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auto immnuneLeft to right: Alex Bennett (left) and cousin, Kara McIntosh

Written by: Heidi Singer
Photos by: John Packman

Alex Bennett remembers the fear she felt as a young child when she visited her arthritis-stricken great-grandmother who was seated in a wheelchair, her hands bent into claws from stiffness and pain. Alex and her cousin Kara held hands on the way home and comforted each other.

Today, they are still supporting each other through rheumatoid arthritis (RA) — their own. Each woman developed the debilitating autoimmune condition after delivering her third child, and each within a year of one another.

On her first visit to Dr. Ed Keystone, a rheumatologist at Mount Sinai Hospital, part of Sinai Health System, Alex could barely hold her three-month-old twins. Her symptoms had progressed quickly from aching palms to crippling exhaustion just days after giving birth. She was terrified and could only look at her babies and weep.

Alex remembers Dr. Keystone telling her: if you were wheeled into my office ten years ago, I would tell you that you wouldn’t be walking out ever. But today I can promise you hope.

Like other autoimmune conditions, RA runs in families: a quarter of patients have a relative with the disease. In the beginning, the cousins thought of their great-grandmother’s suffering with a great deal of anxiety. But their own experience has proven much different, thanks to dramatic advances in treatment in the past 15 years that allow patients to live fuller, more mobile lives. And with greater understanding of the role of genetics, including key contributions from Sinai Health System scientists, many expect that one day most autoimmune diseases like RA will be managed as effectively as diabetes.

“Very few patients ever get in a wheelchair”

When Dr. Keystone started treating people with autoimmune disease in the early 1980s, there wasn’t much doctors could do. He remembers arriving as a medical resident at the old Wellesley Hospital in downtown Toronto and seeing 40 beds filled with people in pain who would stay for weeks on end. He thought of his own mother, who suffered from autoimmune disease.

“We had one or two therapies, and if they failed, then we had nothing,” recalls Dr. Keystone, Director of the Rebecca MacDonald Centre for Arthritis and Autoimmune Disease at Mount Sinai Hospital. “We just watched people suffering. I swore that I would work diligently to find a better way.”

Around the turn of the century, highly effective new medications called “biologics” began to emerge in the fight against RA and other autoimmune disease. Biologics target specific parts of the immune system that attack phantom foreign invaders and cause many of the painful, debilitating symptoms associated with swelling in this group of diseases. Dr. Keystone began using them right away and noticed huge improvements in his patients. Today, “very few patients ever get into a wheelchair and there are half as many joint replacements for rheumatoid arthritis,” he says. Instead of 40 beds in one hospital, there are now only half a dozen beds in all of Toronto for people with RA alone.

But Dr. Keystone has observed that biologics don’t work at all for 10 to 15 per cent of his patients and eventually they stop working for almost every patient. And there is no way of knowing which of the eight biologics to try first.

Sisters Stephanie Gutcher and Krystal DiFrancesco are very familiar with the medication rollercoaster. Stephanie was diagnosed with RA as a toddler but is currently in medical remission. Krystal didn’t develop symptoms until she was 18 but has more active disease. Both sisters have moved from drug to drug, with most lasting a year or two. For Krystal, being on the right drug is life changing. She can dance all night at a wedding or go zip-lining, as she and Stephanie did for her bachelorette party. But when a drug stops working or she’s having a bad day, she worries about the future.

Left to right: Sister Krystal DiFrancesco (left) and Stephanie Gutcher

Customizing treatments

Many patients follow Krystal and Stephanie’s pattern of moving through drugs every year or two. But for some, biologics work for a decade or more. To understand why, Dr. Keystone teamed up with Dr. Kathy Siminovitch, a genetics expert and Senior Investigator in the Lunenfeld-Tanenbaum Research Institute (part of Sinai Health System), whose work has helped identify 100 genes associated with risk for rheumatoid arthritis. They hope to apply this genetic information to guide treatment decisions in the clinic.

