Rebound of disease activity in multiple sclerosis patients after natalizumab withdrawal is a potentially life-threatening event. To verify whether highly destructive inflammation after natalizumab withdrawal is associated with Epstein-Barr virus (EBV) reactivation in central nervous system infiltrating B-lineage cells and cytotoxic immunity, we analyzed post-mortem brain tissue from a patient who died during a fulminating MS relapse following natalizumab withdrawal. Numerous EBV infected B cells/plasma cells and CD8+ T cells infiltrated all white matter lesions; the highest frequency of EBV lytically infected cells and granzyme B+ CD8+ T cells was observed in actively demyelinating lesions. These results may encourage switching to B-cell depleting therapy after natalizumab discontinuation.
When you select a drug, you may consider things like safety and side-effects, efficacy (which is often inversely related to safety), convenience (route and how often you take drugs but also what screening for problems), however you have to also think what next as we know no MS drug is infallible. Even relapses occur after HSCT.
One problem that is evident is the migration inhibition drugs (natalizumab and to some extent fingolimod). The damaging cells are not killed but kept out of the brain. They are there ready to go if the brakes are removed. This is removed when you stop the drug and then there is a time bomb waiting.
Can you get them under control before the damaging cells pile into the brain to cause rebound damage.
This is why you need to plan the exit before you start the entry.
Following fingolimod much needs to be defined, how best to switch, as it is not just a migration blocker but a depleter too.
Do you wait until blood levels increase, but do you risk damaging cells surging out of the lymph glands and bone marrow to cause a rebound.
The transition from Natalizumab is more defined, but occassionally things go wrong, as in this case.
However, in these cases we know disease has been held in check for some time and so when an attack occurs what ever is driving the attack is present.
In this individual there were loads of B cells and these were EBV infected and the virus was not latent but lytic and CD8 T cells were there presumably killing the virus infected cell. Is the trigger for the attack viral reactivation or does the virus activate because the B cells are activated and dividing?
The study infers that a switch to a B cell depleting therapy is needed, but before you accuse me of giving ocrelizumab a plug. I will remind you that we have shown that all MS drugs are memory B cell depleters, some are better than others at this.