Closer than Ever to Achieving a Cure:
An Overview of Arthritis Research with John Hardin, MD
Arthritis Foundation Vice President of Research
You’ve headed the organization’s research program since 2006, but your relationship with the Arthritis Foundation goes back much longer than that.
Oh yes. Before I came to work here, the Arthritis Foundation had supported me through my whole career. My first fellowship in Boston came as a result of an Arthritis Foundation postdoctoral fellowship grant in the mid-1970s. Subsequently, I got another grant from the National Institutes of Health (NIH), which brought me to join the faculty at the Yale School of Medicine in 1976. When I got to Yale, I was awarded another fellowship by the Arthritis Foundation, which helped establish my career.
After the fellowship was completed, I received a Senior Investigator Award from the Arthritis Foundation. In 1984, along with my collaborators, Dr. Joan Steitz and Dr. Michael Lerner, the Arthritis Foundation awarded me the first Lee Howley Prize for outstanding research. It would not have been possible to accomplish what I have without the Arthritis Foundation’s support. And that is the case for so many researchers in rheumatology – the Arthritis Foundation gives a lot of young researchers their start, and as they achieve, we continue to support them. In this field, where funding is so sparse and so critically needed, you appreciate a commitment like that. That’s part of why I’m here. I wanted to give something back, and I think of that every day when I come into work.
How has arthritis research changed over the course of your career?
The most dramatic changes have probably been in the treatment of rheumatoid arthritis (RA). When I first started out, doctors were treating arthritis patients with gold injections and lots of aspirin. And the results were about what would have happened with no treatment at all: One out of three patients would spontaneously get better, one out of three would continue to have the disease, and the remaining third would have aggressive disease that would eventually leave them crippled in a wheelchair. We didn’t put it in such gruesome terms, but that was largely what people could expect.
In the 1980s, we had a breakthrough with a drug called Methotrexate, which was being used in cancer treatment. Today, it helps a large portion of patients get 50 to 75 percent better. But Methotrexate doesn’t work for everyone; and because it regulates immune responses across the board, it weakens resistance to infection overall.
In 2000, we had another breakthrough with biologics, which are medications produced by living cells in an incubator. They bind to a specific molecule and inhibit it. In RA, we believe that the immune system is activated in and around the joints, and that a substance called TNF-alpha is produced that drives tissue injury. The biologic we use to treat it targets TNF-alpha to prevent the injury. Biologics are proving to be extremely effective. The results are absolutely life changing for many people. But most still have some flares of the disease, and they need continued use of these drugs to control that. It isn’t a cure, and a percentage of patients don’t experience an acceptable level of remission.
Where do you envision the next research breakthroughs taking place?
There is significant potential for breakthroughs in so many areas. I believe that the earlier people with rheumatoid arthritis are treated, the more effective the treatment will be – even to the point of being able to withdraw the drugs and cure the disease. To do that, we need to identify biomarkers that can determine what kind of drug is most likely to be successful on a given patient. In other words, we are looking toward more personalized medicine. To achieve that, we need to create registries through which we can analyze and correlate biological and treatment information for large numbers of people with this disease – and that is the goal of two new initiatives we’re helping to fund.
The first is TETRAD (Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database), which was first funded by the NIH in October 2009. There are 10 centers around the country where data and genetic material are connected – and the data coordinator at each site is funded by the Arthritis Foundation. Data entry began in the summer of 2010, and our goal is to correlate genetic data of 2,000 people with rheumatoid arthritis over the next two years.
The other registry initiative is AIR (Arthritis Internet Registry). It was initiated directly by the Arthritis Foundation in July 2010 and it capitalizes on our relationship with the million-plus people who have the disease. Housed on the Arthritis Foundation website, an online questionnaire quickly confirms eligibility and offers an option to consent to participate (and only those individuals who consent share their data are included in the registry). From there, a lab contacts participants to acquire blood samples and process the information before sending it to the Broad Institute of Harvard and Massachusetts Institute of Technology. The goal for this database is to enter data for 10,000 to 20,000 people over two to three years – and we believe that’s achievable. We are already a trusted resource for people with rheumatoid arthritis. So far, 1500 people registered in the first three months.
What can you tell us about recent osteoarthritis and juvenile arthritis breakthroughs?
