The art of switching!


Natalizumab blocks the lymphocyte migration over the blood-brain barrier and is one of our more potent disease-modifying therapies (DMT). In the phase 3 trial, it reduced the annual relapse rate with 68% compared to placebo and it is typically given as a first/second line therapy to pwMS tagged with the unenviable label of ‘highly active’ disease. However, this is as far as the fairy tale goes.

First, there is the natalizumab-associated risk of progressive multifocal leukoencephalopthy (PML), a potentially devastating brain infection caused by JC-virus. Longstanding use of natalizumab immunocompromises the central nervous system, allows JC-virus to accumulate harmful neurotropic mutations and renders pwMS more susceptible to develop PML. Being seropositive and having a high anti-JCV-antibody index are risk factors for developing PML. Therefore, pwMS on natalizumab with a high antibody index are recommended to switch to a different DMT. To complicate matters, the risk of PML does not disappear when stopping natalizumab. There is namely a risk of PML carry-over when switching to a different DMT as it is highly unlikely that the pre-PML mutant strains disappear. Most carry-over PML cases occur within 6 months after stopping the drug. 

Second, there is the risk of rebound disease activity when stopping the drug. Rebound activity coincides with the drop in plasma blood concentrations of natalizumab and implies that pwMS are at risk of a new potentially disabling relapse 4-7 months after stopping the drug.

This means that both treatment interruption and continuation can be harmful leaving neurologists between the devil and the deep blue sea. In the SmPC of natalizumab, the following statement is included:

“PML has been reported following discontinuation of this medicinal product in patients who did not have findings suggestive of PML at the time of discontinuation. Patients and physicians should continue to follow the same monitoring protocol and be alert for any new signs or symptoms that may be suggestive of PML for approximately 6 months following discontinuation of TYSABRI.“

“Use of immunosuppressant medication soon after the discontinuation of natalizumab may lead to an additive immunosuppressive effect. This should be carefully considered on a case-by-case basis, and a wash-out period of natalizumab might be appropriate.”

Switching natalizumab to a different DMT is thus an expert-based art form requiring ‘alertness’.

From observational data in literature, we can deduct the following: 

In an Italian cohort, the median interval to switch from natalizumab to ocrelizumab was 9 weeks (range 9-14 weeks), and 4/42 patients had rebound MRI activity 6 months after starting ocrelizumab. In a Dutch cohort, pwMS having a washout period between natalizumab stop and fingolimod start of more than 8 weeks (18/52) had a 7-fold higher risk of presenting with a relapse compared to a less than 6 weeks interval (16/52). Radiological disease activity increased with longer washout periods: 11.1% <6 weeks and 50.0% >8 weeks.

From the safety data from Roche on ocrelizumab we know that as of March 31, 2020 there are nine confirmed cases of PML reported outside the clinical trial setting: 

  • Eight cases reported by the treating physicians as “carry-over” cases from previous treatment with either natalizumab (n=7) or fingolimod (n=1). The denominator is not clear: we don’t know how many pwMS have switched from natalizumab to ocrelizumab, but it is likely to be a lot.
  • One case where the patient was treated with OCR for 2 years, without history of a previous DMT, but with contributing risk factors for PML, notably old age (78 years) and Grade 1 lymphopenia.
  • A fatal outcome was reported in two cases

This means that to fully prevent disease rebound we will have to accept a small but existent risk of PML carry-over, and to fully prevent PML carry-over you will have to accept a substantial risk of disease rebound. Especially given the fact that the primary aim of starting natalizumab is to reduce relapse frequency in highly active pwMS, it feels counterintuitive to accept the high risk of rebound after stopping the drug. As the manufacturer does not provide clear instructions on switching, each MS centre has their own protocols/habits based on how they interpret relative risks. This leads to important variability in clinical practice, and illustrates that a manufacturer’s responsibility extends beyond starting and should also involve stopping a drug.

Twitter: @SmetsIde

Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

Mult Scler. 2021 Apr;27(5):790-794. doi: 10.1177/1352458520946017. 

Switching to ocrelizumab in RRMS patients at risk of PML previously treated with extended interval dosing of natalizumab

Chiara Rosa Mancinelli 1, Cristina Scarpazza 2, Cinzia Cordioli 1, Nicola De Rossi 1, Sarah Rasia 1, Maria Vittoria Turrini 1, Ruggero Capra 1Affiliations expand

  • PMID: 32749910
  • DOI: 10.1177/1352458520946017


Discontinuation of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) at risk of progressive multifocal leukoencephalopathy (PML) is associated with disease reactivation. Forty-two RRMS patients, who switched from an extended interval dose (EID) of natalizumab to ocrelizumab, underwent magnetic resonance imaging (MRI) and clinical monitoring during washout and after ocrelizumab starting. During the first 3 months, disease reactivation was observed in five (12%) patients; 6 months after ocrelizumab starting, no further relapses were recorded, and Expanded Disability Status Scale (EDSS) remained stable in 38 (90%) patients. In conclusion, ocrelizumab could be considered a choice to mitigate the risk of disease reactivation in patients previously treated with natalizumab-EID.

