Interferon-beta Therapy In Multiple Sclerosis Research Articles

Interferon-beta therapy in multiple sclerosis: the short-term and long-term effects on the patients’ individual gene expression in peripheral blood

Therapy with interferon-beta (IFN-beta) is a mainstay in the management of relapsing-remitting multiple sclerosis (MS), with proven long-term effectiveness and safety. Much has been learned about the molecular mechanisms of action of IFN-beta in the past years. Previous studies described more than a hundred genes to be modulated in expression in blood cells in response to the therapy. However, for many of these genes, the precise temporal expression pattern and the therapeutic relevance are unclear. We used Affymetrix microarrays to investigate in more detail the gene expression changes in peripheral blood mononuclear cells from MS patients receiving subcutaneous IFN-beta-1a. The blood samples were obtained longitudinally at five different time points up to 2 years after the start of therapy, and the patients were clinically followed up for 5 years. We examined the functions of the genes that were upregulated or downregulated at the transcript level after short-term or long-term treatment. Moreover, we analyzed their mutual interactions and their regulation by transcription factors. Compared to pretreatment levels, 96 genes were identified as highly differentially expressed, many of them already after the first IFN-beta injection. The interactions between these genes form a large network with multiple feedback loops, indicating the complex crosstalk between innate and adaptive immune responses during therapy. We discuss the genes and biological processes that might be important to reduce disease activity by attenuating the proliferation of autoreactive immune cells and their migration into the central nervous system. In summary, we present novel insights that extend the current knowledge on the early and late pharmacodynamic effects of IFN-beta therapy and describe gene expression differences between the individual patients that reflect clinical heterogeneity.

Natural killer cell phenotype and clinical response to interferon-beta therapy in multiple sclerosis

CD56(bright) NK cells, which may play a role in immunoregulation, are expanded in multiple sclerosis (MS) patients treated with immunomodulatory therapies such as daclizumab and interferon-beta (IFNβ). Yet, whether this NK cell subset is directly involved in the therapeutic effect is unknown. As NK receptor (NKR) expression by subsets of NK cells and CD8+ T lymphocytes is related to MS clinical course, we addressed whether CD56(bright) NK cells and NKR in IFNβ-treated MS patients differ according to the clinical response. IFNβ was associated to lower LILRB1+ and KIR+NK cells, and higher NKG2A+NK cell proportions, an immunophenotypic pattern mainly found in responders. After IFNβ treatment, a CD56(bright) NK cell expansion was significantly related to a positive clinical response. Our results reveal that IFNβ may promote in responders changes in the NK cell immunophenotype, corresponding to the profile found at early maturation stages of this lymphocyte lineage.

Single-Nucleotide Polymorphisms in Response to Interferon-Beta Therapy in Multiple Sclerosis

Interferon-beta (IFN-β) is one of the main first-line disease-modifying drugs indicated for the treatment of multiple sclerosis (MS). The drug exhibits only limited effectiveness, and does not produce clinical benefits in around 20%-50% of patients. The availability of biomarkers would be beneficial for identification of patients at high risk of treatment failure, before initiation of therapy. Over the last 5 years, the search for such biomarkers has intensified and various promising candidates have been uncovered. Here, we review the main attempts undertaken to identify polymorphic variants associated with response to IFN-β therapy in MS by means of candidate gene approaches and whole-genome association scans. Despite substantial progress made in the field, there is still a long way to go before biomarker discoveries can be incorporated into clinical practice to predict IFN-β-responder status in MS patients.

Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis

The identification of factors that can affect the efficacy of immunomodulatory drugs in relapsing-remitting multiple sclerosis (MS) is important. For the available interferon-beta products, neutralising antibodies (NAb) have been shown to affect treatment efficacy. In June, 2009, a panel of experts in MS and NAbs to interferon-beta therapy convened in Amsterdam, Netherlands, under the auspices of the Neutralizing Antibodies on Interferon beta in Multiple Sclerosis consortium, a European-based project of the 6th Framework Programme of the European Commission, to review and discuss data on NAbs and their practical consequences for the treatment of patients with MS on interferon beta. The panel believed that information about NAbs and other markers of biological activity of interferons (ie, myxovirus resistance protein A [MxA]) can be integrated with clinical and imaging indicators to guide individual treatment decisions. In cases of sustained high-titre NAb positivity and/or lack of MxA bioactivity, a switch to a non-interferon-beta therapy should be considered. In patients who are doing poorly clinically, therapy should be switched irrespective of NAb or MxA bioactivity.

Severe Dermatomyositis Triggered by Interferon Beta-1a Therapy and Associated With Enhanced Type I Interferon Signaling

Type I interferons (IFNs) are common therapeutics for several diseases, including viral infections and multiple sclerosis (MS). Although numerous studies have implicated type I INFs with the production of autoantibodies and the development of certain autoimmune disorders, interferon beta has not previously been described in association with dermatomyositis, to our knowledge. Previous microarray studies of muscle biopsy specimens from patients with dermatomyositis disclosed a type I IFN-induced gene expression profile. The central role of plasmacytoid dendritic cell precursors, together with increased type I IFN production, suggests a pivotal role for type I IFNs in dermatomyositis. We report a case of dermatomyositis exacerbated or induced by interferon beta therapy for MS and provide evidence that demonstrates enhanced type I IFN signaling in this patient. We observed new-onset dermatomyositis in a 57-year-old patient treated with interferon beta for MS. His symptoms were exacerbated temporally by interferon beta injections. Immunohistochemical staining of skin biopsy specimens for myxovirus-resistance protein A (a surrogate marker for cutaneous type I IFN signaling) showed increased staining that correlated temporally with interferon beta treatment and subsequent disease activity. In vitro treatment with interferon beta of peripheral blood mononuclear cells isolated from our patient revealed enhanced type I IFN signaling assessed by interferon-induced gene expression profiles. To our knowledge, this is the first description of dermatomyositis exacerbated or induced by interferon beta treatment. Our results demonstrate enhanced type I IFN signaling following interferon beta treatment in our patient with dermatomyositis.

