When it comes to doing research in RA, it pays to have a good international and a multidisciplinary mix of partners. International collaborations allow for access to a wide variety of scientific expertise, extra resources, and, in clinical trials, a larger number of patients.
While international collaborations can be fraught with complexities, the European Union (EU) seems to have discovered how to facilitate the process by making it relatively easy to establish research networks through the European Commission (EC)—the legislative body of the EU.
“I think the EU is built on a philosophy of cooperation and the idea that there is strength in working together,” says Antonia Mochan, spokesperson for science and research at the EC. “Whether that makes things more or less difficult than in North America, I’m not able to judge. But it’s certainly a cornerstone of our work in science and many other policy areas.”
One such international network is the newly formed AutoCure, which has a mandate to study aspects of inflammatory rheumatic diseases. Indeed, AutoCure consists of 26 partners—19 major universities throughout Europe, six industrial partners (small to mid-size pharmaceutical companies), and the European League Against Rheumatism (EULAR). It was launched March 1, 2006, and has a five-year mandate.
According to Lars Klareskog, MD, PhD, coordinator of AutoCure, there are three main goals for the network. “One is to try to understand the causes of disease, two is to develop better prognostic markers, and three is to develop new therapies,” he says. Dr. Klareskog is also professor and head of rheumatology at the Karolinska Institute in Sweden.
At present, there are 22 research projects in the AutoCure network—a mix of new research and projects already underway at individual centers that now have been combined.
RA: Neglected No Longer
Until recently, rheumatology research in the EU “was a neglected area,” Dr. Klareskog told TR in a telephone interview. Each year, the EC calls for research proposals in specific science and medical areas.
“A number of us formulated the idea for this particular consortium,” he says. AutoCure was proposed, and won.
A total of 25 institutions and more than $14.5 million later (provided by the EC as a result of the competition), AutoCure was born. There is no other body in the world that facilitates the ability for researchers from a relatively large number of different countries to work together in such a way, says Dr. Klareskog. Additional funding also finds its way into AutoCure projects through government and rheumatology-related agencies from different countries, as well as some corporate funding. There are numerous research projects under AutoCure, ranging from basic science to large clinical trials to projects focused on data management and cost-efficiency.
Some of these projects were already operating, but now, as part of AutoCure, they are part of the wider network with access to more expertise, patients, and resources.
International Cohort Approach
Tom Huizinga, MD, PhD, chair of the department of rheumatology at Leiden University in the Netherlands, is principle investigator of a project using existing population cohorts that have now been joined together to study predictors of clinical outcome in patients with arthritis. The project has participants from 16 partners and pulls together three key European cohorts: the Norfolk Arthritis Register (NOAR), the Leiden Early Arthritis Cohort (EAC), and the Swedish Epidemiologic Investigation of Rheumatoid Arthritis (EIRA).
Whereas the cohorts had about 2,000 people each, combined they represent more than 6,000. The cohorts are being used to investigate how genetic and environmental factors affect the chronicity RA in both adult and pediatric populations. Researchers will investigate the patterns of structural damage that occur with chronicity over time in both adults and children, taking into account severity of disease and type of treatment.
This “new pan-European cohort allows us to find even small associations with significant statistical power. This is relevant because it leads to a better understanding of RA,” says Dr. Huizinga. There will be a centralized reading method for X-rays to standardize interpretations, and datasets will be pooled so there will be a common database.
The AutoCure network allows for easier information sharing. “People exchange data earlier, as well as materials, as if they are members of the same club,” says Dr. Huizinga.
Another project is using two large, existing Swedish cohorts to study the predictors of rheumatic disease in healthy populations. Lead by researchers at Umea University in Sweden, with contributions being made by six other partners, the study will use the Northern Sweden Health and Disease Study (NSHDS) and the Maternity Cohort of Northern Sweden (MCNS) cohorts.
The NSHDS cohort includes 122,800 biological specimens from 79,940 people. The MCNS includes 102,800 samples from 78,700 pregnant women who had been screened for rubella since 1976.
