Mar. 01, 2012

Biomarkers in Lupus

By Jenny Thorn Palter

Biomarkers are very much in the news today, in stories about how to determine who is at risk for a disease or condition, or the ways in which a group or population is reacting to a particular treatment. They also play a role in the development of new medications.

And because of how biomarkers are involved in medical research, many of the projects funded through the Lupus Foundation of America’s National Research Program, Bringin Down the Barriers™, involve biomarkers of one kind or another.

Below, we introduce several well-established clinician-researchers currently involved in research on lupus biomarkers through projects funded by the LFA’s unique grant program.

But what exactly are biomarkers?

Understanding Biomarkers

Amy Kao, M.D., M.P.H., assistant professor of medicine and director of biomedical informatics at the Lupus Center of Excellence, Allegheny Singer Research Institute in Pittsburgh, describes a biomarker as “any measurable characteristic that provides information about your health.”

In fact, “a biomarker may be a gene, a protein, a chemical, or any substance that indicates a certain biological state of the body and can be measured and evaluated,” adds Ornella J. Rullo, M.D., in the Division of Pediatric Rheumatology at Mattel Children’s Hospital, University of California, Los Angeles.

Familiar examples of biomarkers include cholesterol and triglyceride levels as indicators of cardiovascular health and risk of heart disease, or tumor size measurements to show growth or shrinkage of cancer cells.

Defining Biomarkers

Biomarkers fall into three categories:

  • Biomarkers that indicate normal biological processes, such as determining blood pressure with two values in a range of low to high.
  • Biomarkers that indicate a result of abnormal processes, such as an elevated white blood cell count due to an infection.
  • Biomarkers that indicate the body’s response to a medical treatment, such as the reduction of white blood cell levels after taking antibiotics.

Biomarkers in Lupus

Proteins, genes, and other biological markers are used every day for diagnosing and treating lupus, and to track the disease course. Antinuclear antibodies (ANA), for example, are found in 97 percent of people with lupus, so their presence helps the physician make the diagnosis. Anti-SSA/Ro antibodies are associated with neonatal lupus heart block in infants of mothers with these antibodies, so their presence allows the obstetrician to be on the lookout for anything unusual in the baby. Antiphospholipid antibodies (aPL) can lead to blood clots, which may mean adding an anticoagulant medication.

But despite all that is known about lupus, it remains difficult to find reliable biomarkers, because lupus symptoms and disease course are different in each individual. Furthermore, not only can lupus be present even if biomarkers such as ANA or aPL are not seen, but these antibodies can also be found in people who do not have lupus at all.

Identifying biomarkers that can be used with accuracy in thousands of people with lupus is truly a challenge. The good news is that the search for lupus biomarkers is getting increased attention from lupus researchers, and each discovery adds to the body of knowledge.

How C4d Affects Lupus

Lupus research being conducted at the Lupus Center of Excellence, Allegheny Singer Research Institute in Pittsburgh showed that approximately 20 percent of those with lupus have abnormal levels of C4d on their platelets.

“Platelets are blood cells that participate in blood clotting,” explains Amy Kao, M.D., M.P.H., the center’s assistant professor of medicine and director of biomedical informatics. “Abnormal blood clotting can lead to heart attack and stroke. Therefore, having a higher level of platelet C4d may help to identify individuals with lupus who might be at elevated risk for blood clotting, and specifically stroke.”

Lupus flare

Kao and her Pittsburgh colleagues, Joe Ahearn, M.D., and Susan Manzi, M.D., in part with funding from the LFA, have been studying proteins in the body’s complement system, called cell-bound complement activation products (CB-CAPs). The complement system is a group of proteins that help the body protect itself against foreign substances. Research conducted in thousands of individuals over a number of decades has shown that, when not working properly, complement is involved in the development and progression of lupus.

