FROM THE EDITORS

What's new in vasculitis?

Eric Matteson, M.D.
Rheumatology

In early June 2008, Mayo Clinic hosted the 8th International Vasculitis Symposium of the Vasculitis Foundation, a biennial event. The Vasculitis Foundation is a patient organization devoted to providing support for people who have vasculitis and their families, as well as to educating patients, families and physicians. The foundation also raises money for research into vasculitis.

Vasculitis generally refers to blood vessel inflammation. It can damage blood vessel walls, disrupt blood circulation, and even be fatal (see our September 2008 edition).

Well over 400 people who have vasculitis attended the symposium. Vasculitis experts from major health care institutions across the United States were there — including physicians from Cleveland Clinic, Boston University, Johns Hopkins University, University of North Carolina and St. Luke's-Roosevelt Hospital.

Many sessions were devoted to explaining the latest in vasculitis research. During breakout sessions, various aspects of vasculitis were discussed, including healthy living and nutrition, skin diseases, lung disease, kidney disease, and nerve disease.

It was exciting for me to meet patients from all over North America and Europe who attended the conference. Some were facing newly diagnosed disease and the uncertainties of their disease course. They wondered what might be in store for them. I also met people who had Wegener's granulomatosis —one in particular who's disease has been in remission for more than 23 years — and another man who's had Churg-Strauss syndrome for more than 37 years.

Meeting these people emphasized the great advances that have been made in improving outcomes for people who have vasculitis. These improvements include preservation of organ function — such as kidney, lung, eye and nervous system — and marked improvement in life expectancy. Still, there are many who have active disease and live with not only the benefits but also the side effects of the drugs required to treat vasculitis. Clearly, much remains to be done to improve the understanding and management of these diseases.

International vasculitis experts discussed how special proteins made by the body — called antibodies — are created and can attack antigens, which are proteins of the body or foreign proteins. They described laboratory studies that provide dramatic new insight into how vasculitis might start in humans, as well as findings that seem to indicate vasculitis isn't a genetic disease.

Experts explained how it isn't so much the genes that are the problem in vasculitis, but more what turns the genes on and off. As with cancer treatment, a new vasculitis treatment approach is to learn how to turn on and off the genes active in vasculitis. Doing so could prevent the widespread inflammation and organ damage that immune system activation can cause.

Another theme of the exciting, new vasculitis research is the application of principles of personalized medicine to these diseases. Knowing your genetic makeup as well as environmental factors that influence how genes might be activated or function can improve how you fare. In the world of vasculitis, "one size does not fit all." The way an individual's body handles a specific trigger (antigen) appears to determine how the disease will act and whether it will or won't be severe. Much remains to be done in understanding these factors.

Symposium speakers emphasized that these insights and discoveries have yet to be applied to patients, but that there is a light in the tunnel, if not at the end of the tunnel. Recently, genes have been identified that are important for how the body handles the drugs used to treat vasculitis. It's now recognized that negative reactions to a drug — especially severe reactions — result from abnormal processing of drugs in the body. This is due to genetically determined enzyme differences. These enzymes are responsible for breaking down drugs used in the treatment of vasculitis.

An example of abnormal enzyme function is the enzyme thiopurine methyltransferase, which is responsible for breaking down azathioprine (Imuran), a key drug in treating vasculitis. Other such enzymes are now being identified that break down mycophenolate (CellCept) and methotrexate, among others. Currently, a test for the thiopurine methyltransferase level is available. Researchers report that routine laboratory tests will become available in the not-too-distant future for enzymes that break down other medications as well.

There are many forms of vasculitis. Some have known causes, such as vasculitis related to hepatitis B infection or vasculitis caused by drug reactions. However, there are many forms of vasculitis for which the cause is unknown. Among these is necrotizing granulomatous vasculitis, which is also known as ANCA-related vasculitis in two forms — one being microscopic polyarteritis and the other is a condition known as Wegener granulomatosis. Other forms of vasculitis on the list for unknown causes include giant cell arteritis, central nervous system vasculitis, Churg-Strauss syndrome, polyarteritis nodosa, Behcet syndrome and Henoch-Schonlein purpura, to name just some.

Researchers, doctors and people who have vasculitis know that different forms of the disease may affect individuals differently. This is due to a complex interaction of factors that prompt the disease process and factors that govern the immune response. What will be important in the future isn't what the disease is called. Rather, it will be what antigen stimulates the vasculitis, how you get it and how you can get rid of it.

There's a lot of research under way. In the United States, medical centers such as Mayo Clinic are looking into various forms of vasculitis. Many collaborative studies are also under way between major research institutions. The Vasculitis Clinical Research Consortium is studying new medications for treatment of vasculitis as well as biomarkers for the disease. The hope is to develop blood tests that will demonstrate whether the disease is active or not in any given individual. Imaging studies using new forms of positron emission tomography (PET) and magnetic resonance imaging (MRI) are being done. Others are looking into the immune system function in vasculitis, including the role of the anti-neutrophil cytoplasmic antibody (ANCA), B cells, T cells and cytokines, which are the proteins responsible for inflammation and regulating cell function. Investigators are also looking carefully at cells called macrophages and dendritic cells, which are among the many components of the immune system involved in vasculitis.

I was particularly interested to see that so many people who have vasculitis also have a strong interest in participating in vasculitis research. Those who attended the symposium had many reasons for wanting to participate, including helping others in the future and advancing the understanding of vasculitis. Many said how important it was for them to participate because they had rare diseases. Rare diseases are very difficult to study without dedicated volunteers. Their participation in the research made them feel empowered in pushing forward understanding of their own disease and taking control of it.

The complex process of drug development was also addressed. In general, new drugs and compounds are evaluated for their safety in very low doses in healthy volunteers. If the drug appears safe in healthy volunteers, it is then evaluated for its safety in people who have the disease. If it still appears to be safe, an open trial — meaning one where the physician and the patient both know what drug or compound the patient is receiving — is conducted, and different doses of the drugs are compared. The goal is to determine whether the drug is safe and whether it appears to offer benefit in treating the disease — in this case, vasculitis.

If the first part of the process is successful, the next step is usually a randomized, blinded study. These studies are designed to compare the new drug with an inactive agent (placebo), or to compare the new drug with a known drug that's considered the best available for treatment. The purpose is to find out if the drug actually does have benefit. In some studies, there is a so-called placebo effect — a natural human desire for improvement. As a result, both the patient and the physician may think the drug is working when it isn't. Many of us know this kind of placebo effect when we have, for example, a headache. Because we know that we can take a medication for it, just that knowledge gives us comfort. This can seemingly reduce the severity of the headache, even on the way to the medicine cabinet. Various agencies and boards must approve of these studies, including the Food and Drug Administration and the ethics or institutional review boards at individual medical institutions.

There are great hopes for improvement in the care and management of vasculitis. Already, the life expectancy for those who have vasculitis has improved over the last two decades, and the amount of damage occurring to the organs as a result of vasculitis has been reduced. But, there is still much more to be done. All of us — patients, health care providers, physicians, nurses and patient advocates — are looking forward to a new era of exciting discoveries related to vasculitis. The conference at Mayo Clinic was extremely encouraging and motivating. It concluded in the spirit of optimism and hope for the future of people who live with vasculitis.