Segal North American Osteoarthritis Workshop Paves the Way for New OA Treatments
The Segal North American Osteoarthritis Workshop V (SNOW V) was held October 26-28, 2012 at the Hyatt Chicago Magnificent Mile hotel in Chicago. Gordon and Carole Segal, founders of the home furnishings store Crate and Barrel, initiated the tradition by sponsoring the Segal Osteoarthritis Research Initiative and suggesting the funded scientists get together to share their findings. The SNOW conference now brings together dozens of distinguished scientists, researchers, and physicians to tackle the most difficult challenges in solving the problem of osteoarthritis (OA). This year, nearly 140 participants from 35 global institutions and universities representing eight countries assembled to discuss key topics related to OA, a disease that affects an estimated 27 million people.
The Hope for Osteoarthritis Research
After an introduction to the meeting an to OA as a disease, the Arthritis Foundation’s vice president for research, Dr. John Hardin, MD, reviewed obstacles currently limiting OA research. Obstacles include a lack of understanding of the disease’s onset, a stagnant drug development pipeline, and dated standards for clinical measures. Given these conditions, Dr. Hardin introduced a proposal to use anterior cruciate ligament (ACL) injuries as a model for change.
The human perspective on OA was not overlooked. Three representatives from the Osteoarthritis Alliance shared how OA has affected their lives. The OA Alliance is the community of people with OA that the Arthritis Foundation serves, with representatives who voice their needs directly to Foundation leadership. All three speakers suffered traumatic injury, which for most has led to pain, disability, medication, surgery, physical therapy, and adaptations to everyday life. As one member of the OA Alliance, Dave Mekemson, put it, “Osteoarthritis is not a life-threatening disease, but a ‘quality of life’ threatening disease.” The hope expressed by all the patient speakers is that funding and research will produce better medications and treatments for OA.
Advice from the FDA
Janet Woodcock, MD, Director of the Center for Drug Evaluation and Research of the Food and Drug Administration (FDA), explained the current FDA status for drugs used to treat OA: there are only symptomatic drugs approved by the FDA, which means only drugs that limit pain, not ones that stop the disease, are on the market. She emphasized that any new drugs must be safe to take long term, without causing or exacerbating other illnesses, and it must show measureable improvements.
Currently, the only way to show disease-altering efficacy is to prove a reduction or reversal of x-ray changes. Those changes are too slow to detect in the time of a typical clinical trial and in clinical practice, x-ray damage has a poor correlation with pain—some people have x-rays that show extensive damage but experience little pain, while others have little damage but are in excruciating pain. Thus, trials showing disease progression need to be large and long. Dr. Woodcock went on to say that new, standardized criteria are needed to signal joint failure, such as one or more biomarkers. Biomarkers are measures that indicate the presence or absence of disease or factors that can increase or decrease your risk of disease. They can be physical, such as a pain scale or duration of morning stiffness; physiological or structural, which might include standard measurements of joint space narrowing, bone changes, or inflammation; or even molecular, whereby specific tests detect inflammatory molecules or a genetic marker identifying someone as likely to develop OA. Because these biomarkers for OA have not yet been standardized and accepted, OA drug development is essentially at a standstill.
An Ideal Biomarker
The topic of biomarkers was prevalent throughout the conference. Scientists have identified several potential OA biomarkers; the difficulty lies in determining the ideal OA biomarker—one that is easy to measure, is linked to disease incidence or progression, and changes quickly with bettering or worsening of disease. There are simply no standard measures of disease progression for OA. Other factors such as age, obesity, trauma, and other diseases only confound the task of defining OA.
A Closer Look at the Joint: Function and Disease
Tom Andriacchi, PhD, winner of this year’s first SNOW award for excellence is osteoarthritis research, suggested that OA should be approached as a system responding to stimulus. For example, an injured knee joint leads to a change in the biology of the joint, which progresses to walking problems, followed by structural changes in cartilage, then ultimately osteoarthritis. Using magnetic resonance imaging (MRI), the Andriacchi lab evaluated whether a 30-minute walk would produce a change in cartilage oligomeric matrix protein (COMP) and was able to correlate COMP with cartilage thinning over time. Could this be the biomarker to look for? Perhaps.