“We’ve conducted several studies specifically focusing on CB-CAPs, which are generated during activation of the complement system,” Kao says. “One that showed promise as a lupus biomarker is called complement 4d, or C4d. When the complement system is activated, C4d is released into the bloodstream and binds, or attaches, to cells circulating throughout the body. In our research, we measured the amount of C4d on red blood cells, platelets, and white blood cells in large numbers of people with lupus, and examined the patterns of how C4d attaches to circulating cells.” Using these research findings, a blood test has now been developed that can aid in the diagnosis and monitoring of the disease.

Lupus nephritis

Lupus is often complicated by organ damage, particularly affecting the kidneys. An estimated 40 percent of those with lupus, including as many as two-thirds of all children and adolescents with lupus, will develop kidney complications. Yet there are few known ­potential markers that can help predict who is at risk for developing lupus kidney disease.

Kao and her colleagues in Pittsburgh recently published an article in the journal Lupus on their LFA-funded research investigating the connection between C4d and kidney involvement. The study found that people with lupus nephritis—severe inflammation in the kidneys—had higher levels of C4d than people with kidney disease who did not have lupus. Those with lupus nephritis also had higher C4d levels on red blood cells and reticulocytes (young red blood cells) than did individuals with lupus but not nephritis, and those with kidney disease but not lupus. This suggests a potential role of C4d as a more reliable and potentially scientifically valid biomarker for lupus nephritis, which Kao says the group will continue to investigate.

Lupus disease activity

There is also excitement surrounding the role of interferon-alpha (IFN-a) as a potential biomarker for many aspects of autoimmune disease. Interferons (IFNs) are proteins that assist with communication between cells in order to trigger the immune system’s defenses.

While research has shown that levels of IFN-a increase when lupus is active, IFN-a also appears to have a role in controlling certain genes that act upon the immune system.

IFN-a levels are themselves regulated by genes. So when LFA-funded researchers Rullo and colleague Deborah McCurdy, M.D., learned that a gene that regulates interferon, known as interferon regulatory factor 5 (IRF5) was associated with lupus in large-scale genetic studies, they decided to examine that relationship more closely.

“We found a connection to the amount of a particular protein in the blood called osteopontin,” Rullo says. “We noticed that osteopontin levels were consistently higher in both children and adults whose lupus was active over a prolonged period of time, which was in turn leading to organ damage.”

She adds, “Kidney health in individuals with lupus nephritis can often be vastly improved if treated early and aggressively. Identifying biomarkers that can tell us who is at the greatest risk for organ damage may become important tools for more personalized care of individuals with lupus.”

Lupus and the nervous system

Difficult to diagnose and treat, neuropsychiatric lupus (NPSLE) has lingered in the background when it comes to research funding in past decades. But the need for expanded knowledge about NPSLE is great, especially for children and adolescents, the most vulnerable populations. Although “lupus fog” is one of the most common occurrences, more severe complications often take a toll on physical health and quality of life.

According to Eyal Muscal, M.D., M.S., assistant professor of pediatrics, Divisions of Rheumatology and Neurology and Developmental Neuroscience at Texas Children’s Hospital/Baylor College of Medicine, lupus affects about 10,000 young people under age 18 in the United States. “Disease effects on the brain are common in children and teenagers with lupus, and may include strokes, seizures, and difficulties with thinking,” he says.

Muscal and his research team believe that advances in neuroimaging technology may help physicians stay one step ahead of the disease and its effects on the young brain and nervous system. “Newer magnetic resonance imaging (MRI) tests that measure brain blood flow and the integrity of brain connections may reveal that brain tissue damage is an early feature of childhood-onset lupus,” he says.

Muscal’s LFA-funded study has several components: to determine whether children with lupus have reduced brain blood vessel flow compared with healthy children of the same age; to see if those who have risks of lupus-associated blood vessel inflammation or inappropriate blood-clotting tendencies have more prominent flow reductions; to investigate whether reduced blood flow is related to damage to the brain connections (the white matter); and to look at whether reduced brain blood flow will be related to poor performance on a computerized thinking test.

“What we learn may enhance our understanding of early vascular and inflammatory brain disease among young people with lupus,” Muscal says.

