Blood test for antibody clumps may support MS diagnosis

Measuring the amount of specific antibody clumps in the blood helped distinguish people with multiple sclerosis (MS) from healthy individuals and people with other conditions with an accuracy of at least 90%, a new study has found.

The findings show that clumps of immunoglobulin G (IgG) antibodies — which are found at high levels in most MS patients — may serve as a promising biomarker for the diagnosis of MS.

The blood test also was able to distinguish patients with secondary progressive MS (SPMS) from those with relapsing-remitting MS (RRMS), suggesting it may identify earlier those who transition to the progressive form of the disease.

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“Ours is a simple process to analyze one drop of blood sample [50 microliters], and any clinical lab can perform the test,” Xiaoli Yu, PhD, an associate professor at the University of Colorado School of Medicine and study lead author, said in a university press release.

“These non-invasive, simple IgG-based blood [tests] can be adapted into clinical practice for diagnosing MS and SPMS and monitoring treatment responses,” the researchers wrote in the study, “Plasma IgG aggregates as biomarkers for multiple sclerosis,” published in the journal Clinical Immunology.

In MS, the immune system wrongly attacks the protective fatty substance surrounding nerve fibers called myelin. Over time, this causes nerve cells in the brain and spinal cord to die, triggering the onset of MS symptoms.

Most patients are diagnosed initially with RRMS, which is marked by sudden episodes of neurological symptoms (relapses), followed by partial or complete recovery (remissions).

Some patients may have progressive disease, or a steady worsening of neurological symptoms even in the absence of disease relapses. If this progression occurs from the onset of symptoms, it is called primary progressive MS (PPMS); if it occurs following an initial RRMS diagnosis, it’s referred to as SPMS.

To diagnose MS, individuals currently undergo a series of physical and neurological examinations, along with MRI scans, to look for neurological damage. Testing body fluids for inflammation and/or nerve damage biomarkers also can help, but many of these are not specific to MS.

IgG antibodies contribute to nerve cell death in MS

Earlier this year, Yu and colleagues discovered that clumps of IgG antibodies contributed to nerve cell death in MS. Such clumps, or aggregates, from SPMS patients caused significantly more nerve cell death than those from RRMS or PPMS patients.

These findings suggested that a blood test to measure IgG clumps may help support a diagnosis of MS and identify those transitioning from RRMS to SPMS, a group with limited treatment options.

“We don’t have very effective drugs for progressive MS, so if the disease can be caught earlier, the patient responds better, and their MS doesn’t move to the progressive stage as quickly,” Yu said. “(All forms of MS) need better treatment options.”

Now, the team developed a test (A-FT) to detect IgG clumps in blood samples, and determined its utility as a potential biomarker to support a diagnosis of MS and monitoring disease outcomes.

The study included a total of 190 MS patients, with a mean age of 47.5 years, as well as a group of 108 individuals with other inflammatory or neurological disorders, and 52 healthy people.

Discovery group and confirmation group results

The researchers first examined a discovery group of MS patients, whose blood samples were collected at the University of Colorado and Innate Immunotherapeutics Limited. Then they validated their findings with samples from a confirmation group, whose samples were collected as part of the Accelerated Cure Project.

In the discovery group, tests revealed that MS patients had high levels of two antibody subtypes — IgG1 and IgG3 — in their IgG aggregates. These levels were significantly higher in patients than in the control groups.

To determine the test’s diagnostic accuracy, the team used a statistical analysis called a receiver operating characteristic analysis (ROC curve), which generates an area-under-the-curve (AUC) value. Generally, AUC values between 70% and 80% show an acceptable ability to diagnose, 80% to 90% is considered excellent, whereas more than 90% is highly accurate.

Using samples from the discovery group, IgG1 as a biomarker yielded an AUC value of 87%, while IgG3 had an AUC of 86%. Similar findings were observed in the confirmation group, in which the ROC analysis generated an AUC of 93% for IgG1, 89% for IgG3, and 90% for total IgG levels.

“These data provide evidence that MS [blood] IgG antibodies retained in the A-FT can be used as sensitive and specific biomarkers,” the researchers wrote.

When looking at patients alone, significantly higher levels of IgG1-containing aggregates were detected in SPMS patients compared with both RRMS and PPMS patients. Similarly, significantly higher levels of total IgG aggregates toxic to nerve cells were found in SPMS over RRMS and PPMS patients, with no differences between RRMS and PPMS samples.

High degree of accuracy in diagnosis of MS

The IgG1 test was able to distinguish SPMS from RRMS with an AUC of 92%, and between SPMS and PPMS with an AUD of 91%.

“Importantly, we also showed that you can make a prognosis for disease progression,” Yu added. “We saw that SPMS patients had higher amounts of the antibodies — so there is a strong correlation (between antibody biomarkers and disease progression).”

Lastly, older age, but not gender, was associated significantly with elevated IgG1, IgG3, and total IgG antibodies in the aggregates. No such relationships were found among the control groups.

“We provide compelling evidence supporting the detection of IgG1, IgG3, and total IgG in the plasma A-FT as biomarkers for MS and for separating SPMS from other subtypes,” the researchers concluded.

“A more substantial number of samples collected from multiple clinics with newly diagnosed MS and with longitudinal [over time] follow-up would be essential to validate the clinical application of these markers,” they added.