Neutralizing Antibodies Are Associated with a Reduction of Interferon-β Efficacy during the Treatment of Japanese Multiple Sclerosis Patients

Abstract

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system. Interferon-β (IFN-β) has been used as the first line therapy for MS treatment in Japan, but patients treated with IFN-β may develop antibodies, known as neutralizing antibodies (NAbs), which abrogate its therapeutic effects. Intramuscular IFN-β 1a and subcutaneous IFN-β 1b are currently available in Japan, but large-scale studies evaluating the prevalence and clinical implications of NAbs against these IFN-β preparations in MS patients have only been performed in Caucasian populations. NAbs positivity has been reported to be associated with HLA-DRB1 alleles, suggesting that the positivity might differ among populations with distinct genetic backgrounds. Clinical information and sera were collected from 229 consecutive MS patients treated with IFN-β in 4 centers in Japan. Sera were tested for NAbs using a luciferase reporter gene assay. In total, 5.2% of IFN-β-1a-treated patients (4/77) and 30.3% of IFN-β-1b-treated patients (46/152) were positive for Nabs. The frequency of NAbs was highest in patients treated for 13 to 24 months. Clinical relapse and contrast-enhancing lesions in the magnetic resonance imaging increased together with NAbs titers in this group. In conclusion, the prevalence of NAbs in Japanese MS patients is similar to that in Caucasian populations and is associated with an increase in disease activity. Therefore, routine NAbs testing is recommended also in Asian populations to ensure the early identification of patients who would benefit from a change in therapy.

Evaluation of the impact of neutralizing antibodies on IFNβ response

“…Real-world studies are in line with randomized clinical trials showing a negative impact of NAbs on clinical (Table 2) [10,[45][46][47][48][49][50][51][52][53]60] and MRI parameters (Table 4) [45,47,52]. Whereas all the observational studies showed an impact of NAbs on the RR or the time to first relapse, the negative effect of NAbs on progression of EDSS was evident in few studies and with low statistical significance ( Table 2).…”

“…Consistent data came from clinical studies lasting more than 2 years, using all the three different IFNβ preparations, designed as placebo-control clinical trials [22,23,44], prospective real-world studies [10,[45][46][47][48][49][50][51][52] or propensity score studies [53].…”

HLA alleles as biomarkers of high-titre neutralising antibodies to interferon-β therapy in multiple sclerosis

“…The prevalence of NAbs in Japanese MS patients is similar to that in Caucasians, and NAb titres are also found to be associated with an increased disease activity in Asian populations 14. Cross-sectional studies of routine data performed in Sweden and Iceland reported a decrease in NAb seroprevalence from 32% in 2003–2004 to 19% during 2009–2010 15.…”

The Current State of Immune Therapy in Multiple Sclerosis in Japan and Future Prospects

“…When patients showed breakthrough for interferon we also have a free support system measuring neutralizing antibody for IFNs at Tohoku Univesity. Because neurralizing antibodies are associated with a reduction of IFN beta efficacy during the treatment 15) .…”