Natalizumab is not 100% effective in stopping immune responses within the CNS #MSBlog #MSResearch
“The following study uses a very old technique of looking for the production of specific antibodies within the central nervous system (CNS), or intrathecal compartment (within the membranous coverings of the brain), to help diagnose PML. The investigators used a so called JCV antibody index to detect antibody production within the CNS against the JC virus. The way this technique works is that they have to normalise the levels of anti-JCV antibodies against a ratio of other proteins to account for a leaky blood brain barrier, which is the norm in MSers. This correction allows you to create a virus specific antibody index; an index greater than 1.5 indicates that there is production of anti-JCV antibodies within the CNS. It implies that there are B cells and plasma cells in the brain and spinal cord that are making anti-JCV antibodies. We know that this occurs commonly in other viral infections of the brain, for example with mumps, measles, rubella and herpes infections. The investigators found that in 70% of MSers who had PML diagnosed using MRI and the detection of virus specific DNA had an index greater than 1.5. This means that 30% did not. In general a diagnostic test has to be at least 80% sensitive (detecting PML) and specific (excluding PML) before it can be used clinically. I am therefore not sure about their conclusion that the index can be used to help diagnose PML. More work needs to be done on this assay. A factor that needs to be considered is the mode of action of natalizumab; it blocks lymphocyte trafficking into the CNS therefore it potentially could prevent and adequate CNS B-cell response which may explain why the only 70% had an index > 1.5 and not a figure closer to 100%. The good news is that their data suggests that there is some immune response to the virus in MSers with PML on natalizumab. This indicates that natalizumab is not 100% effective at blunting the immune responses within the CNS and may explain why some MSers with PML have low-grade immune reconstitution inflammatory syndrome (IRIS) despite still being on natalizumab and that most biopsies done when MSers are on natalizumab show inflammatory cell infiltrates. This data suggests we may need more effective cell trafficking blockers that natalizumab to treat MS. This is the first time I have thought about actually improving on the efficacy that natalizumab provides. Interesting?”
Epub: Warnke et al. The CSF JCV antibody index for diagnosis of natalizumab-associated PML. Ann Neurol. 2014 Apr . doi: 10.1002/ana.24153.
Background: Progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), can occur in MSers receiving natalizumab for MS. JCV detection by quantitative polymerase chain reaction (qPCR) in cerebrospinal fluid (CSF), or brain biopsy is required for probable or definite diagnosis of PML. However, in some MSers only low levels of JCV-DNA (<100 copies/ml) are present in CSF, making the diagnosis challenging.
Objective: To assess the complementary value of a CSF JCV antibody index (AIJCV ) in the diagnosis of natalizumab-associated PML.
Methods: In 37 cases of natalizumab-associated PML and 89 MSers treated with natalizumab without PML AIJCV was assessed. Sera and CSF were tested in a capture ELISA, using JCV-VP1 fused to glutathione S-transferase (GST) as antigen. Albumin levels and total IgG concentration were determined by immunonephelometry, and the AIJCV was calculated as published.
Results: Twenty-six of 37 (70%) patients with natalizumab-associated PML exhibited an AIJCV >1.5, while this was seen in none of the controls (p<0.0001). At time of the first positive qPCR for JCV-DNA, 11/20 (55%) of MSers with natalizumab-associated PML had an AIJCV >1.5. JCV-DNA levels of <100 copies/ml were seen in 14/20 (70%) of these MSers of which 8 (57%) demonstrated an AIJCV >1.5.
Interpretation: Determination of the AIJCV could be an added tool in the diagnostic workup for PML and should be included in the case definition of natalizumab-associated PML.