Science & Research

Quest for the cure

Dr. Hani El-Gabalawy's work with local Aboriginal communities is helping to shed new light on the causes of rheumatoid arthritis - and how to prevent it

Dr. Hani El-Gabalawy
Dr. Hani El-Gabalawy
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U of M selected for national health research institute

Bio: Dr. Hani El-Gabalawy

A close look at rheumatoid arthritis

Stages of rheumatoid arthritis

BY JOEL SCHLESINGER
Winnipeg Health Region
Wave, November / December 2013

Dr. Hani El-Gabalawy produces a colourful strip of paper and places it on the table.

At first glance, it looks a bit like a colour swatch from a paint store - tiny squares of blue, green, yellow, orange and red lined up in neat vertical and horizontal columns.

But it soon becomes clear that this is not a sampling of the latest colour schemes for the kitchen or bedroom. As El-Gabalawy explains, it is a computer-generated analysis of a series of blood tests taken over a number of years.

The end product is called a "heat map," and it is designed to provide a colour-coded indication as to whether the blood tested contains certain types of autoantibodies associated with rheumatoid arthritis (RA), a disease that causes inflammation of the joints and bones.

The presence of these autoantibodies (an antibody produced by the body's immune system) and the role they play in the development of RA are of particular interest to El-Gabalawy.

A professor in the Department of Medicine and Immunology at the University of Manitoba's Faculty of Medicine, the Winnipeg scientist is one of Canada's leading researchers in the field of rheumatoid arthritis. In addition to holding the Endowed Rheumatology Research Chair at the University of Manitoba, he is also the Scientific Director of the Institute of Musculoskeletal Health and Arthritis, one of 13 national research institutes operated by the Canadian Institutes of Health Research.

Over the years, El-Gabalawy has headed or participated in numerous studies that have helped advance the diagnosis and treatment of RA. But it is his current research project, which involves probing the role that autoantibodies play in the development of RA among people living in First Nations communities in northern Manitoba, that may be his most significant to date.

The study, which began in 2004 and is expected to run another five years, has already yielded new information that can be used to help develop better clinical guidelines for predicting the onset of RA, and El-Gabalawy hopes that the data being gathered may also pave the way to stop the disease before it actually starts. 

Unlike osteoarthritis, which is the most common form of arthritis and which is caused by wear and tear on the joints that connect the bones in our skeletal system, RA is an autoimmune disease. It occurs when a person's immune system misfires and causes damage to its own host. This is where the autoantibodies identified in El-Gabalawy's heat map come into play.

When the body's immune system functions as it should, it creates Y-shaped proteins known as antibodies. These antibodies circulate in the blood and are specifically designed to recognize diseases - like measles, chickenpox and influenza.

You can think of these antibodies as security guards charged with the responsibility of recognizing foreign invaders and alerting the immune system's foot soldiers - white blood cells known as leukocytes - to attack and destroy the intruders to protect the body from illness.

"The white blood cells are the ones with all the firepower," El-Gabalawy says. "When you get puss coming from a boil on your skin, those are the white blood cells that are spewing their guts, and what they're spewing is pretty nasty: acid, activated oxygen molecules, even bleach - a potent bunch of stuff that is designed to kill those unwanted bacteria and viruses."

In RA sufferers, the immune system creates dozens of different kinds of these Y-shaped antibodies, but instead of protecting the body, they tell the white blood cells to attack proteins that are normal and essential to good health. "This is why they are called autoantibodies," says El-Gabalawy. The autoantibodies look and work exactly the same way as any other antibody, except they have a potentially dangerous target - the normal proteins that are components of one's own tissues and organs, such as the joint tissues. "The immune system normally fights off foreign invaders in the body, but imagine if the immune systems starts recognizing parts of you as being something to be attacked," says El-Gabalawy.
 
Specifically, these autoantibodies attack the cartilage that connect the bones and allows ease of movement. The joints become inflamed, swollen, stiff and incredibly painful. Left untreated, it can lead to rapid, severe, and permanent disability. Sufferers can become wheelchair bound, unable to carry out the simplest daily activities without severe pain.

