Long-term IFN-Beta Treatment Normalizes Immune Balance in RRMS, Study Shows

Long-term treatment with interferon beta (IFN-beta) corrects the defective immune balance characteristic of people with relapsing-remitting multiple sclerosis (RRMS), a study has found.

The study also identified more than 200 genes with significantly different activity between complete and partial responders to IFN-beta treatment, which could be used to identify which MS patients are more likely to benefit from this therapy.

The study, “Interferon-β corrects massive gene dysregulation in multiple sclerosis: Short-term and long-term effects on immune regulation and neuroprotection,” was published in the journal EBioMedicine.

Most people with MS have significantly reduced levels of IFN-beta, an immunomodulator that works by balancing pro- and anti-inflammatory signals, controlling the number of immune cells, and promoting nerve cell survival.

IFN-beta-based treatments are commonly used to treat MS. These include Biogen’s Plegridy and Avonex, Bayer’s Betaseron, and Rebif (marketed by Merck KGaA, known as EMD Serono in North America), among others.

However, the mechanisms behind the therapeutic benefits of IFN-beta treatment are not completely understood.

To fill this knowledge gap, researchers at the University of Chicago and a collaborator in Austria evaluated the effects of IFN-beta treatment in immune-related genes, and whether it induces long-term normalization of abnormal immune responses in people with RRMS.

Using a technology called high-resolution microarray, which allows the analysis of the products of thousands of genes, researchers analyzed a total of 227 blood samples of 27 RRMS patients treated with INF-beta, 19 untreated RRMS patients, and eight people without MS.

Treated patients, who had clinically stable MS at the time of enrollment, had received previous IFN-beta treatment (250 ug every other day) for a mean of eight years, which was considered sufficient time to reveal persistent treatment effects.

Long-term treatment effects were assessed at study start, after patients spent four days without treatment to reduce the short-term effects of the last IFN-beta injection. Short-term effects were measured four and 24 hours after patients received 500 ug and 250 ug of IFN-beta a month apart. Patients returned to their normal treatment routine after these tests.

After a five-year follow-up, 12 patients were considered complete responders to treatment, while 15 had at least one MS relapse during that time (partial responders). There were no significant differences in demographic data or treatment duration between these two groups of patients.

Blood samples of treated patients also were compared with those of 19 patients who had never received a disease-modifying therapy for MS (10 with stable MS, and nine with active disease), and those of eight people without MS.

Results showed that IFN-beta injection induced short-term changes in 1,200 genes, with the most significantly altered being immune-suppression genes, followed by those related to inflammation, antiviral responses, and cell cycle and death.

Also, untreated patients showed 8,800 dysregulated genes (162 of them previously shown to be associated with MS), compared with patients receiving long-term treatment, who had similar profiles to those of unaffected people.

The data highlighted that long-term IFN-beta treatment corrected MS-associated genetic dysregulation to near-normal levels. This normalization was associated with a reduction of pro-inflammatory molecules, and increased activity of genes involved in neuroprotection and immune system regulation.

“Some of the genes that change with IFN treatment are likely to reduce the frequency, severity, and duration of breakthrough MS attacks and enhance brain repair, help preserve cognition, and perhaps prolong survival in MS, and may affect other autoimmune and neurodegenerative diseases,” the researchers wrote.

The team also detected significant changes in 277 immune- and inflammation-related genes between complete and partial responders. Further studies may help determine the best treatment response biomarkers, and to develop a blood test to potentially identify patients who will be more likely to completely respond to IFN-beta treatment.

Of note, researchers emphasized that their analyses identified a greater number of dysregulated genes than previous studies in MS, and many of these genes were shown to be regulated by IFN-beta for the first time.

“We provide a comprehensive public repository of gene expression data for genetic, neuroprotection, and immune studies, and a resource for effective targeting and discovery of new drugs for MS and autoimmune diseases,” the team concluded.

The study was supported by the National MS Society and Bayer Healthcare Pharmaceuticals.