COPENHAGEN, Denmark — Researchers in Spain have identified lipid-specific antibody bands in the cerebrospinal fluid (CSF) that are associated with an aggressive presentation of multiple sclerosis (MS), and patients with these antibodies seem to have a much lower risk for progressive multifocal leukoencephalopathy (PML) with natalizumab therapy (Tysabri, Biogen Idec).

"The presence of lipid-specific IgM bands in the CSF signals patients with aggressive disease and highly activated immune systems," said Luisa Villar, PhD, Hospital Ramón y Cajal, Madrid, Spain. "We seem to be able to lower the immune system in patients in whom it is highly activated without inducing immunosuppression. So natalizumab is safe to use in this population, and these are the very patients who need this strong drug.

"About one third of MS patients test positive for IgG antibodies," she added. "These patients generally have highly active disease, with many relapses. Beta-interferons don't work well for these patients and so they need a stronger drug right from the start. Therefore natalizumab is a good treatment option for these patients," Dr. Villar told Medscape Medical News. "And now we have shown that natalizumab is actually very safe in this group too. Our cohort of patients, some of whom have been treated for 5 years, have an extremely low risk of developing PML."

Dr. Villar says her hospital now routinely tests for IgM in all new patients with MS. "If positive, I would recommend natalizumab as first-line therapy. I am trying to urge other hospitals in Spain to do the same."

She explained that the IgM antibodies are targeted against lipids and they recognize myelin in the axons of neurons, which is extremely rich in lipids.

Dr. Villar presented their findings at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

In her presentation, Dr. Villar noted that IgM antibodies are believed to have a role in the pathology of MS. "Most patients with IgM bands in the CSF show suboptimal response to beta-interferon, but a good response to natalizumab, with 90% of inhibition of relapse rate and stabilization or improvement of EDSS [Expanded Disability Status Scale] score in most cases."

The aim of the current study was to explore the risk for PML in patients with and without these IgM antibody bands. The study involved 365 patients treated with natalizumab, of whom 240 tested positive for IgM. There were 22 cases of PML reported.

Results showed that IgM antibodies were detected in 70% of patients in the group who did not get PML but in only 1 (4%) of those who did get PML.

"We now have data on 365 patients on natalizumab," she said. "Of these, 240 are positive for IgM and in this group there has only been 1 case of PML. In the 120 patients who are IgM negative there were 21 cases of PML. These data are absolutely significant."

She added that patients who developed PML had a much longer disease duration when they started natalizumab therapy, but the duration of natalizumab treatment in both groups was similar.

Table. Comparison of Patients Who Did and Did Not Develop PML While Receiving Natalizumab

Characteristics Patients Who Developed PML (n = 22) Patients Who Did Not Develop PML (n = 343)
Disease duration before natalizumab (y) 13.5 6.75
Treatment duration with natalizumab (y) 2.78 2.67
IgM antibodies detected (%) 70 4


Upon analysis of JC virus (JCV) antibody status (the virus that causes PML), about half the patients who did not develop PML and all but 1 patient who developed PML were found to be JCV positive.

Dr. Villar reported that the presence of IgM antibodies lowered the risk for PML in patients positive for JCV antibodies to that of patients who tested negative for JCV antibodies.

When asked for a possible explanation of these observations, Dr. Villar noted that patients who test positive for IgM antibodies also have very high levels of CD4 lymphocytes.

"They have highly inflammatory disease, with 20 times more CD4 lymphocytes than IgM-negative patients before treatment with natalizumab." She suggested that in patients with such highly inflammatory disease, the immune system is so activated that the patient is protected against the development of immunosuppression with natalizumab.

Dr. Villar has received speaking honoraria from Bayer Schering Pharma, Merck Serono, Biogen-Idec, Teva Pharmaceuticals, sanofi-aventis, and Novartis.

29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Abstract 180. Presented October 4, 2013.


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