"That's what autoimmune disease is all about. It's damage caused by the same inflammatory cells that are there to deal with infections and protect the host," he says. "It all comes down to the mistakes made by the immune system in recognizing self-proteins, which eventually leads to the inflammatory cells attacking the joints, and other organs such as the lungs and kidneys."

In the research program, the presence and progression of these rogue antibodies is revealed in blood tests and then plotted on the heat map. In a typical heat map, each vertical column represents one test taken during a single year. As you move from left to right, you can see how the proteins have advanced over the years of testing as the colours shift from cool blue to a warmer green, then yellow, then orange and finally red as the body's immune system slowly, but surely, turns against itself. The autoimmunity is heating up.

"This progression from cold to hot colours in the tests represents something we call 'epitope spreading,' when the immune response starts to spread to multiple different proteins in the body, which increases the potential of the autoantibodies to cause inflammation and damage," says El-Gabalawy.

While the presence of these autoantibodies does not guarantee that RA will occur in any single individual, the risk for developing the disease increases progressively over time as the autoantibody levels increase and their scope expands and becomes amplified. Indeed, research shows that when certain combinations of autoantibodies are reached, combined with other risk factors such as a family history of RA, the chances of an individual developing the disease over a period of a few months reaches almost 50 per cent.

It is estimated that there are about 19,000 new cases of RA every year in Canada, and the disease can be devastating for many Canadians if not detected and treated early. But advances in diagnosis and treatment over the years, including the development of new drugs called biologics, have enabled many people with RA to better manage their condition, and enter into complete remission, says El-Gabalawy.

"What we now know for sure with rheumatoid arthritis is that the earlier we treat it, the less damage we will see," he says. "So now, we've gotten people to where the disease is brought into remission quickly and we prevent a lot of damage. As recently as 20 years ago, we used to see many RA sufferers relegated to wheelchairs and their mobility and livelihood completely reduced."

Yet current treatment isn't without its problems. In most cases, patients must take combinations of medication for the rest of their lives. "With that come the risks of infections and other potential problems associated with taking these medications indefinitely," says El-Gabalawy.

Because many of these medications suppress the body's immune system, people with RA, particularly those who also suffer from other diseases, such as heart disease, lung disease and diabetes, are at higher risk of developing severe and unusual infections that are difficult to treat.

"You're hitting the problem with a sledgehammer instead of a laser," El-Gabalawy says. "Over the last 10 to 15 years, we've gotten better medications that are closer to a laser, so to speak."
 
Instead of suppressing the entire immune system, biologic treatments are designed to target specific inflammatory molecules that are attacking the joints and cartilage. A number of different types of biologic treatments exist. The most widely used biologics are injectable drugs that inhibit an important inflammation causing protein called tumour necrosis factor (TNF). Other biologics target the B-cells that produce the abnormal antibodies or other types of inflammation causing cells and proteins.
 
Beneficial as these new drugs have been, El-Gabalawy says there is more to learn about the nature of RA, and how it might be better diagnosed, treated and, possibly, prevented.

To that end, he and his team, which includes researchers from the University of Manitoba, along with collaborators in other universities in Canada, the United States, and Europe, began their studies by approaching the First Nations communities of Norway House and St. Theresa Point almost 10 years ago.

Like many other First Nations communities, Norway House and St. Theresa Point have disproportionately high rates of RA. In fact, most Aboriginals from the North American Plains region have a substantially higher risk of developing RA than other populations worldwide.

"Our estimate is that rheumatoid arthritis affects about one per cent of the general population," El-Gabalawy says. "In the Aboriginal population, it's more like two or three per cent, so it's two to three times higher in this population." Every year about 50 people per 100,000 in Canada will be diagnosed with RA, generally more women than men. But among First Nations, the incidence increases to 100 to 150 new cases annually per 100,000 people.

