After Tysabri – now what?
For people with especially active or aggressive MS, Tysabri has been an invaluable medication for shutting down inflammation in the central nervous system (CNS) and putting a brake on disabling symptoms. This is because Tysabri is highly effective in blocking the passage of active immune cells into the CNS that cause inflammation and tissue damage.
But this approach is necessarily a short-term strategy. Unlike other MS medications, Tysabri doesn’t alter the abnormal immune response seen in MS. It reinforces the barrier protecting the brain, but the activated immune cells – the barbarians at the gate – are still outside and waiting to storm in. If the barrier weakens, such as when Tysabri is stopped, there is a high risk that a person’s MS will return in force and any gains will soon be lost.
The most troubling side effect of Tysabri is PML (progressive multifocal leukoencephalopathy), an often fatal brain infection. The risk of PML increases substantially after two years of exposure to the drug, so many doctors advise switching off Tysabri after you’ve received 24 monthly infusions. But what to do about the barbarians?
A number of studies have looked at whether a new medication will be able to offset the surge in disease activity that often comes when Tysabri is stopped and the barbarians storm the barricades into the brain. One small study found that Copaxone was little better than no treatment in preventing relapses and inflammatory activity after stopping Tysabri (Havla and colleagues. J Neurol 2011;258:1665-1669). A second study then tried giving people a course of steroids followed by Copaxone, but over one-half still had relapses and worsening inflammation on their MRI (Magraner and colleagues. J Neurol 2011;258:1805-1811).
Switching to a more potent medication such as Gilenya also didn’t appear to be immediately successful (Havla and colleagues. J Neurol 2013;260:1382-1387). This prompted some to suggest that since MS got worse when Tysabri was stopped, the best solution was to continue Tysabri indefinitely. But with the risk of PML, this was akin to remaining in a burning house because you’re afraid of being mugged in the street.
However, there was some indication from switching studies that the problem was the amount of time between treatments. Tysabri takes a month or two to leach out of the system; Gilenya takes a few months before it’s fully effective. So if starting Gilenya is delayed, there’s a gap during which your MS can flare up. Three studies then reported that people did better if they started Gilenya within three months of stopping Tysabri (Havla and colleagues. J Neurol 2013;260:1382-1387; Jokubaitis and colleagues. Neurology 2014;82:1204-1211; Cohen and colleagues. JAMA Neurol 2014;71:436-441).
The largest study to examine this issue has now been published (Kappos and colleagues. Neurology 2015; epublished May 29, 2015). TOFINGO was a planned phase IIIb study, later downgraded to phase IV when the study was terminated early by the sponsor. People stopping Tysabri received Gilenya after a delay (a washout period) of two, three or four months. Those who started Gilenya earlier (after two or three months) did better, with fewer new lesions on their MRI. More people were relapse-free with a 2-3 month washout (88-91%) compared to those undergoing a four-month washout (84%). So the results of this study support the idea that a shorter time off treatment is better for preventing an MS flare-up when stopping Tysabri.
There are other options for people who are thinking about stopping Tysabri. Other MS therapies, notably Lemtrada, may be more effective in preventing post-Tysabri relapses, but this will need to be studied. Slowly discontinuing Tysabri by spacing out the last few infusions may also ease the transition (Weinstock-Guttman and colleagues. AAN 2015; abstract P3.287). Whatever the method used, for those stopping Tysabri, it’s best to have an MRI to ensure that there isn’t undetectable PML before the next medication is started.
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