Abstract
BackgroundInterferon-beta (IFNβ) is used to inhibit disease activity in multiple sclerosis (MS), but its mechanisms of action are incompletely understood, individual treatment response varies, and biological markers predicting response to treatment have yet to be identified.Methods The relationship between the molecular response to IFNβ and treatment response was determined in 85 patients using a longitudinal design in which treatment effect was categorized by brain magnetic resonance imaging as good (n = 70) or poor response (n = 15). Molecular response was quantified using a customized cDNA macroarray assay for 166 IFN-regulated genes (IRGs).ResultsThe molecular response to IFNβ differed significantly between patients in the pattern and number of regulated genes. The molecular response was strikingly stable for individuals for as long as 24 months, however, suggesting an individual ‘IFN response fingerprint’. Unexpectedly, patients with poor response showed an exaggerated molecular response. IRG induction ratios demonstrated an exaggerated molecular response at both the first and 6-month IFNβ injections.ConclusionMS patients exhibit individually unique but temporally stable biological responses to IFNβ. Poor treatment response is not explained by the duration of biological effects or the specific genes induced. Rather, individuals with poor treatment response have a generally exaggerated biological response to type 1 IFN injections. We hypothesize that the molecular response to type I IFN identifies a pathogenetically distinct subset of MS patients whose disease is driven in part by innate immunity. The findings suggest a strategy for biologically based, rational use of IFNβ for individual MS patients.
Highlights
Interferon beta (IFNb) is routinely used to treat multiple sclerosis (MS), and in randomized placebo-controlled trials, reduced relapse rates by 30% [1,2,3]
Clinical response varied among individuals, and post-hoc analyses of one study revealed that about 20% of IFNb recipients were poor responders (PR), defined as $3 new T2 hyperintense brain lesions occurring within 2 years of treatment onset [1,4]
IFNb-1a for at least 6 months, which was the predetermined timepoint for determining treatment response based on MRI, for correlation with IFN-regulated genes (IRGs) macroarray results
Summary
Interferon beta (IFNb) is routinely used to treat multiple sclerosis (MS), and in randomized placebo-controlled trials, reduced relapse rates by 30% [1,2,3]. Results from a clinical trial of interferon gamma (IFNc) (a type II IFN) [8,9] demonstrated disease activation in some patients. Because type I and II IFNs regulate overlapping sets of IFN-regulated genes (IRGs), it is possible that some patients may worsen with IFNb treatment. Such an outcome would not be evident from controlled clinical trials, where the majority of patients improve with treatment. Interferon-beta (IFNb) is used to inhibit disease activity in multiple sclerosis (MS), but its mechanisms of action are incompletely understood, individual treatment response varies, and biological markers predicting response to treatment have yet to be identified
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