Although the precise cause of RA is unclear, researchers know that genetics do play a big role. A key gene linked to RA - the HLA-DR4 immune-system-gene - is over-represented in certain populations.

"This RA associated gene is very common in most of the central Aboriginal populations on the Plains, and it may have to do with the waves of migration that happened from Asia 10,000 years ago," says El-Gabalawy. "Because it is a normal immune response gene and because it is so common, its presence may have given the host a survival advantage of some kind, such as immunity to certain kinds of dangerous infections. It is probably not there just to cause RA."
 
In addition to having a higher percentage of RA cases, these Aboriginal populations are also affected by RA differently than other groups. "The disease clusters more in families, afflicting several members of a single family. It's common to find First Nations families where several family members develop RA, whereas in other populations, we tend to see isolated cases," he says.
 
"We know there's a genetic element to rheumatoid arthritis in all populations, but it's usually a weak risk," El-Gabalawy says. "For instance, in Caucasian populations, if you are an unaffected family member of someone with rheumatoid arthritis, your risk may be double that of somebody who doesn't have a family member with rheumatoid arthritis. In the First Nations families we study, particularly families with multiple affected members, your risk for getting future RA is much higher than this."
 
First Nations people also tend to develop the disease much earlier than other populations. The typical onset for other populations is the late 40s and early 50s. In First Nation populations, the average onset age is the mid-30s. "We see lots of young First Nation women in their 20s, in particular, who develop rheumatoid arthritis. Interestingly, the disease often starts in the first few weeks to months after a pregnancy," he says. "This results in a higher burden of disease based on the fact they get it much earlier in life."

The disease also appears to be more severe in Aboriginal populations. "It seems to be more destructive to the joints, particularly big joints like knees, elbows and shoulders. Destruction of these joints causes a lot of disability, especially when it happens rapidly," he says.

Initially, El-Gabalawy and his team wondered whether the severity of the disease could be attributed to a lack of early diagnosis or treatment. But their research suggests this isn't the case.

Over the last decade, the team, which includes experts like Dr. David Robinson at the University of Manitoba and other top experts in rheumatology, has worked with these communities - training community members as research assistants, working with band leaders and even guest hosting local radio call-ins to get the word out about RA. These efforts have put them in touch with families where RA is present, and they've been able to follow RA sufferers and their family members who have yet to develop it. "With improved access to care for these communities that we've worked in, we're still seeing a lot of severe disease despite improved access to medical care," says
El-Gabalawy.

Through its research in northern Manitoba, the team has gained many valuable insights into the disease that could lead to better diagnosis and treatment for both Aboriginal and non-Aboriginal people suffering from RA.

For example, although the HLA-DR4 immune-system-gene is associated with RA, the current thinking among researchers around the world is that the disease is probably triggered by a confluence of multiple genes and how they react within a specific environment. The research conducted by El-Gabalawy and his team supports this theory.

"We've looked at genetic-environmental interactions. What is happening in the environment that can interact with this genetic risk to cause some people to get (RA) and some people not to?"

The Manitoba research points to two main environmental risk factors: smoking and gum disease.

"We know now through our work that certain bacteria that cause gum disease are associated with the immune abnormalities that characterize rheumatoid arthritis," El-Gabalawy says. "We now feel that chronic gum disease may trigger the immune system to make mistakes."

Yet, like all smoking guns in medical science, explaining exactly how these culprits carry out their deeds is extraordinarily difficult, he adds. "The interaction between genetic risk factors, such as HLA-DR4, and environmental risk factors, such as gum disease bacteria or smoking tobacco, is complex and probably involves many different molecular pathways."

Data from the research has also enabled El-Gabalawy and his team to become more precise in diagnosing the onset of RA. Using blood tests and the heat map, they are becoming able to predict with increasing accuracy whether an individual will develop RA in the near future. "We know that the individuals with these patterns of autoantibodies have a high chance of developing within months," he says.

This is important because early diagnosis means early treatment, and that can result in much better patient outcomes. But El-Gabalawy emphasizes that more work must be done before the benefits of these findings are fully realized. 
 
