Laura’s story

L

Barts-MS rose-tinted-odometer: ★ (a very Black & Red Monday)

I received an email from Laura, a young woman with very active MS, who had been on natalizumab (Tysabri) for 7 years and had recently seroconverted to being high-index JCV seropositive. She was put onto natalizumab extended interval dosing (EID), i.e an infusion every 8 weeks, to derisk PML and to reduced the number of infusions she required during the COVID-19 pandemic. Before starting her switch therapy she was told she needed to be vaccinated with the COVID-19 vaccine. Her natalizumab was stopped and whilst she was waiting for vaccine immunity to develop she developed natalizumab-rebound. This is her story. 

“I’m Laura, a pwMS in the UK and I also work in the MS field. Currently, I’m not able to work due to recent rebound disease of MS, following discontinuation of Tysabri, to switch to another DMT. I believe the decision to delay the new treatment, to try to ensure I made antibodies to the second COVID-19 vaccination, was perhaps the wrong decision to be made on my behalf (I did not have any contribution to the decision, I was informed of the decision). 

To risk rebound disease is not a small matter and I would urge conversations around this prior to the switch from Natalizumab (Tysabri) or Fingolimod (Gilenya) and potentially other S1P modulators (siponimod, ozanimod and ponesimod). I was in hospital for several weeks and much more disabled than I usually am; even during a typical relapse.  It was a frightening and traumatic experience, and one I thought I would never endure. My mental health has also suffered as a direct result from the rebound relapse.  I’m now trying to recover at home, to increase my strength and stamina sufficiently to be able to go back to driving again, working and being a Mum to two autistic boys. Independence.

 I do not know of course if I will ever go back to my previous baseline. It saddens me that this was potentially avoidable; that we need to be mindful that rebound disease, by its very definition, is more severe than what has previously been experienced, and although COVID-19 vaccination is of course very important, I would have preferred to reduce my risk of rebound disease as the priority. It is my brain and spine after all. And as we know the more lesions we acquire the less reserve we have for the future. Perhaps rebound disease should be a never event, as when managed carefully it can be avoided.”

Laura’s story is tragic and should never have happened. We know enough about natalizumab rebound to prevent it from happening. It is more likely to occur in patients who have high disease activity and a high level of disability prior to starting natalizumab (see paper below). It also occurs around month 3-4 after the last infusion of natalizumab and probably slightly earlier in patients like Laura on 8-weekly EID when the steady-state levels of natalizumab are likely to lower. 

There is also no scientific evidence to suggest pwMS on natalizumab will make lower antibody responses to the COVID-19 vaccine whilst on natalizumab. In our centre, this patient will have been on 6-weekly and not 8-weekly EID. She would have had all her vaccine doses whilst on natalizumab. On the day of her last natalizumab infusion, she would have had an MRI and lumbar puncture to exclude subclinical or asymptomatic PML. Provided these were negative she would have been switched to her next DMT approximately 3-4 weeks later. If for some unforeseen reason a delay was going to occur we would have given her another infusion of natalizumab. In short, we have seen too many catastrophic rebound associated relapses and would want to prevent this from happening; we know how to prevent rebound relapses so why not? 

Laura, if you are reading this blog post, thank you for agreeing to allow us to publish your story and I sincerely hope you make a good recovery from your relapse. If anything can be learnt from Laura is that please don’t let vaccine-readiness delay starting a natalizumab-switch therapy. 

Laura’s case illustrates my biggest fear during COVID-19 that untreated or undertreated MS is more of a concern than COVID-19. The good news is that we should be getting a definitive answer on whether or not EID is as effective as standard interval dosing (SID) in the near future from the NOVA study (ClinicalTrials.gov Identifier: NCT03689972)

Mustonen et al. Risk factors for reactivation of clinical disease activity in multiple sclerosis after natalizumab cessation. Mult Scler Relat Disord. 2020 Feb;38:101498. 

Background: Natalizumab (NTZ) is widely used for highly active relapsing-remitting multiple sclerosis (MS). Inflammatory disease activity often returns after NTZ treatment discontinuation. We aimed to identify predictive factors for such reactivation in a real-life setting.