Mult Scler 2018 Oct;24(11):1453-1460.doi: 10.1177/1352458517726381. 

Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients

Cyra E Leurs 1, Zoé LE van Kempen 1, Iris Dekker 2, Lisanne J Balk 1, Mike P Wattjes 3, Theo Rispens 4, Bernard Mj Uitdehaag 1, Joep Killestein 1Affiliations expand

  • PMID: 28823223
  • PMCID: PMC6174622
  • DOI: 10.1177/1352458517726381


Background: Natalizumab is an effective treatment in relapsing-remitting multiple sclerosis (MS). Mainly because of the risk of progressive multifocal leukoencephalopathy (PML), a substantial proportion of John Cunningham (JC) virus-positive patients switch to fingolimod. Previous reports show a clear benefit when the duration of a washout (WO) period of natalizumab is 0-3 months in comparison to longer WO periods. However, there is no consensus regarding the optimal duration of a WO period under 3 months. Objective: We compared MS disease activity after different WO periods. In addition, we investigated several factors that possibly influence recurrence of disease activity, including serum natalizumab concentration and lymphocyte counts. Methods: From a prospective observational cohort study of natalizumab-treated patients, we selected 52 patients who switched to fingolimod. We divided the patients in three groups (<6 weeks, 6-8 weeks, >8 weeks WO). Serum natalizumab concentration and lymphocyte count were assessed during and after natalizumab treatment. Results: Patients with a WO period of >8 weeks had a significant higher recurrence of disease activity (odds ratio, 6.8; 95% confidence interval, 1.4-32.8) compared to patients with a WO period of <6 weeks. Serum natalizumab concentration and lymphocyte count did not predict recurrence of disease activity. Interpretation: A short WO period decreases the risk of recurrence of disease activity. The possible impact of a short WO period on the risk of carry-over PML in JC virus-positive patients remains uncertain.

About the author

Ide Smets


  • How about switching from natalizumab to an IRT like alemtuzumab in JCV- patients? I am guessing no washout period at all is required?

    If so, is that enough to counter immune reconstruction risk?

    • In this situation avoiding rebound, is the most important concern and switching within 4/6 weeks would be recommendable. However, there is always a possibility of last-minute conversion from JC- to +. Therefore, the LP and MRI monitoring between switching remains necessary.

  • Natalizumab 👍

    Unfortunally I had to stop due to anti JCV.

    About 7 weeks later I switched to OCR and had no rebound. It went very smoothly.

    OCR 👍

    Still no rebound. Knock on wood. Only my mri keeps showing more and more atrophy. Natalizumab and Ocrelizumab are the same.

  • Not directly related to tysabri but as we are talking about the art of switching, any particular issues with switching from ocreluzumab to HSCT? My non science brain says you are just following one bomb with another so although a lot for the body to endure, no real reason to have a washout period?

    • Yes, but B cells need to repopulate again to at least the lower limit of normal before you can hit the immune system with another bomb. So PML and rebound are no issue here, but there needs to be something to hit (= B cells) before you can launch a new bomb (aHSCT).

      • I’ve been advised 3 months….but this is not long enough to reach the lower end of normal and to do so would surely carry the risk of relapse?

  • Can you comment on how all of this applirs (or doesn’t) to Tecfidera, which of course also carries a risk of PML? I believe there is no WO period when stopping Tecfidera? What are your protocols for a patient on Tecfidera who becomes JCV+ and/or if said patient then comes off Tecfidera? Thank you.

    • No need to wait for that exact reason (confirmed when I talked to the local HSCT unit).

      In fact, some HSCT protocols apparently even include rituximab

      • Those protocols use 1000 mg rituximab, which I think is equivalent to about 150 mg ocrelizumab, and cyclophosmamide. I have a hard time believing the rituximab makes much difference. IMO BEAM-ATG is the way to go if you are going to take the risks of HSCT.

    • In pwMS treated with Tecfidera we do not use the JCV antibody status as a predictor of PML risk. DMF is a more generalised immunosuppressive drug compared to natalizumab, implying the peripheral antibody response to JCV might be less indicative. For people on Tecfidera we know PML risk is associated with persistent lymphopenia. So JCV+ individuals can continue Tecfidera as long as they do not have a lymphopenia (<800/mm3)

  • Hi ide

    i am about to switch from tysabri to cladribine after over a years delay due to covid.

    I am being given a 4 week gap from my last infusion to starting my first course..

    pretty pumped about the change and while a little nervous too, just want to get started and through the first course.


  • Great post and topic IDE.

    Would be nice to see some data on switching from OCR to DMT X. There are some many pwms on OCR but very little data on how to switch off of OCR. Very frustrating.

    Personally, I waited until B cells started to repopulate (9 months) then used TERI for 6 months to keep B cells low, then waited four months to start CLAD. Actually took my first dose of CLAD this morning!! PML baseline scheduled for October.

By Ide Smets



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