Nov. 01, 2012

AVISE™ SLE: Improving Diagnosis, Improving Care

By Jenny Thorn Palter

It is no secret that autoimmune and connective tissue diseases can be difficult to diagnose. In particular, lupus symptoms mimic those of many other illnesses and vary widely from person to person. Symptoms also appear, disappear, and change over time. The disease course is marked by periods of inactivity and disease flares. It may take medical specialists years to arrive at an accurate diagnosis. These factors, taken together, often make diagnosing lupus a long and complicated process.

Adding to the difficulty is that there is no single laboratory test to determine whether a person has the disease. The antinuclear antibody (ANA) blood test has historically been used in the diagnosis of lupus, in conjunction with other factors such as a person’s medical history, the results of other laboratory tests, and a physical exam. But a positive ANA test does not always mean that a person has lupus. A number of other illnesses and conditions are associated with positive ANA test results. About 5 percent of otherwise healthy people will test positive for ANA. Adding to the complexity, a test result may be positive one time and negative another time, and different laboratories may produce different test results.

In any medical situation, knowing the correct diagnosis and learning it quickly are crucial factors in enabling physicians to select the most appropriate treatment in a timely manner. But this is especially important for people with lupus because every day without treatment can mean dangerous and possibly permanent damage to the heart, lungs, kidneys, skin, and other organs. A single test that can help diagnose a complex disease like lupus by ruling out other potential diseases could help physicians reach a definitive diagnosis in a shorter period of time. The AVISE™ SLE test, developed at the Lupus Center of Excellence in Pittsburgh, PA, by a research group led by Susan Manzi, M.D., M.P.H., and Joseph Ahearn, M.D., has been shown to do just that.

Established Mechanism of Action

The technology that makes the AVISE SLE test so accurate involves a group of proteins in the body, called complement, that protect the body against infections and work by strengthening the body’s immune reactions. Complement proteins are used up by the inflammation caused by lupus, which is why people with inflammation due to active lupus often have low complement levels. There are nine protein groups of complement, so they are identified by the letter C and the numbers 1 through 9. When seeking to diagnose lupus, the most common complement tests are C3, C4, and CH50. Low levels of C3 or C4 may indicate active lupus, while CH50 measures the overall function of complement in the blood.

Amy H. Kao, M.D., M.P.H., director of biomedical informatics at the Lupus Center of Excellence in Pittsburgh, was involved with the complement research that Manzi and Ahearn conducted. She says the group’s findings suggested that proteins called cell-bound complement activation products (CB-CAPs), generated during activation of the complement system, might make good biomarkers for lupus. One CB-CAP that they studied extensively when the LFA was funding the work in 2008 was C4d.

“When the complement system is activated, C4d is released into the bloodstream and binds, or attaches, to cells circulating throughout the body,” Kao says. “By measuring the C4d levels on red blood cells, platelets, and white blood cells in patients with lupus, our research showed that specific levels and patterns of binding can aid in the diagnosis and monitoring of lupus. Most significantly, our research showed that measurement of C4d on these cells might be a more useful tool than many of the other tests currently used to diagnose and monitor lupus.”

The resulting blood test—AVISE™ SLE—is available through Exagen Diagnostics, Inc., and includes measurement of C4d as part of its design. Furthermore, it does so in a single blood draw, saving time and money for patients, insurers, and physicians alike.

Increased Accuracy of Diagnosis

Exagen Senior Vice President of Research & Development Thierry Dervieux, Ph.D., Pharm.D., explains that the new test is comprised of five biomarkers. “Two of these biomarkers are the ‘gold standard’ lupus tests: ANA, which tests for anti-nuclear antibodies, and dsDNA, which tests for anti-double-stranded DNA antibodies,” he says. “A negative test result for the ANA helps to ‘rule out’ lupus, while a positive test result for the dsDNA helps to ‘rule in’ lupus.”

Three other markers result in greater accuracy of test results and help differentiate lupus from other conditions, he says. “MCV, which looks for anti-mutated citrullinated vimentin antibodies, helps to ‘rule out’ rheumatoid arthritis. The two cell-bound complement markers—erythrocyte cell-bound complement, EC4d, and B lymphocyte cell-bound complement, BC4d—help to ‘rule in’ lupus, which helps accurately and consistently diagnose lupus,” Dervieux says.

The Avise SLE test has been validated—its accuracy and effectiveness confirmed—in two multicenter studies conducted by lupus experts in the U.S.: an independent validation study with 99 individuals with lupus, conducted by Manzi and Ahearn at the Lupus Center of Excellence in Pittsburgh, and the Complement Activation Products In the Assessment of Lupus (CAPITAL) study with 593 participants (210 with lupus, 178 with other diseases, primarily rheumatoid arthritis and systemic sclerosis, and 205 who were healthy).

The results of the CAPITAL study were presented at the 2011 American College of Rheumatology Scientific Meeting, and the paper—Measurements of Cell Bound Complement Activation Products Enhance Diagnostic Performance in Systemic Lupus Erythematosus—describing the validation study was recently accepted for publication in Arthritis & Rheumatism, one of the top peer-reviewed rheumatology journals. 

This study looked at sensitivity and specificity, two test performance characteristics. According to Dervieux, “sensitivity” refers to how well a test identifies the number of true positives—in this instance, the number of individuals who do have lupus. “Specificity’’ refers to how well a test identifies the number of true negatives—in this instance, the number of individuals who do not have lupus. “Sensitivity is important because tests with high sensitivity are less likely to miss individuals with the disease,” he says. “Specificity is important because tests with high specificity are less likely to misdiagnose individuals with disease—i.e., lupus versus another connective tissue disease.

“Avise SLE is the only balanced diagnostic test with 78 percent sensitivity and 87 percent specificity. These studies showed that, by combining traditional markers ANA, dsDNA, and MCV with these two new CB-CAPs biomarkers, the Avise SLE test improves diagnostic accuracy by approximately 30 percent,” Dervieux says.

Avise SLE+ Connective Tissue™ is a second new diagnostic test that is offered in addition to the Avise SLE test. It is made up of 14 common connective tissue diagnostic markers, and is also completed in a single blood draw. It includes markers for extractable nuclear autoantibodies (ENAs), rheumatoid arthritis and antiphospholipid syndrome autoantibodies—cardiolipin IgG, cardiolipin IgM, beta2-glycoprotein 1 IgG, and beta2-glycoprotein 1 IgM—that help to differentiate lupus from other connective tissue diseases.

Requests and Support

Dervieux says there are several scenarios in which a physician could use AVISE SLE or AVISE SLE+ Connective Tissue tests: “To confirm a case of suspected lupus in a person who is ANA-positive and has been referred by a primary care physician; to differentiate a lupus diagnosis from a diagnosis of any other connective tissue disease; to confirm the lupus diagnosis prior to recommending therapy; or to retest a person whose past connective tissue disease test results were inconclusive.”

Physicians should request the Avise SLE tests directly from Exagen Diagnostics. When the test requisition has been completed, the company utilizes overnight shipping to send the test kit, which includes a serum separator tube and frozen coolant pack. Current estimated turnaround time is seven business days. To learn more, call Exagen Diagnostics at 888-452-1522, or visit the company’s Web site at AviseTest.com.

Avise SLE and Avise SLE+ Connective Tissue are covered by most health insurance plans. Additionally, Exagen has a patient assistance program that can help with qualifying for insurance coverage, including billing the insurer on behalf of the patient. The company also offers assistance to those who can demonstrate financial hardship. For more information, call the Billing/Finance Department toll-free at 877-246-9205, or visit the Web site.


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