From natalizumab to fingolimod in eight weeks – Immunological, clinical, and radiological data in quest of the optimal switch.
Harrer A, Pilz G, Oppermann K, Sageder M, Afazel S, Haschke-Becher E, Rispens T, de Vries A, McCoy M, Stevanovic V, Hitzl W, Trinka E, Kraus J, Sellner J, Wipfler P.
Natalizumab (NZB) discontinuation during a treatment change is associated with recurrence of disease activity in a significant proportion of multiple sclerosis (MS) patients. The immunological basis why disease reactivation occurs in selected patients is unresolved. In search of a prognostic biomarker for a safe and effective transition from NZB to fingolimod, we monitored five parameters related to pharmacokinetic and pharmacodynamic effects of the two drugs in 12 MS patients until six months on fingolimod. Clearance of free and cell-bound NZB, re-expression of alpha-4, and fingolimod-mediated changes on CD8+ and CD4+ T cell subsets showed pronounced interindividual variability. Higher frequencies of memory CD8+ T cells after six months on fingolimod were the sole association with disease reactivation. None of the investigated parameters thus had potential as prognostic biomarker for the outcome of the switch. Our findings rather support the thesis of broad interindividual differences in the immunopathogenesis of MS.
Figure: memory for infections
If rebound after withdrawing natalizumab is news to you, read on…
One of the major reasons for stopping natalizumab is the PML (progressive multifocal leucoencephalopathy) risk, which is dependent on your JCV status. Our group has previously published guidance on switching natalizumab to fingolimod to prevent this, and we have in practice generally done it in 8 weeks to avoid the rebound relapse activity, but at the same time permitting moderate immune reconstitution; thereby lessening the risk of JCV re-activation which you may get with continued immunosuppression (i.e. a washout of treatment, and starting again). The risk of rebound increases the longer you’re off natalizumab (natalizumab wash out of 8-12 weeks is associated with a lower risk of clinical and MRI disease activity than 16 weeks washout). The half-life of natalizumab is 11-16 days, whilst fingolimod takes 4-8 weeks for steady state levels to be reached in the body. Threrfore, by switching you do not completely prevent a relapse, and there is a need to find out why some PwMS are more likely to relapse than others. This is what Harrer et al. were looking into. If you remember mouse doctor has posted on this before and it may be the memory cell sub-class in the T cells and the B cells that are involved.
In addition, Harrer et al. looked at 1) the clearing of natalizumab from the body; 2) the re-expression of the alpha-4 receptor at the blood vessel surface, which is normally blocked by natalizumab; and 3) the redistribution of lymphocytes by fingolimod in the body in those who switch. Their washout period from natalizumab was 8 weeks, and surprisingly half of patients experienced a resurgence of disease activity, mainly MRI activity. With regard to their experimental questions, they found a huge variability in the immune parameters measured between individuals. But, what they noted was a greater expression of memory CD8+ T cells in those with disease reactivation, and surprisingly this was not related to those whose T cells were largely desaturated from natalizumab when fingolimod was started (ie those in which the effect of natalizumab had completely worn off!). Why is this you may wander? fingolimod inhibits the exit of lymphocytes from lymph nodes, but CD4+ T cells are more affected than CD8+ T cells, resulting in a decrease in CD4+/CD8+ T cell ratio. T cells which mainly remain in circulation are mainly effector memory CD8+ T cells, which lack the C-C chemokine-receptor-7 lymph node homing receptor. The accumulation of CD8+ T cells may therefore explain the disease activity under fingolimod treatment in those who switch from natalizumab.
Clearly, this is important to look into in more detail. But, supressing effector memory CD8+ T cells can have unforetold repercussions, remember these are your bodies memory to previous infections that you’ve encountered (see figure above)!