Neutralizing antibodies (Nabs) block the biological effect of interferon in patients with multiple sclerosis (MS), according to a new study that lends weight to the argument that continuing interferon therapy is unjustified when Nabs are present.
Investigators at the Danish Multiple Sclerosis Research Center at the Copenhagen University Hospital Righospitalet in Denmark reported in the Aug. 4 edition of Neurology that even when an MS patient seems to be doing well clinically, the significance of neutralizing antibodies can't be ignored.
“In patients with moderate or high titres of Nabs, absence of disease activity may tempt some clinicians to think that the patient is still responding to therapy — despite the persistent presence of Nabs,” the researchers wrote.”
When IFN-beta?was the only available drug many clinicians were reluctant to discontinue IFN-beta?therapy in Nab-positive patients, because they felt it unpleasant to stop therapy with no alternatives to offer, they noted. But that reasoning no longer holds, they concluded. “As other effective treatments now are available, there is no justification for keeping patients on an expensive and inefficacious therapy.”
The investigators compared blood samples from 12 patients who tested persistently positive for NAbs and who also had no in vivo response to the myxovirus resistance protein A (MxA gene) — which is considered a marker for IFN-beta activity — to blood samples taken from 12 NAb-negative patients who had a MxA response.
The researchers used gene chips to analyze the response of each group of patients to an array of interferon-inducible genes, both before and nine to 12 hours after an injection of interferon.
“Our aim was to determine whether any signs of bioactivity of IFN-beta were retained in patients without an MxA response — in other words, whether measurement of in vivo induction of MxA is a reliable marker of IFN-B bioavailability,” Dan Hesse, MD, one of the researchers, told Neurology Today. They found marked differences between the two groups.
In Nab-positive patients without an MxA response we were not able to detect differential expression of any of the IFN-beta-regulated genes identified in Nab-negative patients, the researchers wrote. That gene chip analysis was then supplemented with PCR analysis of MxA and four other known IFN-beta response markers. Again, there was no sign that interferon had any biological effect in the patients who were antibody positive.
“Our study confirms that the absence of an in vivo MxA response in Nab-negative patients is a reliable indication of completely abrogated bioactivity,” Dr. Hesse said.
TESTING STANDARDS NEEDED
While the study makes a strong case for stopping interferon in the face of neutralizing antibodies, it is not the last word in an often contentious debate that includes questions about what constitutes appropriate testing and what levels of antibodies should be considered significant.
“What's still needed is a generally accepted standard assay for functionally significant interferon antibodies, a generally accepted algorithm for use of that assay, and evidence on which to base treatment decisions when the patient develops Nabs after initiating interferon injections,” Richard A. Rudick, MD, director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic Foundation, told Neurology Today.
CLINICAL SIGNS NOT ENOUGH
Dr. Hesse — who conducted the research with Per Soelberg Sorensen, MD, and Finn Sellebjerg, MD — said that just because an MS patient is not showing symptoms of progressive disease does not mean that interferon therapy is helping. He said guidelines followed in Denmark call for testing at 12, 18 and 24 months after initiating therapy, and the in vivo response to MxA is measured in patients who test positive. Repeat testing is important, he said, because some patients who test positive for antibodies eventually convert to a negative status.
While testing is routinely done in Denmark, there are no established guidelines in the US that mandate testing. Aaron Miller, MD, professor of neurology at Mount Sinai School of Medicine, told Neurology Today that he does not routinely test for neutralizing antibodies in his MS patients, but does so when he is considering switching a patient to a higher dose of interferon or when it's not clear whether a patient is doing well on the therapy. Still, he said there are key issues to be resolved around testing.
“We don't really have standardized, validated testing, Dr. Miller said. “A 2007 report of the AAN Therapeutics and Technology Assessment Subcommittee noted that ‘there is insufficient information on the utilization of Nab testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, and which cutoff titer to apply.’”
According to a review article co-authored by Dr. Rudick and published in the June issue of The Lancet Neurology, neutralizing antibodies develop in up to 35 percent of MS patients on interferon, typically appearing within six to 24 months of starting the drug.
“Several studies suggest that interferon beta-1b is more immunogenic than interferon beta-1a, and that subcutaneous interferon beta-1a is more immunogenic than intramuscular interferon beta-1a,” Dr. Rudick wrote in the review.
Commenting on the Danish study, Dr. Rudick said that “to me it's a clear-cut situation. When neutralizing antibodies develop, they attenuate or completely block the biological and clinical effects of the treatment. If you had MS, would you want to be on a drug that had no measurable biological effect?”
INFLUENCE ON IFN MARKET
But Dr. Rudick noted that there is a lot of money at stake in the interferon debate. “The IFN market is about $5 billion worldwide. If 25 percent of the treated population was discontinued due to antibodies, the market would shrink by $1.25 billion,” he noted. “This creates a powerful financial incentive to downplay the significance of Nabs, and some companies have done this through very effective marketing campaigns.”
The Danish research team raised another point that may be particularly relevant as the debate over health care reform heats up in this country. “Maintaining IFN-beta?therapy in patients with moderate or high levels of Nabs does not only constitute a risk to the patient, who may suffer a disabling relapse at any time because the patient is virtually untreated, but also burden the society with unnecessary waste of resources.”•
Hesse D, Sellebjerg F, Sorensen PS. Absence of MxA induction by interferon-ß in MS patients reflects complete loss of bioactivity. Neurology 2009;71:xyz.
Goodin DS, Frohman EM, Stevens JC, et al. Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: An evidence report: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology
2007; 68: 977–984.
Rudick RA, Polman CH. Current approaches to the identification and management of breakthrough disease in patients with multiple sclerosis. Lancet Neurol