Spinal neurofilament levels are ready for prime time. #MSBlog #MSResearch
"The following study supports spinal fluid neurofilament levels as surrogate marker of neuroaxonal damage and loss in MS. Levels were raised at baseline and decreased during the study, but it was only significant in MSers on fingolimod. Why did levels drop in MSers on placebo? We call this regression to the mean. When we recruit for clinical trials we select MSers with active MS; this is usually based on relapses in the last 12-24 months. MSers with recent relapses are more likely to have raised spinal fluid neurofilament levels as their disease has been recently active. These types of MSers are more likely to go into remission hence the slight drop in levels in the placebo arm. However this drop is nowhere near that which occurs with fingolimod; this indicates that fingolimod is reducing ongoing inflammation and damage and is hence protecting the surviving neurones and nerve processes (axons) from ongoing damage. Please note this is a trial in RRMSers. If this was a study in progressive MSers the levels are likely to go down, but are unlikely to be normalised. The latter has been elegantly shown in two studies of natalizumab treatment in SPMS and PPMS. This is why we think that in progressive MS we need to add a neuroprotective drug on top of an anti-inflammatory drug. The latter is what we are attempting to do in the PROXIMUS trial."
"What is not presented in the abstract is the observation that in individual MSers failing fingolimod or placebo, i.e with relapses and/or disease progression, that the spinal fluid neurofilament levels increase. This indicates that spinal fluid neurofilament levels may be a useful marker in individual MSers to ascertain what is happening to their disease and to sort out 'true relapses' from a 'pseudorelapses'. In other words subtle symptoms, without new neurological signs, in the absence of raised spinal neurofilament levels would indicate that the symptoms were unlikely to be due to a significant new MS lesion. I think we should study the latter in a formal prospective study. What do you think?"
|Blue=Paranodal loops, Orange=microtubules, Green=neurofilaments, Magenta=mitochondria, Red=cross bridges and Yellow=septate junctions.|
OBJECTIVE: We assessed CSF levels of the light chain subunit of neurofilaments (NfL) at baseline and after fingolimod therapy or placebo in MSers with relapsing-remitting multiple sclerosis (RRMS). Changes in NfL levels were also correlated with relapse and MRI outcomes.
METHODS: CSF samples were available, at baseline and 12 months after treatment initiation, from a subset of 36 MSers with RRMS (fingolimod 0.5 mg: n = 9; fingolimod 1.25 mg: n = 15; placebo: n = 12) participating in the 2-year, phase 3 Fingolimod (FTY720) Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study. NfL levels were determined in a blinded fashion using a commercial ELISA kit.
RESULTS: Median NfL levels did not differ between treatment groups at baseline (0.5 mg: 644 pg/mL; 1.25 mg: 659 pg/mL; pooled 0.5/1.25 mg: 652 pg/mL, placebo: 886 pg/mL; p value [fingolimod vs placebo] = 0.619, 0.495, and 0.481, respectively). Following 12 months of treatment, median changes from baseline in NfL levels were lower than zero in the fingolimod groups (0.5 mg: -346 pg/mL, p = 0.039; 1.25 mg: -313 pg/mL, p = 0.035) and pooled 0.5/1.25 mg fingolimod group (-326 pg/mL, 83.3% with reduction, p = 0.002) but not in the placebo group (-214 pg/mL, 66.7% with reduction, p = 0.388). Reductions in NfL levels at month 12 correlated with an improvement in relapse and MRI outcomes.
CONCLUSIONS: Our results suggest a beneficial effect of fingolimod on this marker of axonal injury and support the utility of NfL as a quantitative biomarker in multiple sclerosis.
CoI: This work was done when Jens Kuhle who spent 2 years in London, in the Barts-MS team, on an ECTRIMS fellowship