Rebound on withdrawal of natalizumab and fingolimod

#MSBlog: MSers on more active maintenance treatments are at risk of rebound in disease activity when the drugs are withdrawn and the barbarians attack!

"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?" 

"One eminent neurologist, who will remain unnamed, referred to natalizumab and fingolimod as sticky plaster; i.e. a temporary fix. You remover the sticky plaster and the disease comes back with a vengeance  The advantage of induction therapies, such as alemtuzumab, cladribine, rituximab and ocrelizumab, is that we think they work by rebooting components of the immune system. These treatments don't stop working suddenly; i.e. they kill, or wipe-out, or severely deplete the barbarians. This is why I personally find the philosophy of an induction therapy so appealing. They are also the only therapies that offer a potential cure; that is assuming MS is an autoimmune disease. However, on the down side induction therapies cannot be reversed; once you reboot your immune system you can't unreboot it."

"'Waiting for the Barbarians' is actually a book about apartheid in South Africa. History has shown that the threat that the barbarians were meant to pose never materialised. Apartheid eventually failed and South Africa went on to adopt one of the World's most liberal constitutions. Maybe the barbarians in MS won't materialise either? MS may yet prove to be due to an infection, and not an autoimmune disease. This is one of the reasons why it is so important for us to push ahead with The Charcot Project." 

"'You may be interested to know that 'Waiting for the Barbarians' was chosen by Penguin for its series 'Great Books of the 20th Century' and won both the 'James Tait Black Memorial Prize' and the 'Geoffrey Faber Memorial Prize' for fiction. JM Coetzee went on to great things winning many awards including the Booker Prize, twice, and the Nobel Prize for literature in 2003. He is an extraordinary writer."   

Jander et al. Emerging tumefactive multiple sclerosis after switching therapy from natalizumab to fingolimod. Mult Scler. 2012 Nov;18(11):1650-2. doi: 10.1177/1352458512463768. This report describes an MSer who developed a relapse with MRI features of tumefactive demyelination after switching therapy from natalizumab to fingolimod.

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.

Ghezzi et al. Disease reactivation after fingolimod discontinuation in two multiple sclerosis patients. J Neurol. 2012 Nov 16. In this letter this group describe two MSers with massive rebound after withdrawal of fingolimod.

Gheuens et al.  Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS. Neurology. 2012 May 1;78(18):1390-3. This is a report of an MSer who had widespread PML and severe IRIS after withdrawal of natalizumab. New Gd-enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation.