Stuck in a loop

S

Starting certain MS drugs may get you stuck in a loop that you never bargained for when you started them in your early thirties or forties. The ability to stop taking drugs at an older age is something we more or less take for granted, especially if we have been disease free for ‘X’ many years.

However, in the MS world things are never that simple or straightforward; there is ‘recurrence of disease activity (RDA) or worse ‘rebound’ to consider before stopping treatment.

Rebound is when there is resurgence of disease activity to levels greater than pre-treatment activity.

It is unclear how much of this effect is drug specific (i.e. those drugs that block lymphocyte trafficking into the CNS are more likely to cause this phenomenon, for e.g. natalizumab/fingolimod) or simply person/disease specific. Moreover, much of the evidence comes from case reports and real world post marketing studies, which may over or under-estimate the true occurrence of this phenomenon.

In this recent study from Switzerland focused on fingolimod users (128 in total), they noted that discontinuation lead to recurrence of disease in about a third of individuals and of was severe in 1 in 8. Those with greater disease activity at the start of the disease and younger age at MS diagnosis were more likely to experience it. The former has also been demonstrated before in a meta-analysis of the two pivotal clinical trials for fingolimod in RRMS (FREEDOMS I and II).

But, what is of interest to me personally is the resurgence of disease activity in the older age group upon discontinuation despite being previously stable in their MS on treatment. In this study, the cut-off was 50 and being >50 years of age did not take away the risk of resurgence of disease activity; although it was half as likely to occur as those <50 years old (see Figure below). When they moved the cut-off to 60 years old (this included only 11 patients from the whole group), they noted no evidence of disease resurgence upon discontinuation.

Figure: Recurrence of disease activity in patients younger or older than 50 years old at time of fingolimod discontinuation.

Of course, we need to look at this type of data carefully to fully understand the mechanisms at play, and the factors that have positive and negative impact on it. What you want to avoid is starting treatments and then not have an exit plan should the need arise. With regard to fingolimod, its sister drug siponimod, which has recently been licensed in SPMS is expected to be used in a significantly greater number of individuals, and a significant number will be in the older age group with greater co-morbidities. These individuals may not fair as well with resurgence of disease activity at this point in life, especially if it is anything like what it was at the start of their disease or even worse rebound activity.

Abstract

Mult Scler Relat Disord. 2021 Mar 21;51:102918. doi: 10.1016/j.msard.2021.102918. Online ahead of print.

Recurrence of disease activity after fingolimod discontinuation in older patients previously stable on treatment

Vasiliki Pantazou Caroline Pot Renaud Du Pasquier Géraldine Le Goff Marie Théaudin

Background: Discontinuing fingolimod (FTY) in older patients is a growing concern with little evidence supporting the decision to pursue treatment and reasonable doubt for disease reactivation after withdrawal.

Objective: To estimate the incidence of recurrence of disease activity (RDA) and rebound after FTY withdrawal in patients older than 50 years.

Methods: Retrospective analysis of all MS patients in our clinic who discontinued FTY after at least 6 months of treatment, according to disease activity on FTY and age at discontinuation. RDA was defined as the occurrence of either clinical and/or MRI activity in the 6 months after FTY withdrawal and rebound when the levels of disease activity surpassed pretreatment activity.

Results: From the 128 patients who discontinued FTY since 2011, up to 35.2% of patients experienced evidence of disease activity and 12.5% had a rebound. The incidence of both RDA and rebound was not different among individuals who had persistent disease activity on FTY to those who stopped FTY for other reasons than inefficacy (RDA: 25.5% vs 20.5%, p = 0.353 rebound: 14.5% vs 11%, p = 0.596). Negative predictive factors for RDA were younger age at disease onset (p = 0.036), highly active disease at baseline (p = 0.003) and previous treatment with NTZ (p = 0.013). Older age at FTY discontinuation did not reduce the risk of RDA in patients previously stable on treatment (OR 0.972, 95% CI 0.871-1.085, p = 0.613), although the incidence of RDA/rebound was half less in the older patients (36.5% in the <50 vs 19% in the ≥50 year-old, p = 0.174) and none of the patients over 60 experienced RDA.

Conclusion: Although there is a tendency for a lower risk of disease reactivation in the older patients, the incidence of RDA, and even rebound, is not negligible between the age of 50 and 60 years, even in patients with previously stable MS on FTY.

Disclaimer – Please note that the opinions expressed here are those of Neuro Doc Gnanapavan and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

About the author

Neuro Doc Gnanapavan

23 comments

  • I think of myself as having four ages. The first determined by birth. The second from onset of symptoms. The third from diagnosis. The fourth when I started DMT. While collecting my bus pass tomorrow, I would only be starting school with the others.

    Date of birth is very easy to obtain for a study, but it does have its limitations as a meaningful variable. I have difficulty in giving my date of diagnosis. My discharge from hospital lists the code, but as I was diagnosed remotely with MRIs and tests being directed at a MS Centre and not seen by a Neurologist until several months later.

    Other branches of medicine have removed ageism and not all people have multiple comorbidities.

  • I hope this is good news for me, as I am planning to discontinue fingolimod this summer when I will be 71. It’s been discussed at length with my neuro and he is optimistic that it’ll go OK, given my age and trajectory of the MS (diagnosis at age 53). Whatever the outcome, it does emphasise how delicate these decisions are and how much trust we have to invest in our doctors.

  • “What you want to avoid is starting treatments and then not have an exit plan should the need arise. ”

    Out of interest, what would an exit plan look like for a patient treated with ocrelizumab?