COMP is one of nearly 20 biochemical and imaging (x-ray and MRI) biomarkers included in the Osteoarthritis Biomarkers Project. Presented at SNOW V by Michael Nevitt, PhD, MPH, this research study, sponsored in part by the Arthritis Foundation through the Foundation for the National Institutes of Health (FNIH), is looking at biosamples and images from a group of 400 knees. The goal of the study is to identify OA biomarkers that identify individuals at risk of developing severe OA, develop new measures for clinical progression of the disease, and introduce new treatment options to stop OA.
Cell Processes Inside the Joint
An ancient cell process called autophagy (awt TOF ah GEE) was also proposed as a source of biomarkers. Autophagy is the trash and recycling system of a cell. How could this be important in OA? While cell parts are broken down and recycled, necessary nutrients are also released into the cell. Two presenters, Chris Weihl, MD, PhD, and Martin Lotz, MD, talked about how the process of autophagy is diminished with age and injury, specifically in cartilage. Rapamycin, an immunosuppressant used to treat transplant rejection, was studied in mice by both researchers and was shown to stimulate autophagy. Their studies also showed a reduction in the severity of OA, a prevention of cell loss in cartilage, and reduced inflammation. Perhaps a traceable protein in the autophagy pathway will be a future therapeutic target or biomarker for OA research.
Innovations with Stem Cells in Treating OA
Another exciting area of OA research is stem cell and regenerative medicine, presented by formerly funded AF researchers Rocky Tuan, PhD, and Farshid Guilak, PhD. Stem cells are the blank slates of cells, and given the proper environment, they can be induced to become cartilage. Dr. Tuan grows cartilage on a 3-D structure within the joint of the thigh and hip using a jellylike substance. Dr. Guilak takes fat cells, treats them with growth factors, and differentiates them into new cartilage. Sounds complicated, but the overall goal is to develop a stem cell that can grow new cartilage to replace tissue damaged by OA, ultimately avoiding the need for joint replacement surgery.
ACL Injuries as a Precursor to OA
A significant topic of interest throughout the SNOW V conference was cruciate ligament (ACL) injury and the subsequent development of OA. Interestingly, about 50 percent of people who undergo ACL reconstructive surgery develop OA ten years later. Scientists believe that by studying people with ACL injuries, we can learn a lot about OA. With the financial backing of the Arthritis Foundation and Alpha Omicron Pi Foundation, Christian Lattermann, MD, is launching a pilot study to recruit young people who have torn their ACLs. Short term, the doctors hope to treat pain and inflammation after the ACL tear by injecting a steroid, which may lead to the long-term benefit of reducing their risk of OA. In addition, the study will track patients’ pain at specific intervals; obtain and store samples of joint fluid, blood, and urine; and collect demographic information.
The Future of OA Research
The SNOW V conference highlighted many exciting areas of research in OA, but what happens next? A direct outcome of the past two years’ SNOW conferences and the subsequent work done in the field of ACL injuries and OA, the Arthritis Foundation announced it will be seeking applications from scientists to perform a multicenter feasibility study of ACL injury, chemical and imaging biomarker detection, and OA prediction. This is the first step in proving that images and data collected from several different locations can all be correlated to give consistent results. A special advisory panel at the Arthritis Foundation will work with the partnering institutions in carrying out this two-year project, estimated to cost $1 million.
Once the feasibility study is complete, large-scale trials can take place across the world to prevent OA from developing in a person who has injured his or her ACL. We hope the results of the study will be a springboard in the path to drug development for OA. By 2030, the Arthritis Foundation anticipates spending more than $100 million in their goal toward reducing the number of Americans affected by OA by 20 percent.
At the opening of the conference, Dr. Woodcock shared with the audience that the FDA is receptive to working with outside groups to develop an OA biomarker database within their Biomarker Qualification Program, as well as supporting a consensus of valid standardized clinical endpoints. Part of this process may include identifying a rapidly progressing subgroup, such as those who have had ACL trauma and surgery. According to the Arthritis Foundation’s Dr. Hardin, “The FNIH’s OA Biomarker Initiative and the AF’s ACL Initiative are important tools in achieving this goal.”
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AOSSM, FNIH, NIAMS and OARSIand to Gordon & Carole Segal