For example, current clinical practice guidelines don't allow doctors to prescribe treatment prior to the disease causing measurable joint inflammation.

"We're still trying to understand the ethical issues involved, because giving preventive treatments before joint inflammation is actually detected in the joints becomes more like giving vaccines to prevent influenza or prescribing statin medications for high cholesterol to prevent future cardiovascular disease," he says. "You take statins not because you physically 'feel' the high cholesterol, but the risk model indicates that if we lower cholesterol, it lowers the long-term risk of having a heart attack."

The challenge is that it is not possible to accurately identify everyone at risk for developing RA and to give them prevention treatments. This would involve testing tens of thousands of people regularly to detect the autoantibodies, which is neither practical nor affordable. Also, not everyone with these autoantibodies goes on to develop RA.

Conversely, there's the fact that most people who suffer from common symptoms, such as aches and pains in their joints, do not have, and will never develop, rheumatoid arthritis," says El-Gabalawy.

Once again, research being carried out in Norway House and St. Theresa Point may hold important clues. "We're trying to understand this relationship: which symptoms are the most suggestive as a risk factor for rheumatoid arthritis, and how does the presence of the autoantibodies influence this?"

The research from northern Manitoba is not enough to change clinical guidelines and protocols for the early diagnosis and treatment of RA because the sample size is too small.

But the data gathered by El-Gabalawy in northern Manitoba will be shared with other research groups, which include teams working in the United States and Europe. In this way, the insights gleaned from research in Norway House and St. Theresa Point will help shape the work of El-Gabalawy and other international researchers as they continue working together to develop a clinical model for early diagnosis similar to what family doctors use today to determine whether a patient is at risk for heart disease and should be put on medications to reduce high blood pressure and high cholesterol.

"We want to come up with not just a lab test, but a test combined with certain clinical features that we recognize from talking to individuals about their symptoms, family history, and health problems such as gum disease and smoking. It's not just those fancy heat maps but the relationship of those maps to what people experience," he says. "The good news is that as we follow the study participants from these Aboriginal communities for the earliest signs of the disease, they will have the most to gain because they will be the first to reap the benefits of new treatments for the early stages of RA."

In addition to developing better diagnosis and treatment protocols, El-Gabalawy says the research being done in northern Manitoba may also open the door to a possible cure for RA.

As he explains, if the presence of autoantibodies in individuals at high risk for developing the disease can be detected early enough, and a suitable treatment can be found - a vaccine, for example - the disease may never develop and there would be no need for lifelong treatment.

"The theory is if we use certain tools at a stage before the disease develops, you may only need to use them for a specific period of time, or maybe we can develop a vaccine-like treatment that can turn these abnormal responses off, so we don't have to keep treating them."

The idea of developing a vaccine holds particular interest.

"When we're talking about an RA 'vaccine,' we're talking about an agent that would turn off the autoimmune response as opposed to what vaccines normally do - turning on a stronger immune response," he says. "It would involve trying to stimulate immune system regulation so that the abnormal response gets turned off, and the body's normal checks and balances are restored. We call this restoring 'immune tolerance,'" he says.
The science may not be there yet, but El-Gabalawy is hopeful.

"Our vision is to first develop a good risk model for the development of imminent RA. This prediction model would be based on the autoantibody patterns and on other easily identified risk factors, and it would be easily used in clinical practice at a stage when the disease can be prevented by a safe treatment given over a brief period of time," he says.

"Having said this, if we're only able to delay the start, or we need to keep treating people indefinitely, as we do now, we haven't gained a great deal, so the ultimate goal is disease-free and medication-free, for good."

Joel Schlesinger is a Winnipeg writer.

Wave: November / December 2013

About Wave

Wave is published six times a year by the Winnipeg Health Region in cooperation with the Winnipeg Free Press. It is available at newsstands, hospitals and clinics throughout Winnipeg, as well as McNally Robinson Books.

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