Antibodies to lipids lower the risk of PML

Can we derisk natalizumab further with additional testing? #MSBlog #MSResearch

“The following study suggests that MSers with evidence of increased immune activity within the central nervous system (CNS) have a decreased risk of PML. The marker these scientists use is the presence of a type of antibody called IgM that reacts against lipids. This group has previously shown that MSers with these antibodies in their spinal fluid or CSF (cerebrospinal fluid) have a worse prognosis. This study hints at these MSers with a worse prognosis have a different immune response within their brains and spinal cord. It is possible that this immune response targets the mutant virus preventing it from causing PML. It also raises the question whether or not these MSers are less likely to do well on natalizumab? If there is an ongoing immune response that protects you from getting PML it may be that it is allowing immune surveillance to occur, albeit it at a lower level, that may not be able to control the immune response that is driving MS. Another possibility is that these antibodies are binding to the JC virus preventing it infecting cells. Yet another hypothesis is that these antibodies are a marker of a previous immune response that prevented the JC virus infecting, or colonising, the brain in the first place. I personally favour the latter hypothesis.”

“Could this biomarker now be used to reassure MSers that they are low risk of developing PML despite being JCV positive? Not yet; validating a biomarker for clinical application is a laborious task and takes time. We would have to established and validate the assay in another laboratory; we have to make sure the assay does what is says it does. We then have to confirm these results in another group of MSers and finally we have to do a prospective study in a group of MSers on natalizumab to see how the test performs. A diagnostic or predictive test is not worth anything unless it has a sensitivity and specificity of above 80%; these metrics tell you how many false positive and false negative classifications we make based on the test results. I think a prospective study is now unlikely as most neurologists are derisking natalizumab  treatment so there won’t be enough MSers who are JCV positive on natalizumab to evaluate the test prospectively.”

“A very sobering statistic is that there have been at least 24 Spanish MSers who have developed PML as a complication of natalizumab treatment. This absolute figure is much higher than we have seen in the UK; I am only aware of two PML cases in the UK. It will be interesting to get a denominator to see if MSers in the UK are at lower risk of developing PML or are UK neurologists derisking natalizumab by switching high risk MSers to other drugs and not starting natalizumab in MSer who are JCV-seropositive?”

Epub: Villar et al. lipid-specific IgM bands in CSF associated with a reduced risk of developing pml during treatment with natalizumab. Ann Neurol. 2015 Jan 7. doi: 10.1002/ana.24345.

Objective: Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis(MS). PML risk increases in individuals seropositive for anti-JC virus antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid-specific IgM oligoclonal bands in CSF (IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML. 

Methods: We studied 24 MS patients who developed PML and other 343 who did not suffer this opportunistic infection during natalizumab treatment. Patients were recruited in 25 university hospitals. IgM bands were studied by isoelectrofocusing and immunodetection. CSF lymphocyte counts were explored in 151 MS patients recruited in Hospital Ramon y Cajal in Madrid. 

Results: IgM bands independently associated with decreased PML risk (OR=45.9, 95% CI: 5.9-339.3, p<0.0001) in patients treated with natalizumab. They also associated with significantly higher CSF CD4, CD8 and B cell numbers. Patients positive for IgM bands and anti JC antibodies had similar level of reduced PML risk than those anti JC negative (OR=1.55, 95% CI:0.09-25.2, p=1.0). The higher risk was observed in patients positive for anti JC antibodies, and negative for IgM bands (19% of the total cohort, OR=59.71, CI: 13.6-262.2).

Interpretation. The presence of IgM bands reflects a process which may diminish the risk of PML by counteracting the excess of immunosuppression that may occur during natalizumab therapy. 

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • Prof G; why haven't you updated the PML risk page? How many more cases of PML have been reported and how many deaths?

    • Biogen-Idec have made the decision to move from monthly to 3-monthly reports. I think the next update will be at the end of January.

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