Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: An evidence report

The clinical and radiologic impact of developing neutralizing antibodies (NAbs) to interferon beta (IFN ) while on this therapy for multiple sclerosis (MS) is assessed. On the basis of Class II and III evidence, it is concluded that treatment of patients with MS with IFN (Avonex, Betaseron, or Rebif) is associated with the production of NAbs (Level A). NAbs in the serum are probably associated with a reduction in the radiographic and clinical effectiveness of IFN treatment (Level B). In addition, the rate of NAb production is probably less with IFN -1a treatment than with IFN -1b treatment, although the magnitude and persistence of this difference is difficult to determine (Level B). Finally, it is probable that there is a difference in seroprevalence due to variability in the dose of IFN injected or in the frequency or route of its administration (Level B). Regardless of the explanation, it seems clear that IFN -1a (as it is currently formulated for IM injection) is less immunogenic than the current IFN preparations (either IFN -1a or IFN -1b) given multiple times per week subcutaneously (Level A). However, because NAbs disappear in some patients even with continued IFN treatment (especially in patients with low titers), the persistence of this difference is difficult to determine (Level B). Although the finding of sustained high-titer NAbs ( 100 to 200 NU/mL) is associated with a reduction in the therapeutic effects of IFN on radiographic and clinical measures of MS disease activity, 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, or which cutoff titer to apply (Level U). NEUROLOGY 2007;68:977–984 The development of neutralizing antibodies (NAbs) to proteins administered therapeutically is often associated with a reduction in the biologic actions that these proteins exert. It is therefore surprising that the clinical and radiographic impact of NAbs to interferon beta (IFN ) in the treatment of multiple sclerosis (MS) is controversial. This assessment evaluates the clinical and radiographic impact of NAbs in this setting and considers some of the difficulties in this research area that may explain the ongoing controversy. In this regard, it is useful for readers to appreciate the complexity of this particular biologic system.1-9 Thus, a brief overview of IFN biology is provided in the supplementary material to this asFrom the University of California, San Francisco (D.S.G.); University of Texas Southwestern (E.M.F.), Dallas; Duke University Medical College (B.H.), Durham, NC; St. Michaels Hospital (P.W.O.), Toronto, Ontario, Canada; University of BC (J.J.O.), Vancouver, British Columbia, Canada; The University of Chicago (A.T.R.), Oak Park, IL; and Lutheran Medical Office (J.C.S.), Fort Wayne, IN. Disclosure: The authors report no conflicts of interest. Received August 10, 2006. Accepted in final form December 7, 2006. Approved by the Therapeutics and Technology Subcommittee on July 28, 2006; by the Practice Committee on November 11, 2006; and by the AAN Board of Directors on January 4, 2007. Address correspondence and reprint requests to the American Academy of Neurology, 1080 Montreal Avenue, St. Paul, MN 55116; e-mail: [email protected] Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the March 27 issue to find the title link for this article. Copyright © 2007 by AAN Enterprises, Inc. 977 sessment (available at www.neurology.org). The questions posed by this assessment are as follows: 1) Once NAb-positivity has developed in an individual patient, does this state persist? 2) Are NAbs to IFN associated with a reduced effectiveness in IFN treated patients with respect to the activity or the severity of MS (measured either clinically or radiographically)? 3) Does the prevalence of NAbpositivity (i.e., the seroprevalence) differ between the different IFN products? Methods. A panel of neurologists analyzed the evidence relating to NAbs using a literature search with the key words antibodies and interferon beta. We used the MEDLINE database from 1966 to 2005. In addition, the reference lists of the articles identified were reviewed to identify articles not found by the computer search. Using these methods we identified 627 articles. Twentyseven articles in the English language reporting clinical or radiographic outcomes in both antibody positive and antibody negative patients were reviewed.14-41 The entire panel classified the level of evidence provided by each article. Several studies were classified as providing Class II evidence (table 1), despite a randomized placebo-controlled trial design (RCTs). This is because evidence associated with NAb status is always post hoc and because patients can never be randomized with respect to their ultimate NAb status. Therefore, one can never exclude the possibility that there are patient-specific factors, which both predispose certain patients to the development of NAbs and, in an unrelated manner, make them either more or less susceptible to MS attacks. If so, this will make NAbs artificially appear to increase or decrease the MS attack rate, underscoring the fact that evidence of an association cannot prove causation. Detecting and measuring antibodies to IFN . Antibodies to IFN ultimately develop in many IFN -treated patients.14-41 Two classes of antibodies are recognized. Binding antibodies (BAbs) may or may not interfere with IFN function while neutralizing antibodies (NAbs) interfere with IFN function in vitro, presumably by altering (or blocking) binding to the IFN / receptor. Conceptualized in this manner, NAbs are a subset of the BAbs. Nevertheless, this conception may be simplistic. For example, in a recently presented study,42 some NAb-positivity was measured in patients who were BAb-negative. Because only the BAb assay is specific for IgG, and if there is not some technical reason for this result, this suggests that some measured NAb-positivity may not be antibody mediated. IFN antibodies can be detected through28,43-46 binding assays, including enzyme-linked immunosorbent assays (ELISAs) and radio-immuno-precipitation assays (RIPAs), that measure all BAbs.28,46 Two assays specifically measure NAbs. The cytopathic effect (CPE) assay measures a reduction in the amount of IFN induced inhibition of virally mediated cell lysis.43 By contrast, the MxA assay measures a reduction (either in vitro or in vivo) in the amount of IFN -induced MxA protein (or mRNA) synthesis.44,45 Table 1 Effect of NAbs on clinical and MRI outcomes in MS therapeutic trials Study n Year Clinical