Researchers have identified 2 gene variations that are resistant to interferon (IFN-) therapy. This finding could lead to a biomarker for determining when IFN- is appropriate for the treatment of multiple sclerosis (MS), said Nicolas Couturier, PhD, of the Institut National de la Sant et de la Recherche Mdicale (INSERM), in Toulouse, France. Couturier presented his poster Monday at the American Academy of Neurology annual meeting in Seattle.¹
“Together with clinical, radiological, and maybe genomic markers, this could help to better define which patients to treat with IFN-, a key question at the beginning of the biologics era in MS,” according to Couturier.
Researchers genotyped 584 patients from France, Germany, Ireland, and Spain for 8 candidate genes and found 2 genetic variations in the PGx1 and PGx2 pathway genes that were previously associated with nonresponse to IFN- treatment.²
Treatment with interferon was started, and patients were monitored for 2 years. One group included 269 patients who had no relapses and no increase in adverse effects as measured by Expanded Disability Status Scale (EDSS) scores after 2 years. Another group included 345 patients who had 2 or more relapses, an increase of 1 point in the EDSS score, or a combination of these factors. A strong majority (87.43% of all patients from all centers participating in the study) had relapsing remitting MS (RRMS).
The original cohort included 1043 patients, but to minimize the risk of misclassification researchers excluded from the final results 459 patients who experienced a relapse during therapy, followed a nonconforming therapy, or had incomplete medical records. Couturier plans to genotype 200 more patients in France and add their data to the study.
Which patients to treat with first- or second-line therapies remains a major question for physicians. Biomarkers such as polymorphisms in genes may help to better determine a subgroup of patients with the best efficacy to risk ratio for each drug. For example, genotyping has already proved useful in treatment plans that include warfarin, and the FDA recommends prospective patients receive genotyping for 2 gene variants before they are introduced to the drug.
The efficacy of IFN- as a first-line therapy for MS was demonstrated during the 1990s for its ability to inhibit viral multiplication and modify the body’s immune response. IFN- drugs also prevent inflammation and demyelization in the CNS. Clinical studies have found that interferons can reduce the frequency and severity of MS exacerbations by 30%. Other evidence suggests that interferon therapy can slow the progression of RRMS.
Interferons are now sometimes prescribed after the first outbreak to reduce the risk of “MS defined,” the occurrence of a second outbreak of the disease, or the appearance of new lesions in a patient under MRI observation. Second-line agents, such as mitoxantrone and natalizumab, would probably provide better efficacy but also cause more severe adverse reactions than IFN-, according to the researchers.
1. Couturier N, Gourraud PA, Comabella M, et al. IFNß-pathway gene polymorphisms influence response to multiple sclerosis treatment. A European study. [IN2 1.010] Integrated Neuroscience Session: Recent Advances in Genetics and Molecular Biology in Global Neurology, April 27, 2009.
2. Fusco C, Andreone V, Coppola G. HLA-DRB1*1501 and response to copolymer-1 therapy in relapsing-remitting multiple sclerosis. Neurology. 2001;57:1976-1979.