“The potential rebound in MS disease activity that is commonly seen after withdrawal of natalizumab, and now fingolimod, reminds me of the book ‘Waiting for the Barbarians‘ by JM Coetzee, which I read as a teenager. In the book the locals, and imperialist forces, wait for the barbarians to attack, but they never do. Instead the imperialist forces go out and make a pre-emptive strike against the natives or barbarians, based on the ideology or false belief that they are malicious peoples.”
“Both natalizumab and fingolimod are drugs that work by keeping auto-reactive immune cells, or the barbarians, from gaining access to the brain and spinal cord. Natalizumab blocks lymphocyte migration across the blood-brain-barrier (barricades) and fingolimod traps them inside lymph nodes (concentration camps). When you remove the block these lymphocytes pour back into the brain and exacerbate MS; the so called rebound activity. The relapses and MRI lesions that occur as part of this rebound can be fatal and cause severe disability, which is why we are now reconsidering our policy of a defined wash-out period before switching from natalizumab to fingolimod. The idea of the wash-out period was to allow lymphocytes back into the brain to detect any early or subclinical PML and allow the immune system to flush it out. PML clearly has an asymptomatic or pre-clinical period of a few months before it manifests. Our current proposal is to now do an MRI, to look for any new lesions that looks suspicious of PML, and a lumbar puncture to make sure there is no JC virus in the spinal fluid. If these two tests are negative to then start fingolimod immediately after stopping natalizumab. By doing this you will hopefully trap the autoreactive lymphocytes or barbarians in the lymph nodes before the natalizumab wears off. The obvious danger of this approach is if your MRI and spinal fluid analysis are falsely negative and you then go onto develop PML, whilst on fingolimod. The only treatment we have for PML is to let the immune system do its job and allow the T-cells back into the brain to fight the infection. If you are on fingolimod, when you develop PML, it takes weeks for the drug to wash-out of your system. In the time it takes for fingolimod washout and the lymphocytes to recirculate, PML can cause a lot of damage. So this strategy is clearly a balancing act between keeping the barbarians at bay and making sure there are no traitors (JCV) within the central nervous system to cause problems. Who said treating MS was simple?”
Rinaldi et al. Switching therapy from natalizumab to fingolimod in relapsing-remitting multiple sclerosis: clinical and magnetic resonance imaging findings. Mult Scler. 2012 Nov;18(11):1640-3. doi: 10.1177/1352458512464282. In this study 22 RRMSers were switched from natalizumab to fingolimod after a 3-month washout period. Disease reactivation was observed in 11/22 (50%) MSers: clinical relapses in 6 MSers (four MSers within the first month of therapy) and MRI activity in a further 5 MSers (3 MSers within the first month of therapy).
Laroni et al. Early switch to fingolimod may decrease the risk of disease recurrence after natalizumab interruption. Mult Scler. 2012 Nov 26. This is an descriptive report comparing MSers who switched from natalizumab to fingolimod or other immunomodulatory drugs (interferon-beta or glatiramer acetate); the number of relapses was lower in the fingolimod switchers. These group included a washout period of ~18 weeks before starting the fingolimod.
Havla et al. Rebound of disease activity after withdrawal of fingolimod (FTY720) treatment. Arch Neurol. 2012 Feb;69(2):262-4. This report describes an MSer who discontinued fingolimod treatment after a local malignant melanoma was diagnosed. Three months after cessation, he had a striking rebound of multiple sclerosis activity.