, Department of Electrical and Computer Engineering, University of Manitoba

Cynthia Swarnalatha Srikesavan PhD graduate student
Applied Health Sciences, University of Manitoba

Introduction

It's no sleight of hand – a computer based rehabilitation platform we developed at the University of Manitoba is helping to monitor and improve hand function among people with arthritis that affects their hands.

Difficulties performing everyday activities when patients have arthritis of the hand is accepted as part of the disease, leading to more disability and restricted participation in the activities of daily living, including social life. Our platform meets the urgent need for home programs (HP) supplemented with informed client support and regular monitoring, to improve hand function and, in doing so, relieve disability and restore some of the satisfactions of daily life.

Developing the platform

Our disciplines don't often cross paths, but beginning in 2006, we began a collaborative effort, as researchers of the School of Medical Rehabilitation and Department of Electrical/Computer Engineering. Our purpose was to design and validate a portable "interface device" that can effectively replace a standard computer mouse when doing exercises to rehabilitate hand function (specifically manipulating objects with the fingers). This smart device converts signals from miniature motion sensors to signals equivalent to that of a computer mouse. In this way nearly any object or utensil – or even body part – can be changed to function exactly as a computer mouse simply by attaching the motion sensor. Multiple objects with varied sizes, shapes, weights and functional demands for precision can be used for exercise and to practice a variety of gross or fine motor skills and, importantly, while playing fun computer games. Not only do the object and task have specific therapeutic value, but so does the choice of computer game. Different commercial video games require different levels of movement amplitude, speeds, accuracy and repetition as well appeal to individual preferences. We have tested and categorized a hundred easily accessible, inexpensive commercial computer games. Thus a broad range of objects and computer game combinations are available to exercise two, three, or four fingers or the whole hand/arm.

In a parallel phase of the research we developed a game–based rehabilitation telemonitoring application. This addressed the challenge of quantitative and objective outcomes measurement and gave us a means to obtain electronic records for Telerehabilitation. The game software automatically logs clients' performance and computes their movement quality, efficiency and accuracy during the manipulation task. The software also prompts the clients to self–report pain and stiffness levels related to each manipulation task or training session. The resulting mobility data, pain and stiffness levels can then be used to track change as a function of intensity, volume of practice, and tolerance.

From 2008 to 2011, we conducted a series of studies of both healthy young adults and individuals with arthritis in order to establish and validate the game–based exercise system and embedded monitoring. We wanted our intervention to focus not only on physical impairments, but to include goals and outcomes related both to activity (carrying out tasks) and participation (involvement in life situations). We evaluated finger and hand function while handling a wide variety of objects/utensils involved in common daily activities described by the International Classification of Functioning, Disability and Health (ICF). Standardized game tasks were performed, for example, by manipulating a small knob or key, salad tongs, long stem wine glass, water jug and liquid detergent bottle. Based on the experimental data, direct observations and self– reports, a framework was developed to match objects with their specific therapeutic values. Depending on physical and ergonomic properties of common objects, many different object–task combinations are possible. Knowledge of the therapeutic value can allow the therapist to prescribe graded exercises to target specific goals, for example, mobility, strength, speed, accuracy or endurance. This innovative approach provides a highly flexible and personalized treatment tool.

We have now begun a pilot randomized controlled trial to test the effectiveness of our computer game–based hand exercise program in the home of individuals with arthritis. The control group performs conventional hand exercises, while participants in the experimental group receive therapeutic objects to use with the Telerehabilitation hand–exercise platform. We worked with knowledge users to shape the research questions and develop the training program based on several key principles:

  • Client–centred care: A personalized training program based on individual abilities and treatment needs.
  • Motivation: Maximizing participation is an important goal of long–term interventions. An emerging treatment approach is to combine effective activities with computer games, thus making exercise and rehabilitation interactive, engaging and enjoyable.
  • Cost–effectiveness: Having an affordable computer–based platform that integrates both treatment and assessment is efficient and time saving; can document compliance by monitoring volume of practice and intensity; provides timely feedback and support to client and health–care provider; and provides electronic records.
  • Trend analysis: The platform and applications enable training of multiple functions. It includes data analysis methods that identify performance of each training session. This can be used to track the trajectory of change, and determine dose–response relationships.

Preliminary findings of the pilot project indicate that individuals with arthritis were actively engaged with each therapy session, felt that exercises done with gaming were fun, and had less pain and stiffness after task training. One participant, who has had rheumatoid arthritis for 22 years, said the complex therapy program has helped her deal with her pain.

"Simple exercise programs are so monotonous. This is interesting and challenging because it's exactly like playing a video game... It's fabulous. It's going to help people a lot."

"The program they've developed is very detailed because the hand has so many fine motor functions and (the objects used in the games) allow you to use all functions of the hand," she said. "Plus, simple exercise programs are so monotonous. This is interesting and challenging because it's exactly like playing a video game... It's fabulous. It's going to help people a lot."

Outcomes

Dr. Tony Szturm, Cynthia Swarnalatha Srikesavan (PhD graduate student), and Dr. Barbara Shay, University of Manitoba.

We now know that the system we've developed – both the platform and the application – has the potential to deliver high–quality and personalized hand rehabilitation programs with assessment in a home setting. In addition to helping people with arthritis, our system could streamline rehabilitation services, leverage therapist time and permit extended, regular practice at times that are most convenient for the people using it.

The system also has potential to be expanded. It could, for instance, be adapted to provide quality prevention and rehabilitation programs for people in rural and remote communities, something that is currently in short supply. It also has potential beyond simply arthritis. In recent work, we have adapted it to assist the declines in balance, mobility, vision, and cognition that can come with aging. This approach enables individuals to be monitored and supported in various community settings by their health team and through a client–centered e–health application.

Acknowledgments

Individuals, communities/cities/ regions and organizations involved: Corrie Billedeau, Emeritus Member of Consumer Advisory Council, Canadian Arthritis Network; Patient Partners, Health Sciences Centre, Winnipeg

Funding: Canadian Institutes of Health Research (CIHR), Canadian Arthritis Network (CAN), Manitoba Centre of Excellence Fund (MCEF)

Footnotes

footnote 1

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footnote 11

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Footnote 16

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Footnote 18

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Footnote 19

Keyserling, T.C., Samuel–Hodge, C.D., Ammerman, A.S., et al. (2002). A randomized trial of an intervention to improve self–care behaviors of African–American women with type 2 diabetes: impact on physical activity. Diabetes Care, 25, 1576–83.

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Footnote 20

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footnote 21

Doull, M., O'Connor, A.M., Robinson, V., et al. (2005). Peer support strategies for improving the health and well–being of individuals with chronic diseases (Protocol). Cochrane Libr, 3:CD005352.

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Footnote 22

Tran, C.S.J., Nyhof–Young, J., Embuldeniya, G., et al. (2012). Exploring the learning and support needs of individuals with inflammatory arthritis. Univ Toronto Med J, 89, 88–94.

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Footnote 23

Sandhu S., Veinot V., Embuldeniya G., Brooks S., Sale J., Zhao A., Richards D., Bell M. J.. Peer to Peer Mentoring for Individuals with Early Inflammatory Arthritis: Feasibility Pilot. Accepted for publication BMJ Open January 2012.

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