Optimal Response to Natalizumab in MS Patients

Results from a small study found that inhibition of intrathecal antibody synthesis is associated with a complete therapeutic response to natalizumab in patients with aggressive multiple sclerosis (MS). Treatment with natalizumab decreased the rate of disability progression and reduced the number of relapses in the overall study group. Furthermore, nearly half of the patients remained free of new disease activity [Arch Neurol. 2012;69(2):191-197].

MS is a central nervous system (CNS) disease with neurologic symptoms that involve the immune system. Natalizumab is a monoclonal antibody that inhibits the migration of activated immune cells to the CNS. This disease-modifying therapy induces freedom of disease activity in about 40% of treated patients with MS.

In this investigation, the authors sought to explore cell subsets and molecules that changed specifically in patients with MS who had an optimal response to natalizumab. The investigation was a prospective study of intrathecal immunoglobulin synthesis and cerebrospinal fluid (CSF) lymphocyte subsets in patients with MS before and 1 year after beginning treatment with natalizumab. The researchers monitored clinical and magnetic resonance imaging (MRI) activity during a median 2 years. Main outcome measures were the difference between patients free of disease activity and patients with active disease during treatment.

Conducted at 2 tertiary hospitals from the Spanish National Health Service, 23 patients diagnosed with MS received 300 mg of natalizumab by intravenous infusion every 4 weeks. Patients were examined every 3 months, with an additional neurologic assessment in cases of relapse. Samples of CSF and blood were taken from patients before and 1 year after starting natalizumab.

All patients had high inflammatory activity before treatment. The mean number of relapses in the 2 years before starting natalizumab was 3.04 (median, 3; range 1-7; interquartile range [IQR], 2-4). The median number of T2 lesions before treatment was 31.7 (median, 30; range 2-89; IQR, 9-43). Of the 23 patients, 19 showed immunoglobulin G (IgG) and immunoglobulin M (IgM) oligoclonal bands restricted to CSF, and 2 patients showed IgG but not IgM oligoclonal bands in CSF. Patients were treated with natalizumab for a mean of 24.48 months.

The patients were divided into 2 groups according to their response to treatment. The first group (n=13; 56.5%) included patients who had relapses or new lesions despite natalizumab treatment. Disease activity was defined as experiencing any of the following events (alone or in combination): onset of MS relapse; sustained increased Expanded Disability Status Scale score for >3 months; or new or enlarging T2 hyperintense or enhancing lesions on MRI scan. The second group (n=10; 43.5%) remained free of disease activity during follow-up. The authors did not find differences in demographic variables or clinical data between both groups before natalizumab therapy.

The results showed that after treatment with natalizumab, the patients free of new disease activity experienced a reduction in IgM and IgG indices. The mean IgM index decreased from 0.19 before treatment to 0.06 after treatment (P=.001). The mean IgG index changed in these patients from 1.11 to 0.68 (P=.052), although not statistically significant.

For patients with ongoing disease activity during treatment, natalizumab was not associated with significant changes in IgM index (mean, 0.29 before treatment vs 0.15 after treatment; P=.97) or IgG index (mean, 1.05 before treatment vs 0.99 after natalizumab; P=.75). Patients free of disease activity also showed a lower percentage of total B cells (P=.01), particularly of CD5⁺ (P=.007) and CD38 (plasmablasts; P=.009) that virtually disappeared after treatment with natalizumab, according to the study results.