The databases are especially useful for long-term studies because each person in the Sweden is identified by a unique national identification number. These numbers are used in a centralized disease register which is part of a national socialized healthcare system, and makes it easier to do long-term tracking of health changes.
In the study, people who develop early RA will be identified through the national disease register. Their identification number will be matched to the two cohorts to identify blood samples that had been donated prior to disease onset. From this, various genetic and antibody studies can be undertaken to look for disease markers. Also, the populations who develop RA will be surveyed about environmental influences that may be linked to their disease.
In about a year, researchers anticipate integrating a third cohort into the study, this one from the United Kingdom, which also has a national, socialized healthcare system.
Tease out Disease Predictors
Sharing cohorts comes in handy for AutoCure’s second goal: that of developing better prognostic markers for disease. “You need large cohorts that you can follow over many years where you can take samples and test new assays,” says Dr. Klareskog.
Another project lead by Dr. Huizinga and colleagues at the University of Leiden, entails 11 research groups working together to find predictors of response to new therapies. This will be done through a series of clinical trials, including newly launched trials and expansion of previously existing trials.
“Many projects in AutoCure have been going on for years, but now can be brought together,” says Dr. Klareskog.
Clinical trial formats within AutoCure will be standardized, and researchers will investigate new targeted therapies in patients with recent onset disease. Standardization between different international centers will ensure patient selection and evaluation is performed using the same protocols, and that data collection and analyses are done in the same rigorous manner.
In fact, a multi-center clinical trial that was already being conducted by three of the network members, Stop Arthritis Very Early (SAVE), is now part of AutoCure and will be expanded. The trial investigates whether an additional pulse of prednisone added to standard medication is beneficial for treating RA. Plus, several targeted therapies that were already under development by some of the partners will be available to AutoCure trials for further study.
Another key advantage to the conduct of clinical trials under the auspices of AutoCure, is that promising biomarkers and assays being developed by other arms within the network can be used. Information such as genetic and environmental data pertaining to patient populations can also be incorporated into findings from the trials.
“The network allows for easier crossover between studies and sharing of materials—such as the biomarkers, and new therapies being integrated into the clinical trials,” says Dr. Klareskog.
One project relating to prognostic factors is being lead by Scandinavian researchers Tore Saxne, MD, PhD, and Dick Heinegard, MD, PhD, from Lund University in Sweden. They are working with five other AutoCure partners to investigate cartilage and bone markers to predict outcome and response to therapy. The research, which is just starting, will aim to develop and evaluate markers that can be used to monitor tissue processes in both in vitro and in vivo systems.
According to an AutoCure document, the work will help elucidate “the structural events during development and progression of rheumatoid arthritis, and also to use the technology as a tool to explore the tissue protective potential of novel treatment modalities.”
Work will focus largely on four specific proteins: the recently described cartilage intermediate layer protein, cartilage oligoneric matrix protein, chondroadherin, and fibromodulin.
But to make such a large network work smoothly, research isn’t limited to basic science and clinical trials. There are other factors that need to be taken into account when so many partners are working together and dealing with so much data. One research group, consisting of five international partners, will focus on developing secure data management and information systems.
Tools to Secure Data
Other groups within the network are working on aspects pertaining to bioethics and legal issues, commercialization of any resulting products or technologies, and the cost-effectiveness of therapies against RA. Commercialization is important because this is what gets treatments to the patients who need them.
To this end, six partners in the AutoCure network are small to mid-sized biotechnology and pharmaceutical companies—Arthrogen B.V, Biovitrium, BMD, Genmab, Oligene, and Future Partner.
“We preferred small, start-up to mid-size companies rather than multinational pharmaceutical companies,” says Dr. Klareskog.
Findings from studies will be freely published, although procedures for commercialization of any therapies or technologies developed via AutoCure are still being ironed out by one of the AutoCare research groups. Thie group includes three university-based partners and all six industrial partners.
The EU has always supported and encouraged the formation of international research networks, but AutoCure, by far, is the most exciting one for rheumatologists.
Pippa Wysong is a medical journalist based in Toronto.
