Surge in Biomarker Research Signals New Hope for Diagnosing and Managing Lupus

Promising Biomarker

LRI-funded researchers Maureen McMahon, MD, and Bevra Hahn, MD, have found large amounts of damaging “pro-inflammatory” (piHDL) versions of the normally “good” HDL cholesterol in people with lupus that might explain the predisposition to atherosclerosis and help identify those at risk for heart disease. In one study (above), nearly 45% of people with lupus had the damaging piHDL as compared to 20% of people with RA (rheumatoid arthritis) and 4% of healthy controls.

In the year 2007, a life with the chronic and unpredictable multi-system disease that is lupus remains rife with uncertainty. “Will I get sicker?” the person with lupus asks. “Will my kidneys start to fail? My heart? Will my siblings or children get lupus? Will a new drug work for me? Will I ever feel better?”

Doctors asked these questions today can only give the vaguest of answers—estimations and educated guesses based on signs and symptoms that reflect damage already underway, the behavior of the disease to date, and what might happen to people in similar situations. Years of costly tests provide only a vague picture of what is going on inside the body of a person with lupus.

Biomarkers, in many cases simple blood or urine tests, could change all this, drastically minimizing the guesswork in diagnosing and treating the disease. Biomarkers provide tools with which to peer into the immune system and witness the earliest indications of problems.

“Because lupus is so unpredictable, managing the disease is a great challenge,” explains LRI Scientific Board Chairman William E. Paul, MD, chief of the laboratory of Immunology at the NIH's National Institute of Allergies and Infectious Diseases. “Biomarkers can take the guesswork out of treating lupus and help in creating a meaningful plan of action tailored to each person. They can also speed the development and approval of more effective and less toxic drugs, which are desperately needed.”

From its beginnings in the year 2000, the LRI recognized that biomarkers have the potential to illuminate the body’s “control panel” and even guide treatment to change the outcome of disease.

As yet, no single biomarker has been accepted widely or used routinely for any aspect of lupus—in fact, because lupus develops and affects people so differently, it is highly unlikely that any single biomarker will provide all the answers for everyone, experts say.

“In the simplest terms, biomarkers are lab tests. You want to know what is going on with the person's illness—whether they're doing well, whether they're going to flare, whether they are responding to treatment. We need biomarkers so that we can better predict and manage the disease, as well as speed development of new therapies. Biomarkers are crucial.” – LRI Grant Recipient Elahna Paul, MD, PhD. Massachusetts General Hospital.

“Am I likely to get lupus? Will I probably have mild or severe disease?”

LRI-Funded Researchers Discover Potential Biomarkers of Risk and Flare

Although still a subject of scrutiny and debate, most scientists point to a likely mix of genes and triggers in the environment as the cause for lupus. LRI-funded research has generated compelling findings in this arena.

For example, after discovering that the SLAM family Ly108 gene causes susceptibility to lupus in mice, Edward K.Wakeland, PhD, at the University of Texas Southwestern Medical Center in Dallas is now launching a search for the human equivalent of this gene to see if it could be used to identify people susceptible to the disease.

In New York at the Hospital for Special Surgery, Mary K. Crow, MD, and colleagues are working to validate two promising novel markers of lupus flare that they have identified— interleukin-8 (IL-8) and an unnamed gene product that emerged repeatedly in their preliminary data.

"By identifying good markers that measure the early phase of disease activity and, in particular, flares, we can one day intervene earlier with new or existing drugs and treat a patient before disease becomes clinically active," Dr. Crow explained.

Work begun by Timothy W. Behrens, MD, researchers at the University of Minnesota Medical School in Minneapolis similarly aims to uncover very early indicators of an impending flare or remission. They are testing approximately 1,500 blood samples from 300 people with lupus with sophisticated technology tools. The goal: to identify shifts in certain protein levels that signal lupus activity.

And in an intriguing reversal sparked by LRI-funded researchers in New York and Chicago, auto-antibodies such as those that attack genes inside cells (anti-dsDNA) have reemerged as potential biomarkers after being largely dismissed because of their inconsistency in predicting or portraying lupus activity.

Interest has been revived by two LRI-funded scientists who have discovered, in mice with lupus, two potential new autoantibody biomarkers: Chaim Putterman, MD, at the Albert Einstein College of Medicine in the Bronx identified x-actinin reactive autoantibodies which appear to be an alarm bell for kidney involvement, and Martin Weigert, PhD at the University of Chicago identified “editor” auto-antibodies in lupus, which could be a biomarker for very earliest stages of the disease.