Methods: We conducted a retrospective survey in four Finnish hospitals. A computer-based search was used to identify all patients who had received NTZ for multiple sclerosis. Patients were included if they had received at least six NTZ infusions, had discontinued treatment for at least three months, and follow-up data was available for at least 12 months after discontinuation. Altogether 89 patients were analyzed with Cox regression model to identify risk factors for reactivation, defined as having a corticosteroid-treated relapse.

Results: At 6 and 12 months after discontinuation of NTZ, a relapse was documented in 27.0% and 35.6% of patients, whereas corticosteroid-treated relapses were documented in 20.2% and 30.3% of patients, respectively. A higher number of relapses during the year prior to the introduction of NTZ was associated with a significantly higher risk for reactivation at 6 months (Hazard Ratio [HR] 1.65, p < 0.001) and at 12 months (HR 1.53, p < 0.001). Expanded Disability Status Scale (EDSS) of 5.5 or higher before NTZ initiation was associated with a higher reactivation risk at 6 months (HR 3.70, p = 0.020). Subsequent disease-modifying drugs (DMDs) failed to prevent reactivation of MS in this cohort. However, when subsequent DMDs were used, a washout time longer than 3 months was associated with a higher reactivation risk at 6 months regardless of whether patients were switched to first-line (HR 7.69, p = 0.019) or second-line therapies (HR 3.94, p = 0.035). Gender, age, time since diagnosis, and the number of NTZ infusions were not associated with an increased risk for reactivation.

Conclusion: High disease activity and a high level of disability prior to NTZ treatment seem to predict disease reactivation after treatment cessation. When switching to subsequent DMDs, the washout time should not exceed 3 months. However, subsequent DMDs failed to prevent the reactivation of MS in this cohort.

Figure from Front. Immunol.

Riancho et al. Does Extended Interval Dosing Natalizumab Preserve Effectiveness in Multiple Sclerosis? A 7 Year-Retrospective Observational Study. Front Immunol. 2021 Mar 25;12:614715. 

The extended interval dosing (EID) of natalizumab has been suggested to be associated with a reduced risk of progressive multifocal leukoencephalopathy (PML) and short-term preservation of efficacy but its long-term effectiveness remain unknown. We aimed to determine the long-term effectiveness and safety of natalizumab in an EID setting in a cohort of patients with multiple sclerosis (MS) treated for more than 7 years. We conducted an observational retrospective cohort study, including 39 (34 female, 5 male) patients with clinically definite relapsing-MS, initially treated with standard interval dosing (SID) of natalizumab (mean time 54 months [SD29]) who were then switched to EID, every 8 weeks (mean time 76 months [SD13]). The main outcome measures included the following: i) annualized relapse rate (ARR), ii) radiological activity, iii) disability progression, and iv) NEDA-3 no evidence of disease activity index. EID preserved ARR, radiological activity, and prevented disability worsening during follow-up. The proportion of patients maintaining their NEDA-3 status after 24, 48, and 72 months of natalizumab administration in EID was 94%, 73%, and 70%, respectively. Stratified analysis according to history of drug therapy showed that the EID of natalizumab was slightly more effective in naïve patients than in those previously treated with other immunosuppressive drugs. No cases of PML or other severe adverse reactions were reported. In conclusion, long-term therapy with natalizumab in an EID setting following an SID regimen maintained its disease-modifying activity, and was safe and well tolerated for over 7 years. These encouraging observational results need to be confirmed in controlled clinical trials.

Conflicts of Interest

Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

51 comments

  • “I did not have any contribution to the decision, I was informed of the decision.”

    That is disgraceful.
    That we, as patients, will suffer the consequences of the whims of doctors – with no recourse and potentially little, if any, support – is a disgrace.
    Whatever happened to informed consent?
    This is simply outrageous and my heart goes out to Laura, I hope she recovers fully from her rebound episode and I hope lessons are learnt so patients stop having potentially permanent brain damage imposed upon them like this.

    • Well come to the world of paternalistic medicine; we only kid ourselves that it has been replaced with joint decision-making.

  • I’m a Lay person and even I know the basics that Natalizumab doesn’t work in the same way as other DMTs so doesn’t affect vaccine response. How a neurologist could stop treatment makes no sense. I’m so grateful to be a Barts patient, honestly – as a person on Natalizumab, this is scary stuff.

