Research advances in rheumatoid arthritis is spreading

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By combining their expertise in epidemiology, immunology and genetics, researchers at Karolinska Institutet have gone a long way towards mapping the disease that is rheumatoid arthritis. The concept is now also being used to study other diseases.

15 years ago very little was known about the causes of rheumatoid arthritis. In a bid to find out more about how genes, lifestyle and environmental factors affect the risk of developing the disease, professor Lars Klareskog from the Department of Medicine, Solna set up the EIRA project for the epidemiological investigation of rheumatoid arthritis at Karolinska Institutet together with professor Lars Alfredsson from the Institute of Environmental Medicine.

EIRA is now the world's largest register of rheumatoid arthritis patients, and includes data collected over a long period from just over 3,000 patients and around 4,000 controls. The register contains information on the patients' disease and treatment results as well as lifestyle and environmental factors. Furthermore, blood tests from some of the patients have been stored in a biobank and can be used in genetic studies, for example.

"The register is unique and means that we can carry out the worlds largest genetic studies on patients with rheumatoid arthritis," says Lars Klareskog. "But more than that, the good design of the register means that we can also see how lifestyle and environmental factors interact with a patient's genes, and how they affect treatment results."

An important discovery courtesy of the register is that smokers with a specific genetic profile are at greater risk of developing rheumatoid arthritis.

"We noted that smoking increases the risk of developing rheumatoid arthritis 20-fold in patients with certain genes," says Lars Klareskog. "This increases to 40-fold for heavy smokers, compared with people who don't have these genes."

Working with lung specialists, the researchers then went on to look at what happens in the lungs when we smoke. They found that the smoke causes a change in some types of protein so that the amino acid arginine, one of the building blocks of proteins, is converted into citrulline.

Patients with these particular genes, known as transplantation antigens, have a tendency to have a very strong immune response to these citrullinated proteins.

As such, an immune reaction starts many years before the disease manifests itself in some smokers who have these genes.

The fact that this immune reaction can then cause rheumatoid arthritis has been shown in animal trials by professor Rikard Holmdahl's research group at Karolinska Institutet's Department of Medical Biochemistry and Biophysics. The genes in question are to be found in around 60% of all rheumatoid arthritis patients, and these patients also have antibodies to citrullinated proteins that can be measured with blood tests. The remaining 40% of patients do not have these antibodies, and in their case it is other, sometimes unidentified, genes and environmental factors that lie behind the disease.

"In terms of risk factors, they are two completely different diseases even though they share the same diagnostic criteria," explains Lars Klareskog. "We've also seen that the efficacy of some treatments varies between these two variants of the disease, and here we see the beginnings of personalised treatment for patients with rheumatoid arthritis."

Combining expertise

Klareskog goes on to explain that combining register information on lifestyle and environmental factors with genetic studies of patients' blood samples and basic research in the laboratory into how the immune system reacts, has taught researchers a great deal about the disease so that it is now possible to offer more personalised advice and treatments.

"This approach, of combining epidemiological, immunological and genetic expertise, has proved extremely successful," he comments. "It has then been possible to apply the techniques and working methods developed in our study of rheumatoid arthritis in research into other rheumatic inflammatory disorders such as myositis or Sjögren's syndrome, as well as other chronic diseases."

The researchers are now using the same method to hunt for more environmental factors and genes that can be linked to a higher risk of developing rheumatoid arthritis. Given that the research is based heavily on register data, it is vital that this data is correct if the researchers are to come to the right conclusions.

"Getting good patient information is one of the greatest challenges facing clinical research," says Lars Klareskog. "Which is one of the reasons why we teamed up with the Swedish Rheumatism Association to start the Patient Research Partner programme so that patients can get together with research groups and have a say on how data is collected."

The researchers also work closely with their colleagues from the Department of Learning, Informatics, Management and Ethics at Karolinska Institutet, where Staffan Lindblad among others devotes himself to "improvement research" for the patient register.

Many patients with rheumatoid arthritis saw a dramatic improvement in their lives when biopharmaceuticals were introduced at the beginning of the new millennium, with TNF-alpha inhibitors proving to be the most successful. Around 30-40% of patients with rheumatoid arthritis are now completely symptom-free thanks to treatment.

"But 60-70% still have symptoms or suffer with side-effects from the drugs, and many have to stop work," says Lars Klareskog. "Doctors are often forced to try out lots of different drugs before finding the best treatment. And the new drugs are also very expensive, so we still really need better treatments, but this requires greater basic knowledge about why the disease occurs."

Rikard Holmdahl explains that even though we now know that both environmental factors and a whole raft of genes increase the risk of developing rheumatoid arthritis, we still know very little about why the joints become inflamed. Current treatments are designed to stop damage from the immune reaction, but ideally we would be able to prevent the inflammatory reaction completely.

"We know that there are already changes in the body five to ten years before the disease causes problems for the patient," says Rikard Holmdahl. "We can measure the autoantibodies in the blood and use them to reliably predict whether an individual is likely to get rheumatoid arthritis long before there are any symptoms. This means that the disease starts well before we get going with treatment, and it would probably be good to treat people far earlier."

However, seeking out individuals who are at risk of developing rheumatoid arthritis by measuring autoantibodies would be pointless as there is no preventive treatment at present. The drugs available to patients diagnosed with rheumatoid arthritis have side-effects and, in some cases, the long-term effects are unknown. Giving these medicines preventively to a symptom-free patient is not an option, believes Rikard Holmdahl:

"We don't know enough about what happens in the body before the disease produces symptoms. Our most important role as researchers is to find out more about what causes the disease so that we can develop a preventive treatment that can be used at an early stage."

Holmdahl's research group makes extensive use of animal trials in its work to find out more about the causes of rheumatoid arthritis. This involves putting human genes into animals to understand how these genes affect the development of a disease. By replicating human diseases in animals, it is then possible to test drugs and identify which genes are implicated in a disease.

Free radicals thought to be protective

One of the research projects is looking at the role of free radicals in rheumatoid arthritis. Free radicals are molecules that form in the body during inflammation and have previously been linked to an increased risk of disease.

Rikard Holmdahl's research group has identified a gene, NCF-1, that is necessary for the formation of free radicals. In animal trials they have seen that a fully active gene offers complete protection against the disease, in other words free radicals are thought to have a positive, protective effect, contrary to what was previously believed. However, there are individual variations in genetic activity, with some people having high levels of activity while others have low levels.

It is hoped that developing a drug that stimulates NCF-1 will make it possible to increase production of free radicals in those individuals with low production. This has already been successful in animal trials.

Another project is aiming to produce a vaccine against rheumatoid arthritis, though so far this has been tested only on animals. Holmdahl believes that this basic research is important for developing new treatment strategies:

"We can't just keep refining the treatments we've already got. It's easy to forget that today's successful treatments are based on knowledge gained from tests on mice 30 years ago. I'm convinced that rheumatoid arthritis and many other rheumatic inflammatory diseases are completely avoidable, that it must be possible to eradicate them - we just need to find out how."

Text: Cecilia Odlind. First published in "Medical Science", number 3, 2010

EpidemiologyRheumatologySocial Medicine