Anti-interferon antibodies in multiple sclerosis. Molecular basis and their impact on clinical efficacy

Low levels of naturally-occurring, high-affinity antibodies directed against cytokines can be found in the circulation of individuals who have never been exposed to exogenously-supplied cytokines. These antibodies are thought to play a regulatory role in the intensity and duration of immune response. Interferon (IFN) beta has been shown to attenuate both relapsing-remitting multiple sclerosis (MS) and secondary progressive MS in several well-powered, randomized, controlled clinical trials. IFN therapy can induce the production of anti-IFN neutralizing antibodies (NAb), usually in the second 6 months of treatment, in 3 to 45% of treated patients. This variation in the proportion of NAb-positive patients is probably due to the immunogenicity of different formulations of IFN beta, as well as the assay used, which are not currently standardized. The occurrence of NAb appears to be directly correlated with the dose of therapeutic IFN administered, up to a certain dose threshold. If the dose is increased beyond this threshold, the levels of NAb decrease. The biological significance of anti-IFN NAb is not yet known, nor has it been proven conclusively that they affect the clinical response to IFN beta therapy. The presence of NAb is therefore not an indication that treatment should be changed. Indeed, any treatment decision should be based only on the clinical response to therapy.