ARTICLE IN BRIEF
Investigators found the antibody testing was not strongly predictive of clinical outcomes for myasthenia gravis.
SAN DIEGO—What is the value of antibody testing in monitoring a patient with myasthenia gravis (MG)? Perhaps less than you think, according to a study presented here at the AAN annual meeting in March.
“You really can't use the antibody level as a strong indicator of clinical improvement in your clinic, or in clinical trials,” the lead author Donald Sanders, MD, professor of neurology at Duke University School of Medicine in Durham, NC, said at an AAN meeting plenary.
“There has been equipoise on the question of whether commercially available antibody measurements in MG accurately reflect clinical change in patients,” Dr. Sanders said, despite a long history of their use for that purpose.
In myasthenia gravis, antibodies block, alter, or destroy the receptors for acetylcholine at the neuromuscular junction. The disease was shown to be due to the presence of antibodies against the nicotinic acetylcholine receptor in the early 1970s, and, following that, a series of reports suggested than antibodies fell when patients improved.
“Based on that information, there was a strong feeling among clinicians that they could use the antibody test to monitor response to therapy,” Dr. Sanders said, and antibody levels have often been used as a biomarker for improvement in clinical trials. “But over the years, physicians who treat a lot of myasthenia gravis have been struck by the fact that the antibody levels often don't correlate very well with how the patient is doing. That equipoise led us to do this study.”
Indeed, that uncertainty about the effectiveness of the antibody test was on display at the start of his plenary talk, where about half the audience of 100 physicians, when asked, indicated they believed antibodies were a good reflection of clinical severity, while the other half did not.
Dr. Sanders and colleagues collected data from two sources: patients in the Duke myasthenia gravis registry, and patients in a recent clinical trial of mycophenolate mofetil (MMF). Because test results on a single sample can vary depending on the laboratory conducting the test, he restricted samples to those from patients who had at least two tests performed at the neuroimmunology lab at the Mayo Clinic in Rochester, MN, a major center for commercial MG testing. Together, there were 151 patients who met the criteria.
Initial antibody levels don't correlate well with clinical severity, Dr. Sanders noted, a fact that has been clear from early on, so a patient's drop in antibody level was expressed as a percent change, rather than an absolute change. He found that the decline in antibody levels after 12 weeks of MMF treatment “correlated only weakly” with changes in clinical outcome measures, including the Quantitative MG and MG-Composite scores. Among the Duke MG registry patients, antibody levels fell in 90 percent of those who improved by clinical assessment, but also in 63 percent of those who were clinically unchanged or worse.
Combining results from the two cohorts, a fall in antibody levels had a sensitivity of 92 percent but a specificity of only 37 percent for clinical improvement. The positive predictive value of the test was therefore 83 percent.
“How well does a falling antibody level predict clinical improvement? We think that is probably the question most clinicians would like to have an answer to when they see patients,” Dr. Sanders said. His statistical analysis indicated that 20 percent of patients would be misclassified as improving, based on the results of the antibody test. “So if you used the fall in antibody level to determine if the patient had improved or not, you would be wrong about 20 percent of the time.”
“Our conclusions are that you really can't use the antibody level as a strong indicator of clinical improvement in your clinic or in clinical trials,” Dr. Sanders said. Clinical measurement of improvement remains the standard.
But an antibody test might still be useful as an indication of non-response to therapy. “Since almost all patients who improved had a decline in antibody level, if you don't see a fall, that could probably be taken as an indication that the patient is not being effectively treated,” and there should be a reconsideration of the treatment approach, Dr. Sanders said. “If your patient is not improved, it's time to rethink your therapy.” The test also remains essential to confirming the diagnosis of MG, he said.
Vanda Lennon, MD, PhD, professor of immunology and neurology at the Mayo Clinic in Rochester, MN, said: “Overall, I don't think there are a lot of surprises there.” She noted that her lab conducted the antibody determinations, but since all samples are de-identified before arrival, she had no knowledge of that fact before Dr. Sanders's presentation.
The lack of correlation between clinical and antibody measurements is likely due in part to the nature of the assay, she said. Patient serum is mixed with solubilized receptors, which exposes many more epitopes to patient antibodies than would be exposed in vivo. “You will be detecting some antibodies that are very useful for increasing the sensitivity of diagnosis, but do not necessarily correlate with the pathogenic potential.” A more useful test might have been a bioassay, which detects antibodies with functionally significant effects on neuromuscular transmission.
But the message for the clinician is to focus on clinical improvement, not antibody levels. “It is useful to always check the level before starting immunotherapy, to have a documented baseline, and I would think you should check it again after six months or so, when the patient is stabilized, but you don't need to be checking it at every visit,” she said. “Monitor them, but don't obsess about them.”
David Richman, MD, professor of neurology at the University of California, Davis, said: “My clinical observations with very large numbers of MG patients treated with various immune-directed treatments, over the years, is that the acetylcholine receptor antibody titers do go down, but very slowly, so that the change in antibody titer may be a better marker of long-term remission rather that short-term improvement.”
Future trials, he suggested, might look at the correlation of antibody levels and clinical change at time points of a year or more. However, he said, clinical changes in response to therapy are “quite significant,” and may be sufficient for determining the effectiveness of any new treatment in a trial.
TUNE IN: MYASTHENIA GRAVIS: Does a change in ACHR-antibody level predict clinical change? In a new paper from the AAN annual meeting, researchers found that antibody testing was not strongly predictive of clinical outcomes for myasthenia gravis, and that clinical exams and observations are better indicators for clinical status. In a video interview, Neurology Today's Editor-in-Chief Steven P. Ringel, MD, and Associate Editor Robert Holloway, MD, discuss the implications of these findings and why they reinforce the need for clinicians to “choose wisely” the tests they use to diagnose and provide prognosis on neurological conditions: http://bit.ly/aNQ4KB.