Lupus drug development

The role of biomarkers in clinical trials is crucial to the development of new therapies and treatments: They help researchers understand why an investigational treatment might work, as well as the effect that the treatment is having on a particular biological pathway or processes.

Yet in order for the Food and Drug Administration (FDA) to consider approving a new drug, clinical studies must show that the drug is safe and effective—not just in one person or 10 people, but in hundreds or even thousands of people. For example, if a company wants to prove that its drug product can reduce the incidence of lupus flares, a marker or series of biomarkers must be able to show this reduction in flares in several hundred individuals—and must be able to do so consistently.

Once again, the very things that make lupus so difficult to diagnose and treat also pose the greatest challenge for drug development: the wide range of symptoms, the unpredictability of what causes flares, and, in clinical trials, the “background” medications being taken by study participants.

Jill P. Buyon, M.D., vice chair of rheumatology at New York University School of Medicine, who spoke on biomarkers at the annual 2011 scientific meeting of the American College of Rheumatology, says, “While researchers look at biomarkers for prognostic use—that is, to project the overall course of the disease and to forecast flares and severity of symptoms—biomarkers are also used to predict who will respond to a particular drug, and then to gauge how well that drug does what it was designed to do.”

Perhaps the best-known example is Benlysta® (belimumab), the first-ever drug specifically for lupus, which was developed by Human Genome Sciences (HGS) and GlaxoSmithKline (GSK).

In lupus and certain other autoimmune diseases, elevated levels of B lymphocyte stimulator, called BLyS, had been shown to contribute to the production of autoantibodies—antibodies that attack and destroy the body’s healthy tissues. Clinical studies had found that if BLyS could be prevented from attaching to B cell receptors and further promoting the activity of those B cells, the harmful levels of autoantibody would be reduced, which would help to control autoimmune disease activity.

But HGS and GSK researchers had to show that lupus disease activity was improved in large numbers of people with lupus—without harmful side effects, and in a way that lasted over time. Because they were able to do so, the FDA granted approval of Benlysta. Today the BLyS biomarker is being used by other pharmaceutical companies as they work to develop potential new treatments for various aspects of lupus.

Why Do Biomarkers Matter?

“Biomarkers are of great importance to help determine when a person is healthy, or has a disease, or is at risk for an illness or disease flare,” says Ornella J. Rullo, M.D., in the Division of Pediatric Rheumatology at Mattel Children’s Hospital, University of California, Los Angeles. “They are essential to patient care in terms of diagnosis, monitoring of illness or disease, and predicting outcome.”

“Biomarkers also can help doctors monitor disease activity, by serving as indicators of how the disease is behaving; that is, whether you are getting better, remaining stable, or getting worse,” adds Amy Kao, M.D., M.P.H., assistant professor of medicine and director of Biomedical Informatics at the Lupus Center of Excellence, Allegheny Singer Research Institute, in Pittsburgh.

Kao gives an example of a common biomarker used in monitoring diabetes. “Poor blood glucose control in people with diabetes is associated with medical complications such as cardiovascular disease, renal disease, and diabetic retinopathy,” she explains. “Blood glucose is measured by the level of glycated hemoglobin—the biomarker known as HbA1c—in a drop of blood taken from a finger.

“If the HbA1c is elevated, the physician will need to improve the blood glucose (glycemic) control by changing the current treatment,” Kao says.

In this instance, it’s not a case of a positive or negative test result, but instead the biomarker level that helps the physician decide what to do next.

The Future

While BLyS is a single marker, Buyon predicts that biomarkers for lupus will be most valuable when they are used in combination. “The ways in which lupus affects the body are diverse, and the severity of disease varies from person to person,” she says. “Biomarkers are likely to mirror these characteristics and therefore may not be a ‘one size fits all.’

“Although further studies will be needed, we have made considerable progress,” Buyon says.

Through its continued commitment to advancing the science and medicine of lupus, the LFA looks forward to funding today’s researchers as they discover the lupus biomarkers of tomorrow.

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