Rebound in MS disease activity occurs when coming off highly-active drugs. It refers to a return in MS activity that is more than before. The drugs most likely to demonstrate this are the highly-active treatments that are given on a regular basis (i.e. maintenance treatments, such as natalizumab and fingolimod – it is too early to say with ocrelizumab) that create a gating system for the immune system and once released from the hold result in an inflated rebound phenomenon. But, this is not to say that it doesn’t occur with induction strategies, and I have witnessed this with alemtuzumab.
The strategy then is to step down/up or switch individuals to an equivalent or more highly active preferably induction treatment, especially one that is a immune cell depleter. An example, is to switch fingolimod to alemtuzumab, ocrelizumab or cladribine, or natalizumab to alemtuzumab, fingolimod or cladribine. My preference over the years, however, has been to rely exclusively on switching to an induction strategy as this gives room for the body’s own homeostatic/regulatory aspects to act in between the induction courses to prevent that sudden alteration that comes with directly switching to another maintenance strategy.
I learnt this observing the haem-oncology patients receiving bone marrow transplant and various induction courses of immune cell treatments and use the term ‘de-escalation’ when referring to this type of protocol, as you are by in large de-escalating the rebound risk or another risk perceived with the parent compound.
The drug you choose to de-escalate with is critical and should be of similar or better efficacy than the parent compound. So, no use de-escalating fingolimod to interferons, or dimethyl fumarate for that matter as they’re not highly active enough to smooth over the rebound that will occur once the gate is re-opened.
In this modestly sized study reported below the authors talk about how best to de-escalate fingolimod, whether cladribine or rituximab would be better. It is no surprise that this study has come out now, it most likely stems from the lack of COVID-19 antibody response to vaccines with fingolimod and clinicians are trying to see how best to withdraw out fingolimod.
And, much as I do champion cladribine, it is to be expected that rituximab would fare better in the outcomes (See Figure below). It is important to note that the baseline make-up of the individuals undergoing either switch were very similar and therefore this result is due to the drugs that they switched to.
I might also add that using a pure B-cell depleter in the context of an MS rebound phenomenon doesn’t make much sense. If this is a B-cell lymphoma then I would say certainly, but really I would have used a higher efficacy global agent (both T and B-cell depleter), such as alemtuzumab – although I agree with the authors that the data on alemtuzumab for this purpose is conflicting. Another point to make is that age matters and this is because of senescence of immune system over time, and being young when making these switches may be one of the most important factors in rebound. Moreover, the more highly active in terms of Gad enhancing lesions at the start of your MS the more likely that you will experience rebound when switching treataments.
Risk of fingolimod rebound after switching to cladribine or rituximab in multiple sclerosis
Background: A sudden onset of extensive disease activity, including severe clinical relapse and extensive brain or spinal magnetic resonance imaging (MRI) lesions, termed “rebound” disease activity has been reported after withdrawal of fingolimod in patients with multiple sclerosis (MS).
Objective: To compare the risk of rebound after switching from fingolimod to cladribine or rituximab in MS.
Methods: All patients switching from fingolimod to cladribine or rituximab were included in a retrospective cohort study utilizing prospectively collected data from two university hospitals with different treatment strategies.
Results: A total of 73 patients with at least 6 months follow-up after switching were identified, 33 patients had switched from fingolimod to cladribine and 40 patients to rituximab. No patients in the rituximab group and seven (21.1%) in the cladribine group qualified for rebound disease activity. Ten (30.3%) of the patients using cladribine and five (12.5%) of the patients using rituximab experienced a relapse. MRI disease activity was seen in 18 (54.5%) and eight (20.0%) of the patients using cladribine and rituximab, respectively. Younger age and previous high relapse rate were associated with increased risk of rebound in the cladribine group.
Conclusions: We identify a lower risk of rebound during the first year after switching from fingolimod to rituximab compared to cladribine, indicating a better initial clinical outcome with the former treatment strategy.