NEW YORK (360Dx) – By combining three biomarkers, each a harbinger of disease risk, a research group has developed an index that clinicians might be able to use to diagnose the chronic autoimmune condition lupus, or systemic lupus erythematosus (SLE).
The index uses an algorithm to identify the risk of a patient developing lupus based on the concentration in blood serum of IgG and IgM anti-double stranded DNA antibodies, and levels of C1q, a protein complex associated with protection from lupus.
Describing the results of a study published on Friday in Molecular Medicine, the researchers said that the index could eventually be used to assess the effectiveness of early interventions with lupus patients, and that it suggests new therapeutic approaches for the treatment of SLE.
In diagnosing lupus, clinicians look for signs that patients have at least four of 11 clinical criteria or measurements identified by the American College of Rheumatology, including rashes, arthritis, and abnormal levels of antinuclear antibodies. While that standard of care includes testing for a single biomarker among its criteria, the new multimarker risk index would provide a way "of actually deciding whether patients are progressing" to full-blown lupus, Betty Diamond, one of the index developers who is head of the Center for Autoimmune, Musculoskeletal, and Hematopoietic Diseases at the Feinstein Institute for Medical Research, said in an interview.
In developing the index, the group used known information about how autoantibodies are central to the pathogenesis of the disorder, Diamond said.
If the risk index proves its accuracy and utility in future studies, it could then be deployed as a clinical test that predicts who has incomplete lupus, and who might be on the way to developing full-blown lupus, including lupus flares, she said.
"Lupus is similar to other diseases," Diamond noted, "in that it needs to be treated before it gets out of control and starts damaging tissue. An algorithm that says a patient is getting worse or getting closer to a lupus flare would, therefore, be very important."
David Pisetsky, a professor of immunology at Duke University School of Medicine, said in an interview that in its early phases, lupus can be difficult to diagnose with current laboratory tests. However, by more carefully diagnosing and tracking these patients, therapy could be started sooner, he said,
"The proposed test by Dr. Diamond and her coworkers provides a new way of measuring anti-DNA antibodies, a key specificity in lupus, by assessing two different components of this response," said Pisetsky, who was not involved in developing the lupus risk index. He noted that the index could prove especially useful in providing information when other tests fail to provide a definite diagnosis. Further, it could be used in patients thought to be at higher risk of disease, such as family members and especially sisters of lupus patients, he said.
All three biomarkers that are part of the index are measured on separate ELISA platforms, which would make the test accessible and inexpensive if it proves itself in additional studies, Diamond said.
To compare potential biomarkers of systematic lupus erythematosus among women with varying levels of disease risk, the researchers analyzed blood serum samples in five cohorts: 40 West African women with a history of malaria infection; 51 African-American lupus patients; 80 healthy African-American women; 98 unaffected sisters of lupus patients; and 16 Caucasian women.
"We've known for a long time that anti-DNA antibodies are very important in lupus pathogenesis and are essentially diagnostic of the disease," Diamond said. "It's also been known that anti-IgM DNA antibodies can protect against the disease," and between 80 and 90 percent of people get lupus when they are born with a deficiency in C1q because of a genetic mutation.
The group wanted to examine whether they "could use these three very simple metrics that are available from clinical labs all over to try to define a risk for developing lupus," Diamond said.
In their study, the risk index demonstrated that patients with lupus had the highest score on the risk index, and unaffected sisters of women with lupus had a score that was next highest. West African women were two to three times more likely than Caucasian women to develop lupus, and they had the third highest risk score, Diamond said. Caucasian woman and women from malaria endemic regions that have had exposure to malaria had the lowest levels of lupus risk.
"In mouse models, it had already been shown that malaria infections protect against lupus. They increase the level of C1q in the blood," Diamond said.
Additional clinical studies
Diamond noted that while the results are promising, the group still needs to prove the utility of the test in larger populations before they can think about making it available to clinicians.
The main components of the test are available, but developing "a new diagnostic or prognostic test always requires analysis in a much larger study of patients and controls," Pisetsky said. Measuring concentrations of IgG and IgM anti-DNA antibodies along with levels of C1q requires use of existing, established technology, but producing a routine test would require refining, establishing reproducibility, and possibly validation in other populations, he said.
The main challenge in developing a successful test based on risk is being able to determine the risk "in patients for whom a definite diagnosis cannot be made, or for populations who may be at increased risk for lupus," Pisetsky noted. Establishing risk can "require follow-up of patients over time, or the availability of samples that allow this assessment," he said.
"In the long run, we want to implement this in a clinical setting," Diamond said, adding that the group plans to collaborate with a diagnostic company to launch a test and pursue necessary regulations. Prior to that, the algorithm "has to behave well and do what we are hoping it will do [in other clinical studies], and if it does that I am hopeful it would not take too long [to commercialize it] because these are not complicated or expensive assays," Diamond added.
Diamond said that she and her team hope to obtain access to blood samples from a long-term military study that showed autoantibody lupus risk biomarkers present in patient blood 10 years prior to the onset of the disease. The group would test the predictive strength of its algorithm and monitor whether measurements changed as patients got closer to developing the disease, she said.
Diamond noted that the group wants to conduct more in-depth clinical studies, but that it is at the beginning stages of this work.
An effective therapy
The urgency associated with getting an effective test on to the market is underscored by the availability of Plaquenil (hydroxychloroquine), a treatment prescribed by physicians for patients with lupus and other conditions, Diamond said. Hydroxychloroquine is used frequently to treat lupus patients and prevent flares, and studies have shown that patients treated with it have a longer time to progression of the clinical disease, she said.
"We know that it is a good treatment, and therefore it would be really useful to have a good risk score" to identify people who could benefit most from the treatment, she said. Further, because therapy with hydroxychloroquine delays disease onset, the group anticipates that its therapeutic effect could be reflected in the risk index.