Antibody Testing Affects MS Therapy Management
In a randomized trial, access to antibody testing affected MS management. Serum binding antibodies predicted positivity to neutralizing antibodies in patients on high-dose interferon.
Access to antibody (Ab) testing affected management in persons with multiple sclerosis (MS), according to findings from a randomized, controlled, open-label, parallel-group, multicenter study published April 4 in BMC Neurology (Fox et al., 2014). In that study, serum binding antibodies (BAb) predicted positivity to neutralizing antibodies (NAb) in patients on high-dose interferon β (IFN-β).
“Many patients with relapsing-remitting [MS] treated with high-dose [IFN-β] develop [BAb] and [NAb],” wrote Edward Fox, from Central Texas Neurology Consultants in Round Rock, and colleagues. “NAb reduces the biological activity of IFNβ, which contributes to clinical failure in these patients. We investigated whether access to [Ab] test results would alter usual care of IFNβ-treated patients and whether BAb could predict NAb.”
In this trial, 1358 participants with MS received usual care or Ab testing with standard assays to measure BAb and NAb titers. The proportion of participants in whom IFN-β therapy changed was the main study endpoint, and the type of and reasons for therapy changes were secondary endpoints.
Nearly one in five participants (19.6%) in the Ab testing group had changes in their treatment during 12 months of follow-up, compared with 14.0% in the usual care group (P = 0.004). The reason for therapy change was that results from Ab testing were more likely in the Ab testing group than in the usual care group (P < 0.0001).
The investigators found therapy change to be significantly more likely in participants with NAb and BAb positivity, and these findings were also associated with a lower likelihood of adverse events related to use of IFN-β.
BAb titers predicted NAb positivity (P = 0.0012), and NAb positivity also varied by formulation and dosage frequency of IFN-β treatment. Participants treated with IFN-β-1a 44 μg subcutaneously three times weekly had higher positive NAb test results than those treated with IFN-β-1b 250 μg on alternate days or IFN-β-1a 22 μg three times weekly.
“Access to Ab test results impacted therapy management,” the study authors wrote. “BAb titres can predict NAb positivity in patients on high-dose IFNβ.”
In both study groups, initial positivity for BAb and NAb affected the overall number of participants in whom therapy changed (P < 0.05).
Limitations of this study include the absence of paired clinical response data and the imbalance in clinic visits that the Ab testing group would have received compared with the usual treatment group. In addition, the study duration was only 12 months.
“Testing for NAb is an important aspect of MS management in terms of predicting treatment response to IFNβ,” the study authors concluded. “Using BAb testing before screening for NAb titres, and defining a cutoff point for the BAb titres at which to discontinue IFNβ therapy, may reduce the necessity for the more expensive NAb testing assays.”
Key open questions
- At what rates do Ab titers develop for different IFN-β treatment regimens?
- What is the optimal use for BAb testing to guide NAb testing and subsequent management?
Disclosures and sources of funding
Teva Pharmaceuticals funded the study and employed three of the study authors. Some of the other study authors reported various financial disclosures involving Teva Pharmaceuticals, Acorda Pharmaceuticals, Bayer, Biogen Idec, EMD Serono, Genzyme, Novartis, Opexa, Sanofi-Aventis, Avanir, GlaxoSmithKline, Ono, Eli Lilly, Roche Genentech, Wyeth Pharmaceuticals, Pfizer, Sun Pharma, and/or Takeda Pharmaceuticals.
Comments
I was not involved in this study, and I do not have any conflicts of interest regarding this study. We run the neutralizing antibodies against interferon β at our university, and we have provided NAb testing for reference centers across Japan since 2011. Probably most clinicians commonly use the neutralizing antibody results plus disease activity (clinical and/or MRI) to make decisions, not antibodies alone. Dr. Fox and colleagues found that the influence of access to binding and neutralizing antibody testing against interferon β increased therapy changes compared to usual care in a randomized, controlled, open-label study with 1358 MS patients. The effect of antibody testing was lower than the presence of clinical relapses and/or disease activity on the MRI, named as clinical composite. The items in the clinical composite are used to classify the patient as a nonresponder or treatment failure, but they do not explain the reason for failure as the presence of neutralizing antibodies do. The significance of binding antibodies is unclear, but neutralizing antibodies are shown to reduce bioavailability of interferon β. Therefore, despite the relationship between binding and neutralizing antibody results as stated by the authors, patients with binding antibodies should be tested for neutralizing antibodies to confirm the loss of biological effect, and the use of binding assays as a single assay has some limitations. However, the use of binding antibody assays as a screening tool to test only the positive patients may be a resource-saving approach, as neutralizing antibody requires functional assays that are more time- and resource-demanding. The occurrence of therapy changes in the group of patients who were tested for neutralizing antibodies is expected, because these patients were at risk of not having the benefit of interferon-β treatment. Another interesting piece of evidence for loss of activity is that patients who were positive for neutralizing antibodies had fewer side effects, such as flulike symptoms and injection site reactions, in the past month. Interferon β has been used for two decades to treat MS, so the safety profile is well known. The use of neutralizing antibody assays in clinical practice may work as a complementary tool to clinical and MRI disease activity, so neurologists can identify patients with loss of benefit and redirect these patients to other treatment alternatives.
As a national speaker for many years for all the drug companies that produce MS treatment medications, as well as a biochemist and physician involved in the treatment and research of MS since 1972, I find this article very useful.
Since the discovery of NAbs to interferon-beta treatment medications, I have been concerned about the evidence that these NAbs interfere with the efficacy of the interferons. In my experience, the evidence has been of sufficient strength to cause me to discontinue interferons in patients who are persistently NAb positive, and I routinely test patients for the presence of NAbs between 18-24 months on therapy.
However, the committee convened by the American Academy of Neurology to review this topic determined that there isn't strong enough evidence to show that interferons are ineffective in the presence of NAbs. This is contrary to experts in other countries throughout the world, who are of the opinion that NAbs make the interferons ineffective.
This article supports the fact that many neurologists throughout the United States believe that the evidence is strong enough to recommend that in the presence of NAbs, interferons should be discontinued and other disease modifying therapies should be prescribed.