In the field of osteoarthritis, we are also looking at the potential for significant breakthroughs. The Centers for Disease Control and Prevention (CDC) estimates that 27 million Americans have osteoarthritis today; that number is conservative and it is growing. Our population is increasing. We have an obesity epidemic, and obese people often get osteoarthritis at early ages. We also have increasing athletic injuries – especially anterior cruciate ligament (ACL) injuries in girls and women – and about 50 to 75 percent of people who injure this ligament go on to experience life-altering arthritis in that joint.
We are working to identify biomarkers for osteoarthritis, just as we have seen that cholesterol levels are biomarkers for heart disease. Our strategy is to take the 12 known candidate measures of osteoarthritis and correlate them with clinical outcomes as we follow patients for five to six years. The NIH already has a database of radiological records, clinical data and biomaterials information for approximately 6,000 people with osteoarthritis, often starting from before they showed symptoms of the disease. And we are in a position to lead the analysis and correlation of that information.
It also turns out that pharmaceutical companies have products on their shelves that could change the outcome for osteoarthritis. But because of the way osteoarthritis develops, relevant clinical trials could take 10 years to complete, and no pharmaceutical company wants to do a trial that long. So we are working with the Food and Drug Administration (FDA) to find ways to encourage pharmaceutical companies to address these clinical trials. I believe we will see new drugs that can change the outcome of this disease. Ultimately, we believe these two initiatives could lead to new interventions that improve the outcome for people with osteoarthritis.
In the area of juvenile arthritis, in addition to supporting researchers investigating arthritis in children, we’re working closely with the Childhood Arthritis & Rheumatology Research Alliance (CARRA), a national network of pediatric rheumatology centers, which we helped found. Our investment in the accelerated juvenile arthritis research that CARRA makes possible will enable us to identify the best ways of matching patients with the right treatments at the right time in the presentation of the disease. Again, the key is correlating information and ultimately creating a more personalized approach to treatment. CARRA is an integral component to our efforts to shape national research in juvenile arthritis and complements the research we fund through the Arthritis Foundation. For example, the Arthritis Foundation awards a number of grants in the area of juvenile arthritis that actively seek highly talented investigators whose research will take advantage of the CARRA network.
How critical is the need for funding to make these initiatives happen?
There is no question that arthritis research and funding have got to accelerate. We are talking about a disease that is a principal driver of health care costs in this country. There is no way to predict exactly how and when any breakthrough will take place, but these are concrete initiatives, and we know how much investment they will require. For the TETRAD initiative, it will cost $100,000 per year to pay for the data and biological sample collection and analysis at each of the 10 sites, so that is $2 million. It will cost $1,000 to conduct the genome analysis for each of the 2,000 samples, so that is another $2 million. Correlation of all that data and genome sequencing will cost another $4.5 million. Then there is additional research – determining what each element of the information means – so that comes to approximately $10 million.
The AIR initiative has been started essentially at no cost – only with in-kind donations of time and labor. But to continue and complete the project, we will need to hire a data coordinator to work at the data center in Omaha, Neb., where the clinical data is housed, hire clinical coordinators to interface with patients, and so on. That will cost approximately $1 million per year, in addition to the costs of sequencing DNA.
The initiative to identify biomarkers for osteoarthritis has a price tag of $2.8 million and we have committed to cover approximately one-third of that. None of these breakthroughs is going to happen without significant funding. And, of course, we need more than funding alone.
What else will be necessary to achieve the next level of breakthroughs?
To move this field forward, it is critically important to encourage patients to participate in clinical trials. Pharmaceutical companies fund some research. But not enough. The NIH is expected to continue to contribute, but NIH grants usually only cover research already fairly established. That is why the Arthritis Foundation funds Innovative Research Grants, which enable researchers to pursue and prove new approaches and ideas. And that is also why the Arthritis Foundation needs funding to support more research at greater levels of depth than we currently are able to cover.
So research and trials are very important. But the next level of breakthroughs will also depend on improvements in patient education and advocacy to get these drugs into the marketplace and ensure their safety. The Arthritis Foundation is very active in advocacy efforts. We are the organization that represents the interests of patients with arthritis – and those efforts must continue.