  • Prof G – my daughter (23yo) is switching from Fingolimod to Ocrevus, and stopping Fingolimod to allow for this in a months time (proactive, rather than reactive decision) – which is very scary re rebound potential. Her visible MS symptoms are well controlled by Fingolimod and she is switching to try to have a better outcome re ‘smouldering’ in the longer term. She had 1 year from CIS to going on Fingolimod – with multiple MRI lesions in that period. Could you tell me what the current best practise is to minimise/manage the chances of a rebound relapse occuring? I’d be really grateful to know. Thank you

    • Does she need a vaccine? If yes, we would bridge her on natalizumab to prevent rebound and allow her peripheral immune system to recover and have the necessary vaccines. After 6-12 months on natalizumab we would transition her onto ocrelizumab.

      If she doesn’t need a vaccine we would stop fingolimod and check her lymphocyte counts at 3 weeks and then weekly after that. Once her total lymphocyte count was trending upwards and got above 800/mm3 we would dose her with ocrelizumab. This has prevented rebound in the past. The reason we wait for the lymphocyte count to recover is that a small number of patients remain lymphopaenic on withdrawing fingolimod and we don’t want to treat these patients with a depleting antibody. This protocol was developed for alemtuzumab, which is quite a sledgehammer compared to ocrelizumab so the risks associated with ocrelizumab post fingolimod are probably less than with alemtuzumab.

      • Thanks SO much for replying. She has had the vaccine on Fingolimod – but I see from following you that her B cell responses will be nearly as poor as those with Ocrevus (accepting we don’t yet know about vol / impact of any T cell response)? Hospital only asked whether she has ‘had’ the vaccine – the low tech answer is ‘yes’ .
        They plan stop Fingolimod beg August, start Ocrevus beg Sept – with an xray and blood test end Aug (presumably for Lymphocytes check). Sounds close to your protocol above. Just – for my sanity – need to know we are doing everything possible to minimise rebound. Esp as she is so young, technically stable on Fingolimod and is ‘choosing’ to switch (brave and understandable). Thanks fo r this and EVERYTHING.

  • A sad story and I wish Laura all the best. It brings back memories of a rebound attack I had which left me confined to bed for a week and OH bringing round a Zimmer frame, stool for my shower and a stand for getting on and off the toilet – pretty degrading for a 30 year old with young children. MS makes life so difficult and is particularly cruel for young adults starting careers, families etc.

    Unfortunately, the anti-relapse therapies are either only mildly effective (injectables) or come with a host of risks (PML, rebound risks, infections, other autoimmune disease). Most depressing is the notion that these anti-relapse drugs have minimal effect on smouldering MS which drives progression!

    Prof G – when is this position likely to change? When will future patients like Laura be offered a combination of treatments to address all aspects of MS so that they can look forward to a future without hospitalisations or fear of accumulating disability? MS research has come a long way, but the case above in 2021 really highlights how much more there is to do. How far are we away from combinations of treatments that will shut the disease down and allow patients to live ‘normal’ lives?

    • Re: “Prof G – when is this position likely to change?”

      It is changing in many centres. This would not have happened in our centre and I suspect in any MS centres in the UK. Adoption of treatment principles takes time and education. This is one of the reasons why we run this blog and I post using the hashtag #NeuroSpeak to inform neurologists about these sorts of things.

      • Prof G,

        My question was about combination therapies to address both relapses and the real MS. Rebound with Natalizumab (which is usually bad) shows that the disease processes in the brain have rampaged out of control and that once off Natalizumab the external immune system piles in. When can we expect to see drugs targeting the disease processes in the brain?

        • Combination therapies as licensed therapies are years if not decades away. The regulatory framework for testing them is not in place yet, which is surprising. The problem is the regulators demand clinical outcomes, which make these trials very large.

          • So how would this work if the Sizomus trial showed positive results? Will it be decades before the drug gets a licence ie if it is combined with an anti-relapse drug?

            Why have you been raising the issue of the need for combination therapies if they are “ years if not decades away”?

          • Our study is a safety study and proof-of-concept study using CSF biomarkers. Our trial will take ~3 years to complete. If our study is positive then Takeda, or another company, will need to do two or three trials with ixazomib as add-on therapy in MS and show clinical benefit to get a license. The latter takes 5-7 years to complete. This is how I get to 10 years. Science moves very slowly and in series. It would be lovely if we could do everything in parallel, but drug development does not work like that.