“We have many treatment options for rheumatoid arthritis and that’s why we have an opportunity to personalize care — not just for RA but for all autoimmune disease, because many of these conditions share genetic roots,” says Dr. Siminovitch. “But there’s a lot of work to do: most patients respond to treatment, but only half respond fully and go into clinical remission.”

Genetic analyses can help doctors select the best treatment for each patient. This is a relatively new field, called “pharmacogenetics”. Already, it’s helping the Sinai team to distinguish patients with extremely different outcomes of disease — those who do well for many years on the same drug versus those who failed to respond to any medication. The hope is to learn from the first group to find new “druggable targets” for the second one. Alex and Kara have both contributed their blood samples to this project, along with dozens of other Sinai Health patients.

Dr. Siminovitch has also identified genes involved in primary biliary cirrhosis as well as vasculitis — a rare but very severe autoimmune disease. She is now complementing this approach with a cutting-edge technology — immune-phenotyping — that allows for very detailed characterization of a patient’s immune responses over time. This information can be analyzed in relation to the patient’s symptoms at the time the sample was drawn: Was the person experiencing a disease flare-up or feeling entirely well? If, for example, the test reveals that certain immune cells are unusually active before a disease flare occurs, doctors could detect these “activated” cells and treat them with a drug that suppresses their activity, preventing a flare-up.

Predicting and preventing

The other frontier for Drs. Siminovitch and Keystone is in the area of disease prevention.

“Because our information and understanding of autoimmune diseases is so much better now, we have an unprecedented opportunity to begin treatment before disease is clinically apparent,” says Dr. Siminovitch.

Recently, scientists have started to appreciate the importance of a “pre-disease” period, in which immune changes can be seen in apparently healthy people that suggest RA may develop. By monitoring those at unusually high risk for RA for selected immune markers in the blood, Dr. Siminovitch says it is possible to identify those who will develop the disease. As these people get closer to developing RA, levels of these markers increase, allowing scientists to predict who will develop overt disease within the next few years.

Above: Dr. Kathy Siminovitch

Efforts to prevent disease onset by pre-disease treatment are now being actively explored, says Dr. Keystone. And with Dr. Siminovitch’s genetic expertise, he hopes to identify new markers and treatment approaches to make disease prevention a reality.

“We’ll rethink the equation: the patients, the type of medications they used previously,” says Dr. Keystone. “Just bashing the immune system may not be good enough. You might have to more selectively target the areas that are causing the problem.”

Drs. Keystone and Siminovitch have also started a unique study that takes advantage of Sinai’s expertise in pregnancy and delivery. At the suggestion of his daughter, Dr. Keystone is studying the genes and immune profiles of women whose RA remits during pregnancy, 80 per cent of who will have a flare-up within two months of delivery.

Perhaps it’s not surprising that autoimmune flare-ups are influenced by the hormonal shifts of pregnancy, since three-quarters of patients suffering from an autoimmune disease are women. That the disease can first strike when a woman has a new baby, as it did with both Alex and Kara, underscores its cruel timing.

Krystal, now 34, was struggling with the first RA symptoms 16 years ago when she learned that her cheerleading team would travel overseas for the first time to compete in Hong Kong. “They had to tell me I couldn’t go,” she recalls. “I don’t remember if I cried right there or if I just tried to hold it in. But I had to stop coaching gymnastics and cheerleading. I thought, there goes my world.”

These days, Krystal is still active, doing Crossfit and hiking. But like Stephanie, Alex and Kara, she has learned to adjust to the rhythms of RA. She must constantly decide when it’s worth paying the price by pushing her body a little too far. For her, it’s dancing at a wedding — even though she’ll spend the entire next day in pain. For Alex, it’s acting like everything’s ok during an unexpected downturn for the sake of her three kids. Despite amazing advances in treatment, everyone — physician, researcher and patient alike — struggles against the unpredictability of autoimmune disease.