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Longterm treatment of parenterally administered interferon beta (IFNb) is one of the mainstays of multiple sclerosis (MS) therapy [1]. The first trials were conducted in the early 1980s when human fibroblast derived IFNb was administered intrathecally in an open-label fashion [2]. In ten patients treated monthly for 6 months a significant reduction of the annualized relapse rate was noted compared to the relapse rate at baseline. This effect was not observed in ten control patients with MS that, for ethical reasons, did not undergo repeat sham lumbar punctures. This prompted a larger multicentre trial in which again human IFNb purified from cultured fibroblasts was administered intrathecally [3]. After the advent of recombinant techniques to produce larger amounts of IFNb, the first pivotal trial of IFNb-1b administered subcutaneously every other day in 372 patients with relapsing-remitting MS was published in 1993 [4], and the drug was approved by the FDA for use in MS the same year. Since then two additional IFNb-1a products were evaluated in pivotal trials that yielded positive results and have been marketed subsequently [5, 6]. Treatment with IFNb was also shown to delay disease progression and halt disease activity in patients with clinically isolated syndromes [7–9]. This observation along with neuropathological and MR imaging studies emphasized the importance of early diagnosis and treatment initiation of patients [10]. Overall the effect size of the IFNb preparations is comparable and moderate [1] and the effects of these drugs have been proven to be sustained for more than 15 years [11]. Additionally the long-term safety profile of IFNb treatment is excellent [12, 13]. However, with a so called biological, i.e. a proteinaceous therapeutic compound, the issue of IFNb immunogenicity is inherent and has remained a matter of debate [14]. Antibodies against IFNb can be detected in up to 47% of patients undergoing treatment with IFNb (Table 1) [14]. These antibodies are either purely binding, and then termed binding antibodies (BAbs) or inhibit IFNb activity and then termed neutralizing antibodies (NAbs) (Fig. 1). The proportion of NAbs is variable and differs between available IFNb products (table 1) [14]. Once the bioactivity of injected IFNb is blocked by persistent and hightiter NAbs the beneficial clinically detectable treatment effects of IFNb seem to vanish, albeit with a latency of some one to four years. A diminution of the downregulatory effect on MR disease activity becomes apparent earlier, i.e. 6-18 months after development of high titer Nabs. [15]. Immediate negative effects have not been sufficiently demonstrated. It is of note that most analyses were done in a post-hoc fashion on data from trials originally designed and powered to show treatment effects of IFNb rather than detrimental effects of NAbs [16]. Thus, there is ongoing controversy regarding the clinical impact of NAbs on the management of MS patients [17]. Current European guidelines recommend switching therapy in patients with persistently high-titer NAbs with suspected clinical or MRI activity [16, 18]. Importantly, NAbs may also affect endogenous IFNb as cross-reactivity between antibodies against IFNb-1a or IFNb-1b and endogenous, human fibroblast derived IFNb was shown only recently by us [19]. Antibodies to IFNb are measured in a two-step procedure. First, BAbs are detected by standard antibody assays. In a second step the neutralizing capacity of these T. Menge H.-P. Hartung (&) B. C. Kieseier Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Dusseldorf, Germany e-mail: Hans-Peter.Hartung@uni-duesseldorf.de

Neutralizing antibodies in interferon beta treated patients with multiple sclerosis: knowing what to do now