      • “This is one of the reasons why we run this blog and I post using the hashtag #NeuroSpeak to inform neurologists about these sorts of things.”

        So you are saying there is no formal way to inform neuros of best practices
        so patient’s aren’t permanently harmed…and the only way is if they one by one
        find your blog or tweets.?

        And this case shows how well that’s working out…I just don’tt hink these kinds
        of things happen in oncology. Or if they do..they do something about it
        other than blog posting.

  • I have a question regarding rebound activity, as I’m on NTZ myself. Are there drugs (Dmts) that administered after NTZ lower this risk of rebound?

    • Yes, fingolimod, anti-CD20 therapies and IRTs. The use of IRTs (cladribine and alemtuzumab) post-natalizumab are a bit riskier in relation to carryover PML. But we have done all.

      • If ixazomib will prove safe and preliminary effective will this open a space for off-label prescribing?

        • Fabio,

          This was my next question, but the thread ended. We keep being told that time is brain and that combination therapies are needed, but the latter are always decades away. There’s no urgency! If a therapy proved effective in early trials eg ixazomib, or an anti-viral, I’d hope there’d be option for those with progressive MS without relapses eg an add on if the drug is already approved or compassionate use. I can’t wait another decade for a therapy for progressive MS without relapses.

        • You will probably be able to find a sympathetic doctor somewhere (you could even travel to Russia or Mexico if you must) to prescribe it off-label but you will definitely have to pay out of pocket, and this is quite an expensive cancer drug, unfortunately. It will be another haves and have-nots situation like with HSCT where the rich will pay out of pocket and the poor will be at the mercy of national healthcare systems/insurance companies and will lose an extra ten years (if they are lucky) of brain.

          • “…another haves and have-nots situation like with HSCT where the rich will pay out of pocket and the poor will be at the mercy of national healthcare systems/insurance companies and will lose an extra ten years (if they are lucky) of brain.”

            I am afraid in the u.k. you have no-one to blame but prof G as 10 years ago he had a chance to start a hsct unit in u.k.

          • “Anon below we do have HSCT clinic”

            Well aware…and know that probably 2x the number treated there vs. russia or mexico.
            Mexico has treated 200 a year for the past 5 years..how many treated have been to barts hsct clinic..?

    • Relapses- I hate to say this, but have found some comfort in the information Laura has kindly shared with the blog. I ‘m almost 6 weeks into what appeared like a sensory relapse down right side from ear to foot. Some numbness has lifted, but physically & mentally I am a mess. Had first huge relapse 10 years ago & was treated with alemtuzumab, had much smaller relapse 5 years ago, took a couple of months maximum to get over. Have been on copaxone the last 8 years.
      This time, although my ms team are nice enough & I have been into relapse clinic, I’ve been told to basically sit it out. I didn’t really want steroids & clinician thought they weren’t needed.
      I am currently at such a low point though. I just wondered if this was other people’s experience & also how they got through it?

      • “This time, although my ms team are nice enough ”

        Not very nice…if they put you on Copaxone..a more
        effective treatment might have prevented that relapse in
        the first place. You do not want to be undertreated.

        “Have been on copaxone the last 8 years.”

  • This is unconscionable – (I did not have any contribution to the decision, I was informed of the decision).

    This is not emergency medicine where you are scooped up by ambo and carted into A+E and critical lifesaving choices need to be taken then and there. The patient, at that stage, is an object and the preservation of life is an immediate concern: a completely understandable scenario.

    In contrast, what Laura is talking about is a lifelong condition where every decision has ramifications that extend far beyond the immediate life or death scenario of emergency medicine, yet it feels that this is how her treatment was being decided for her.

    Is this because medics are so habituated to rapid decision making, which by necessity doesn’t include the patient, that they can’t shake off the mindset?

    I can’t believe it is done with ill-intent so there has to be a reason. Ideas?

  • Tragic and also it is infuriating that whoever made this incredibly stupid decision will not suffer any negative consequences, in sad contrast to poor Laura.

  • Truly heartbreaking!
    I can’t believe that this kind of thing is still being inflicted on anyone with MS.
    Best wishes for your recovery Laura.