We need to bring arthritis into the public consciousness like never before. We have such a deficiency in pediatric rheumatology and we need more people to pursue it as a career. Our advocacy program is focused on legislation to enable this – and is encouraging our government to pass it. It will improve funding for arthritis. It will bring more people into the field and encourage the development of arthritis specialists. And it will encourage the development of products and societal strategies to confront this disease. This legislation passed in the House of Representatives in September, which means that will be considered by the Senate.
Arthritis is a fundamental element of the health of the nation. It is a huge challenge – and the Arthritis Foundation is up to that challenge. But we need our colleagues, supporters and friends to join with us to address it. The power of basic science today, compared to when I first began, is amazing. Who could have imagined how far we would come? When I started working in this field, we could hardly imagine how to isolate proteins in the body. Now we can produce them in a test tube. We have models that replicate most of the diseases we confront. We have microscopes that show us incredible things on a molecular level. The scientific capability for a cure is in our hands. Think about the HIV that causes AIDS. It was an overwhelming devastating disease that killed almost everyone who got the virus. But there was a great push for advances in treatment, and now it is so much more controlled. We need the same push in arthritis that was originally brought to bear in HIV treatment.
Why is support of the Arthritis Foundation of particular importance today, more than ever?
The Arthritis Foundation is involved not only in innovative research, advocacy and education but also in pulling these elements together to take scientific discoveries and get them through the process of research, funding and development, and to make them commercially available. The good news is that the scientific community in the United States is very strong. We have outstanding medical schools and research institutions that prepare people to embark on careers where they really can make a difference. Basic science has advanced dramatically, with discoveries surrounding the human genome being a driving force. The challenge is to convert these advances into things that really change lives – traversing that area between where basic science ends and clinical product development begins. That is how you take a scientific discovery and get it through the process of research, funding and development.
Unfortunately, a huge percentage of potentially important research ideas go unfunded. Of all the grants submitted to the NIH, 90 percent are not supported. Some of that is because the NIH doesn’t typically approve funding for research that uses unproven strategies.
That is why the Arthritis Foundation’s Innovative Research Grants encourage scientists to think in new ways, to try unproven strategies. We believe that is where breakthroughs begin. We are enabling the feasibility testing that helps these ideas ultimately gain federal funding. That benefits our researchers significantly because for every dollar we invest in these grants, an average of $12 is ultimately applied to that project through more traditional means, such as NIH grants.
We are very proud of the grants we’re funding – they are really top notch. But right now, we are only able to fund 10 percent of the grant applications we receive. That means a lot of great ideas go unfunded. That concerns us. But more than that, it motivates us.
Where will that motivation take arthritis research? What trends do you find most exciting and encouraging?
There are so many. For one thing, we now know how to use stem cells to create chondrocytes. Chondrocytes are cells within cartilage that make the molecules that give cartilage its strength, flexibility, resilience and ability to renew itself. So we should be able to use those chondrocytes to produce the perfect cartilage to line joints. The Arthritis Foundation has funded seven laboratories around the country that are learning to convert stem cells into chondrocytes and apply growth factors to produce the cartilage matrix that joints need to function. Some of those labs are exploring the possibility of larger research projects over the next couple of years. Depending on how those go, I am hoping we will see real applications in humans sometime in the next five years or so.
Doctors used to advise people with joint injuries and joint diseases to protect their joints by limiting physical activity. We know now that advice is wrong. One of the most important things we can do to fight the effects of arthritis is encourage activity. It reduces symptoms. It improves mobility. It affects pain receptors and reduces pain. We have established an evidence-based exercise program for people with arthritis – Walk with Ease – and our public health efforts are using every possible channel of communication and information to encourage people to be physically active.
The establishment of new biological data registries is bringing us closer than ever to moving beyond controlling symptoms and achieving a cure. It isn’t some vague dream of what we wish we could see happen someday. It is a goal with real strategies and tactics that can bring them to fruition.
The Arthritis Foundation plays a critical role in these trends and so many others. We encourage new research. We work with the FDA to encourage trials. We have been working with the Department of Defense to understand the critical need for arthritis research and to achieve new and supplemental funding. We are working with the NIH and our relationships within the CDC are deeply rooted. All of this enables people to pull together, to strengthen and advance our understanding of arthritis and other rheumatic diseases in more ways than ever before.
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