Arthritis Research | Arthritis National Research Foundation | Lupus Research Aims To Prevent Heart Attacks
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Lupus Research Aims To Prevent Heart Attacks

Lupus Research Aims To Prevent Heart Attacks

Systemic Lupus Erythematosus (lupus) is a chronic autoimmune disease that arises when the body’s defenses go awry. Subtly, often silently, the body attacks its own tissues and organs. Symptoms tend to come and go, occasionally flaring and subsiding. Jason Knight, MD, PhD, an Assistant Professor of Rheumatology at the University of Michigan, is using his funding from the Arthritis National Research Foundation to drive his lupus research and investigate new potential treatments.

In lupus, as the compromised immune system battles against self tissues, the body’s disease-fighting defenses unleash a cascade of potentially lethal complications. These complications mean that nearly 1.5 million Americans with lupus are at risk for blood clots, heart disease and organ failure.

“Lupus has a startling ability to damage any organ in the body—kidneys, lungs, liver, brain and blood vessels,” says Dr. Knight.

Arthritis Research of Dr. Jason Knight

Autoimmune disorders like lupus and rheumatoid arthritis overwhelmingly afflict women, especially during the childbearing years. “Women are 10 times more likely than men to develop lupus,” says Dr. Knight. “In this country, African American women are especially at risk—1 out of every 250 will be diagnosed with lupus.”

In an effort to better understand the underlying causes of lupus, scientists are studying how inflammation sets the stage for chronic autoimmune diseases like lupus. New treatments are desperately needed to prevent life-threatening damage to vital organs. Although survival has improved since the 1950s—when less than half of those diagnosed with the disease lived for 10 years—lupus remains a deadly threat.

Currently, immune-suppressing drugs are used to prevent sudden disease flares and symptoms. “Despite decades of research on immune system cells, precision therapies have been slow to emerge,” says Dr. Knight. “Immune-system suppressing treatments are ‘nuclear options’ because they disrupt the entire immune system, including its ability to defend against infection.”

Lupus Research | Jason Knight

While no longer a death sentence, lupus still lags behind other autoimmune diseases when it comes to treatment options. In 2011, the FDA approved Benlysta (belimumab), the first new medication for lupus in more than 50 years.

Today, thanks to medications and kidney transplants, the odds of dying from kidney disease have decreased sharply. As patients live longer, cardiovascular diseases such as heart attacks, strokes, and blood clots—have emerged as the new leading cause of death from lupus.

“When someone develops blood clots, we prescribe potent blood thinners,” says Dr. Knight. “These drugs must be taken for life, but pose dangerous bleeding risks. The fact that we treat an autoimmune disease with blood thinners is inherently dissatisfying to both the patient and the physician.”

In an autoimmune disease, the body turns on itself as circulating antibodies in the bloodstream attack and destroy healthy cells. Patients with lupus often experience antiphospholipid syndrome, which is a condition in which the immune system mistakenly attacks normal proteins in the blood. Patients with antiphospholipid antibodies are at a much higher risk for blood clots. “More than 20 percent of lupus patients experience a clotting event within 10 years of diagnosis,” says Dr. Knight. “When they develop a blood clot, they are diagnosed with antiphospholipid syndrome, or APS.”

Researchers are creating targeted therapies to treat, and ultimately prevent, life-threatening cardiovascular complications in lupus.

How can Dr. Knight’s lupus research prevent heart attacks?

Neutrophils, the most abundant type of disease-fighting white blood cells, attach to the walls of the blood vessels to block assaults on the immune system. Neutrophils extrude their sticky insides into spider web-like structures, perfect for capturing invaders. Although these neutrophil extracellular traps (NETs) help stave off microbial infections, they also serve as excellent ‘scaffolding’ for the assembly of blood clots.

“We hypothesize that the over-exuberant release of NETs is why lupus patients form blood clots,” explains Dr. Knight. “We have demonstrated that neutrophils of patients with lupus/APS—the type of lupus with the highest risk of blood clots—extrude NETs more readily than the neutrophils of healthy individuals.”

Lupus Research | University of Michigan

Gene-profiling experiments have revealed that molecules responsible for “adhesion” are highly expressed on the surface of neutrophils from patients with lupus/APS. These molecules function like Velcro, making the neutrophils stickier and more likely to adhere to the blood vessel wall.

“We ‘trick’ healthy neutrophils into releasing NETs by exposing them to blood and antibodies from patients with lupus/APS,” says Dr. Knight. “What’s more, we have shown that these NETs activate specific enzymes that cause the blood to clot.”

With funding from the Arthritis National Research Foundation, Dr. Knight’s laboratory is pioneering advanced gene techniques and cutting-edge microscopy. “We believe the NET-releasing weapon is not fully activated until a neutrophil sticks to the blood vessel wall,” he says. “If we can block those interactions, we can prevent clotting, which in turn may prevent heart attacks.”

Researchers are working to discover how genes, hormones, and an over-reactive immune system spur the development of autoimmune disease. “As a physician, I was drawn to rheumatology by unanswered scientific questions in the field,” he says, “and especially by the opportunity to develop relationships with patients over many years—as we attempt to answer these questions together.”



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