    • Not sure. It depends on the current standard of practice in the UK. It would have to be out of sync with what happens elsewhere. In the UK medicolegal trials often flounder on the latter.

  • “This time, although my ms team are nice enough ”

    Not very nice…if they put you on Copaxone..a more
    effective treatment might have prevented that relapse in
    the first place. You do not want to be undertreated.

    “Have been on copaxone the last 8 years.”

    • Yes, any neurologist who prescribes copaxone, except in very special circumstances or by explicit patient request, should lose their medical license. There is no excuse for this kind of negligence anymore.

          • Probably because MS is not their sub-specialty and big pharma has hammered home the concepts of escalation therapy and new lesion formation as the benchmarks for successful treatment.

          • Pharma is not responsible for escalation therapy. If anything pharma are the ones who really get it and are working on treatments for smouldering disease because they realize anti-CD20 isn’t good enough, while clinicians and professional academics stick their heads in the sand and paternalistically enforce escalation therapy while insisting that MS is all about lesions on MRI. Many of them are still talking about T cells for God’s sake.

  • Laura my heart goes out to you. Living with MS and being Mum to autistic boys is tough enough without this huge setback.
    With very best wishes for a complete recovery 😊

  • Like another reader, I can’t understand why Laura’s team stopped her treatment because of her Covid vaccination. Surely it was never in doubt, except perhaps very early on in the vaccination’s introduction, that people on Tysabri would develop antibodies?!
    But I just want to wish Laura well. Like many readers, I’m sure, I know how frightening a major, disabling relapse can be and how it also affects mental health and confidence. I hope you will receive lots of sensitive and careful support to get well again – from physiotherapy, occupational therapy, neuro psychologists and anyone else who can help. It is the very least you deserve.

    • Apologies if I had not made it clear in the post: I was changing dmt due the reasons given, and I happened to have the 2nd covid jab in the February, so the idea from the dr was to allow my immune system to develop antibodies: thus delaying the next treatment (dmt) for a couple of months ( infusion given end April by which time the relapse had already started). The issue I believe was the new treatment could have hindered my antibody response, so it was the new infusion, rather than the tysabri, that was the issue. So rather than have another tysabri infusion or just getting on with new infusion there was a delay, a delay which unfortunately I’m paying for

      • I don’t think you understand…the relapses are not the only time you suffer
        damage…you get ms brain atrophy even when there is no relapse.
        The disease is brain atrophy not relapses…of course you can’t feel brain atrophy…you only feel relapses. This is why people have alemtuzumab and hsct…to preserve their brain cells. Copaxone and Tysabri does not preserve your brain tissue or stop your relapses.

  • Just want to say there is no evidence that people taking natalizumab dont make a COVID vaccination response and I have seen some responses

  • Can you get a similar relapse after delaying Ocrevus treatment? If yes then how long is a “risky” time to delay the next infusion? You mentioned that B cells are killed for a while after the infusion so I presume delaying to 9 months in MOST people with MS would not pose much of a risk? Of course if we get infections or stress out I imagine the risk would increase again.

    • There is data following treatment cessation after COVID-19 that disease was not reactivated, we have posted paper on this but I think a 3 month delay, with rituximab after a few cycles this have been extened by over 6 months. In the phase II extension trial there was an 18 month delay and in many cases most people did not relapse but they were not absent, but not all there were no relapses.

    • If you delay between Ocrevus doses you get less of an effect on brain atrophy, which means more brain damage, regardless of what happens with lesions and relapses… Don’t delay.

      • Laura, Sandra, and others dealing with relapse, keep faith you will recover! I had to focus on a purpose outside of myself to keep going; my young children. It took several years for me to regain independence, but I did it. I tried to do everything to help my body heal. I started a DMT and brought a hematologist on board early to treat me with very high dose B12 injections, supplemented with vit d, c, e, and A with neuro setting amt, and did a lot of aqua therapy in a cool temp pool with therapist. “Running” on an underwater treadmill gave me hope I wld be able to walk unassisted on land. I had Speech and driving therapy. My occupational therapist helped me develop safe ways to care for my baby. After 3 yrs , I did yoga and suspension training, and short bursts of HIIT on own, and kept seeing improvement over a total of 7 years. Best wishes for your own recovery Laura and Sandra.

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