Pharmacogenomics of the Response to IFN-β in Multiple Sclerosis: Ramifications from the First Genome-Wide Screen

Evaluation of: Byun E, Caillier SJ, Montalban X et al.: Genome-wide pharmacogenomic analysis of the response to interferon-beta therapy in multiple sclerosis. Arch. Neurol. 65(3) 337-344 (2008). Specifically, IFN-beta is the most widely used disease-modifying therapy for the treatment of multiple sclerosis. The main benefits of the therapy, fewer and less severe relapses as well as delayed disease progression, are seen in only approximately 50% of the patients. Genetic polymorphisms may constitute in-built determinants of individual differences in response to IFN-beta. Prior attempts to identify such 'predictors of response' were hypothesis-driven in that they were based on preselection of candidate genes associated with Type I interferon pathways. In the present study, the authors performed the first ever nonbiased genome-wide association screen in an attempt to identify response-predictive SNPs. Using a robust four-stage completion strategy coupled to advanced SNP ranking/clustering algorithms, 18 significant SNPs were identified, many of which are located in genes that have never before been linked clearly to Type I interferon biology or therapeutic effects. While this study was not designed per se so as to validate earlier findings, genes arising from previous pharmacogenomic studies were generally not confirmed. This is due to major discrepancies between interstudy sets of used SNPs, but may also reflect differential strategies for ascertainment of response to IFN-beta, or simply Type I/II errors. The 100-K SNP screen by Byun et al. hallmarks a new stage of pharmacogenomics research applied to multiple sclerosis treatments. Through the judicious implementation of DNA pooling on SNP microarrays, it vividly demonstrates that informative genome-wide pharmacogenomic screens can be performed at a fraction of the cost of individual microarray genotyping. Although, unquestionably, higher-density SNP screens and further replication studies are needed, this study is instrumental in bringing the concept of personalized medicine a (small) step closer to the multiple sclerosis patient. In addition, it has generated a flurry of novel information of likely importance in furthering our understanding of Type I interferon biology.

Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.

BackgroundMultiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNß in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNß therapy.MethodologyLarge scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNß therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays. Subsequent expression analyses on specific genes were performed after three and six months of treatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFNß. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation.Principal FindingsPharmacogenomics revealed a marked variation in the pharmacological response to IFNß between patients. A total of 126 genes were upregulated in a subset of patients whereas in other patients these genes were downregulated or unchanged after one month of IFNß therapy. Most interestingly, we observed that the extent of the pharmacological response correlates negatively with the baseline expression of a specific set of 15 IFN response genes (R = −0.7208; p = 0.0016). The negative correlation was maintained after three (R = −0.7363; p = 0.0027) and six (R = −0.8154; p = 0.0004) months of treatment, as determined by gene expression levels of the most significant correlating gene. Similar results were obtained in an independent group of patients (n = 30; R = −0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNß indicating that differential responsiveness to IFNß is an intrinsic feature of peripheral blood cells at baseline.ConclusionThese data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNß.

Severe Acute Hepatitis After Resumption of Interferon-Beta Therapy for Multiple Sclerosis: A Word of Caution

Grieco, Antonio M.D.1; Montalto, Massimo M.D., Ph.D.1; Vero, Vittoria M.D.1; Maria Vecchio, Fabio M.D.2; Gasbarrini, Giovanni M.D.1 Author Information

Cytokine changes during interferon-beta therapy in multiple sclerosis: Correlations with interferon dose and MRI response

We investigated serum (IL-10 and IL-12p70) and cellular cytokine levels (IL-10, IL-12p40, IL-12p70, IFN-γ) in stimulated PBMC over 24 weeks in 15 relapsing–remitting multiple sclerosis (MS) patients randomized to receive once-weekly (qw) IFN-β-1a 30 μg intramuscularly (IM) ( n = 8) or three-times-weekly (tiw) IFN-β-1a 44 μg subcutaneously (SC) ( n = 7). Overall, IFN-β treatment increased cellular IL-10 ( p < 0.01) levels and the ratios of cellular IL-10/IL-12p40 ( p < 0.01) and IL-10/IL-12p70 ( p < 0.02) while cellular IFN-γ levels were reduced ( p < 0.01). Serum IL-10 levels were decreased in non-responders to therapy based on MRI-defined criteria ( p < 0.01) but did not change in responders over the course of treatment. In addition, non-responders demonstrated a decrease in serum IL-10/IL-12p70 ratio ( p = 0.031) and a decrease in cellular IL-12p70 ( p < 0.02). A decrease in cellular IFN-γ was observed in responders ( p = 0.013). This is the first study that compares cytokine changes between the two IFN-β regimes and demonstrates that serum IL-10 levels decrease in those patients who continue to have active MRI lesions while on interferon-beta therapy.

Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis

Objective: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some...