“Are my kidneys all right?”

LRI-Funded Researchers Discover Possible Kidney Biomarkers

The kidneys are crucial to overall health, filtering out wastes, balancing body fluids, and regulating hormones that control blood pressure. But in as many as 1 in 3 people with lupus, inflammation in the kidneys’ filtering units prevents blood toxins and waste from getting processed as they should.

Because no one blood or urine test can check for this serious complication, people with lupus often undergo frequent biopsies. Now researchers are making headway in finding biomarkers for rendering these uncomfortable, costly, and sometimes risky biopsies obsolete.

For example, Anne Davidson, MD, at the Albert Einstein College of Medicine in New York, has found that proteins made in the kidneys of mice during the earliest stages of the disease can also be detected in their urine and blood. She now plans to investigate these proteins in a people to determine their potential as biomarkers.

By identifying which pathways of kidney cell activation contribute to kidney damage in lupus, Elahna Paul, MD, PhD’s research at the Massachusetts General Hospital in Boston could lead to new treatments that block kidney failure in lupus.

At Columbia University College of Physicians and Surgeons in New York, Robert Winchester, MD, is making headway in confirming the presence of certain genes expressed in white blood cells in cases of early kidney injury.

“A simple urine test that could tell us what’s going on with my kidneys?” asks the patient. “That makes a difference in the way I live.”

“How Is My Heart?”

LRI-Funded Researchers Discovery Possible Cardiovascular Biomarkers

One of the most exciting and productive areas of LRI-funded biomarker research is in detecting and preventing heart disease—a serious and potentially fatal complication that along with stroke develops in as many as a third of all women with lupus.

Having biomarkers to signal which people are developing the first signs of arthrosclerosis might enable doctors to be aggressive about trying to stop the process and prevent long-lasting damage.

One of the most promising of these biomarkers is an abnormal plaque-promoting molecule in the blood called piHDL (pro-inflammatory high density lipoprotein). Bevra Hahn, MD, Maureen McMahon, MD, and colleagues at the University of California in Los Angeles are testing whether this biomarker—which they identified with LRI funding—could help predict the risk for atherosclerosis in people with lupus.

In a novel conceptual advance that involves measuring level and type of cells that line the body’s blood vessels (endothelial cells), Mariana Kaplan, MD, at the University of Michigan in Ann Arbor is examining whether a blood-based test that measures the number of these cells that are dying could be used to identify people with lupus at particular risk for cardiovascular disease.

In related work, Robert M. Clancy, PhD, at the Hospital for Joint Diseases in New York has found that concentrations of endothelial protein C receptor are increased in people with lupus who are developing atherosclerosis but yet haven’t shown any signs or symptoms—yet another possible tool for identifying problems before damage occurs.

In the course of her research on imaging techniques for detecting heart disease in people with lupus at the University of Pennsylvania in Philadelphia, Joan Von Feldt, MD, found that high blood levels of homocysteine (a marker of inflammation) were often present in those with early signs of atherosclerosis. It is a pattern she is investigating further to determine homocysteine’s value as a biomarker.

Those with lupus who have APS (anti-phospholipid antibody syndrome) and have suffered a blood clot are left wondering if another clot will strike. Robert Roubey, MD, at the University of North Carolina, Chapel Hill, is examining various blood clotting proteins as indicators of risk for future blood clots.

The Power of Biomarkers

The biomarker hunt is hardly exclusive to lupus, with federal agencies, cancer centers, biotech companies and others investing millions in these “early predictors” for multiple diseases.

For a disease such as lupus—so difficult to diagnose, manage, and treat—the stakes and the hopes are high indeed. In recognition of the stakes at play, the LRI has joined with several other organizations to campaign for the creation of a collaborative public-private S.L.E. Biomarker Initiative that would pool findings and resources for lupus biomarkers.

One of the primary goals of the Initiative is to lead researchers to new drugs for lupus, of which there have been none approved in nearly 50 years.

"To know if a drug works,” explains Mary Crow, MD, “we have to assess how active the disease is and how that activity changes in response to the drug, If proven valid, the potential new biomarkers will stimulate drug companies to get in the game. “

“Eliminating the uncertainties of lupus—that’s the power and hope of biomarkers,” explained LRI Executive Director Margaret Dowd. “We can make this happen.”