    Do B-cells need to repopulate to a sufficient level before other treatments, cladribine, for example, could be considered as a highly efficacious substitute?

    Thank you.

    • For Ocr you’ll need to wait for some safe level of repopulation before starting new treatment. I personally would wait for lympho count of 0.8. Will also check the CD19 (surface marker on B cells) to see what level this is at as total lymphocyte counts can be misleading. Just a note of caution however, return of relapses off treatment can occur before lymphocyte counts repopulate

      • Doc, is this the case (having to wait for repopulation) for HSCT post ocrelizumab? Logic would suggest not

        • No not for HSCT. If there’s breakthrough activity on Ocrevus withdrawal then I would go with the simplest step, which is redosing the individual and attempting at a later date to stop should the individual wish to do so. Most data point to over 70 being ok for this.

      • “Just a note of caution however, return of relapses off treatment can occur before lymphocyte counts repopulate”……I received three full courses of Orc before having to stop due to becoming “allergic” to the drug. Circulating CD-19 B cells began to repopulate around 9 months post infusion. However, my B cells jumped from 1/ul to 32/ul at month 10, at which time I experienced a mild relapse and worsening of existing symptoms. So yes, caution must be taken.

        Here is the most current published data I could find on switching to cladribine from other DMTs. It was funded by the drug company. Unfortunately, the paper includes recommendations for must DMTs except Ocr. (doi: 10.1007/s40120-020-00177-5)

        P.S. I continue to strongly oppose the recent ban of MD1. Bring back the Mouse! Bring back the Mouse!!

  • This is a very good post. This is a dream for any company .. drugs to be taken every day for your life and being unable to stop .
    I was on Fingo from the very beginning it was good to stop relapses unfortunately I had to stop twice with massive rebound. After only nine years I was left with only one arm moving stuck on a wheelchair. Amazingit is still given there are so many other choices .

    An interesting study would be how many people got very disable less ten years on intermittent fingolimod vs Placebo

    • I think this is safer done as a survey of everyone’s databases. I’m sure the American insurance databases also have this info. Rebound can occur potentially with many other highly active MS DMTs also.

      • Would that be the case for ocrevus as well or cladribine? I was under the impression that this effect was associated with natalizumab + S1PM only..

        Thank you

  • I’m in my twenties and have been on Tysabri for the last 4-5 years. I most definitely do not want to be going to hospital every month for the rest of my life. Risk of rebound does worry me but my hope is natalizumab SC Injections will come out or even better, a cure by the time I’m 50!

    • Anon,

      “a cure by the time I’m 50!”

      I’m not sure about a cure, but hopefully within the next 10 years a combo of different treatments will give new MSers a near normal life. We just need a concerted effort to start these combo trials – I can’t believe there aren’t enough MSers who would be happy to participate in such trials. We really need to move on from mono-therapies ie DMTs which only tackle focal inflammation. I like the following crystal ball gazing:

      Prof A Coles in September 2019 in an interview with the MS Society said that: “I hope in 10 years’ time, a person will be given a handful of treatments to tackle all the different elements of MS, and they will be offered hope that their life will be minimally affected by the condition.”

      Dr D Ontaneda in March 2021 responding to the question of how MS care might change in the next 10 years said that: “Difficult to predict, but some form of anti-inflammatory DMT, neuroprotective DMT(simvastatin?), a remyelinating agent, something that helps energetics/metabolism….”

  • Are people always being warned for this before starting treatment with the S1P receptor modulators/natalizumab?

    I refused treatment with ozanimod because of this exact reason, but I am not sure whether this would have been discussed with me if I hadn’t brought it up myself (being aware of it from previous posts of your blog)..

    I am now waiting to start treatment with either ocrevus le Mavenclad after I get the covid vaccine, opening the door to a different world of potential dangers.. however being able to stop a medication without the fear of a disabling rebound effect sounds definitely like a plus..

    • I was put on beta interferon injections after being diagnosed with rrms in 1999. I was then moved onto Fingolimod when the tablet treatment was made available…rebound if stopping was never mentioned. I only found out from Prof Gs posts about vaccines and still not from my neurologist. When the covid jab was offered I asked my ms nurse specialist about vaccine efficacy and rebound during my last phone consultation…she suggested I join the Barts forum for info!
      So as we come out of lockdown I am still on Fingolimod, having had one Pfizer jab and awaiting the second – with fingers crossed that I get some protection.

    • Patient information sheets are the way to go, this takes time for each team to construct as I believe they should be individualised to the team’s practices and experience. I don’t advice going down the consent form route as how much is too little or too much information when it comes to these types of things.

  • Perhaps reduced dosing with age is an option for some drugs. You could reduced DMF to 1x daily or fingolimod to every other day. Makes sense to reduce the amount of immunosuppression as one ages. What age would be appropriate, 50?

    • I took charts to mean resurgence less likely over age 50 but not eliminated. And Dr’s explanation that resurgence is worse disease activity than before treatment is frightening and not an issue to be dismissed. Having required in home care at my worse point, I understand exactly what I could lose if I have a resurgence. I think specific case studies on MS resurgences would be helpful to eduate others about such harm. Thank you for posting this study. While pharma may benefit from lifelong use of DMTs, the payer of funds (gov’t or private insurer) has great financial incentive to curtail DMT use as we age. Studies like this are important reminder that drs should examine impact of a DMT on the quality of life of an MSer and not make blanket determination that mere factor of being over 50 in age means DMT can be safely discontinued.

    • That is a clinical trial waiting to be done. The MS community did it with natalizumab during COVID and can be done again!

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