Do we have enough evidence to stop MSers walking the natalizumab-rebound gauntlet? #ClinicSpeak #MSBlog #MSResearch
"The tragic case report below highlights what we know already that when you stop natalizumab MS comes back with a vengeance. This poor lady had massive rebound and when they decided to restart natalizumab her conditioned go much worse. I assume they were worried about her having PML, or a tumour, so that did a brain biopsy that showed acute demyelination with a large number of B cells present. This case highlights that whatever is driving MS must reside within the central nervous system, and that if keep the immune system out nothing happens. If you remove the sticky plaster, or natalizumab, the immune cells pour back in find what they are meant to find and cause severe inflammation and in this case a life-threatening and devastating relapse."
"I have been proposing for a few years now that we need to use natalizumab rebound as a model of MS relapse to study the disease. If MS is due to a virus the best tissue to use to search for this virus must be tissue from natalizumab treated patients."
"I am so sensitised to natalizumab-rebound after seeing it several of my own patients that I don't allow people to stop natalizumab treatment without starting some other form of alternative treatment. I am using fingolimod at the moment, but we really need evidence for teriflunomide and DMF in this situation. The data on using interferon-beta, glatiramer acetate and steroids in this situation is not good; rebound occurs with all of these agents. I have highlighted my concerns about using alemtuzumab in this situation; in this post and have proposed that the safest option is the bridging option (see figure below). The biggest problem we have are woman wanting to come off natalizumab to fall pregnant. I have one patient who had been stable on natalizumab for over 8 years, having previously had only 2 relapses, who stopped natalizumab to start a family. Four months later she came in with a devastating spinal cord relapse and an MRI that lit up like a Christmas tree with 60-80 gadolinium-enhancing lesions. Needless to say she went back onto natalizumab and has decided against starting a family. I am aware that some neurologists are instructing their patients to fall pregnant on natalizumab before stopping it and then restarting it just before, or shortly after, delivery. Other neurologists are telling patients to stay on natalizumab throughout pregnancy. All this advice is not evidence-based; we simply don't have enough data to say whether or not natalizumab is safe during pregnancy. Natalizumab is a so called IgG4 antibody and will cross the placenta. In a small series of babies born to mothers on natalizumab there were transient minor changes to their blood counts. Although small this series is reassuring in that these babies had not long lasting effects of natalizumab on their bone marrow function. This is where alemtuzumab, an induction therapy, has the advantage over natalizumab and other maintenance therapies."
"The authors below hypothesise that restarting natalizumab during rebound made things worse as it affected the population of cells in the brain of this patient. I am not sure I buy this at present as all the cases that I have been involved in have not had worsening of lesions when restarting natalizumab. I think we need to be vigilant and watch out for this in this situation in the future."
"I can't help but feel very sorry for this lady; it shows you had bad MS can be despite having been treated with a transformational drug."
Beume et al. Massive exacerbation of multiple sclerosis after withdrawal and early restart of treatment with natalizumab. J Clin Neurosci. 2014 Aug 20.
We present a 46-year-old woman with a relapse of multiple sclerosis (MS) that began 3 months after withdrawal from long-term treatment with natalizumab. Shortly after restart of a single dose of natalizumab she developed a fulminant MS rebound with stupor and tetraparesis. Cerebral MRI showed massive progression in the number of lesions and tumefactive lesions with ring gadolinium-enhancement. Stereotactic brain biopsy revealed acute demyelination and B-cell dominated inflammation. The patient improved during therapeutic plasma exchange. We speculate that early restart of natalizumab in the case of a relapse may worsen disease evolution possibly by modifying regulatory immune effector processes during an inflammatory rebound phase. A restart of natalizumab in MS patients suffering from a recent relapse or with signs of active inflammation should be considered with caution.