When should I stop my interferon-beta safely?

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Figure: EDSS score

There are two main reasons for stopping an MS drug: 1) it no longer works for you i.e. there is break through disease activity, in which case you should be on a better drug, or else 2) it no longer works for you as you have now entered the progressive stage of your disease. The latter has proven very difficult to define clinically and radiologically, making it harder to know exactly when to stop the immunosuppressive treatment. You may have noticed that when you asked your neuro about this, the reply may have well been ‘don’t know’ or a confused regurgitation of evidence from natural history studies on whether it’s a good idea or not.

The reality of the matter is that we do not know in a clinically meaningful way when the inflammatory phase of MS stops. The progressive phase of the disease can start as early as when you first note walking difficulty, cognitive/memory problems or bowel/bladder dysfunction. And often what you find is that they co-exist together.

Previously, in a large retrospective study carried out by the MSBase Registry group it was noted that those with RRMS on injectables with no relapses for +5y, in those that stopped treatment there was no difference in those who continued in terms of time to the next relapse compared to those who didn’t, but in those who stopped, the time to disability progression was shorter. And this is because the two phases, inflammation and progressive disease are intertwined in MS. Secondly in those who had entered secondary progressive MS (disease stable for 2-20y) and stopped their treatment, 11.7% had a resurgence of their disease activity, but this occurred in an even larger proportion (58.8%) in the relapsing-remitting population who stopped their drug. When they studied specifically those with secondary progressive MS older than 60y they noted that in those 29.7% of those who stopped their treatment, only one relapsed. So, it is potentially possible that it’s safe to stop treatment after the age of 60.

This study from Italy looks at stopping interferon-beta in those with secondary progressive MS. They enrolled those who had evidence of walking limitation (EDSS 4.0) to requiring a stick (EDSS 6.0). They then studied the time to reach an EDSS score of 7.0 (individual who is unable to walk beyond approximately 5 m even with aid and is essentially restricted to a wheelchair). The participants also had to have absence of clinical or radiological activity for at least 24 months i.e. non-active SPMS.

What they found was that when the interferon-beta was stopped (Group A), there was no appreciable difference from those who didn’t stop (Group B) in reaching an EDSS score of 7.0 (see Figure below). During the study, six patients (four in group A and two in Group B) had clinical relapses, with a median time of 17.6 ± 7.9 in Group A and 15.8 ± 6.8 months in group B. Seven had radiological activity (three in group A and four in group B 14.5 ± 6.5 and 15.1 ± 5.8 months).

Figure:  Time to 24-weeks confirmed EDSS 7.0 between the two groups.

What does this all mean if you’re a patient on interferon-beta who has just been given a diagnosis of SPMS? If this is you and your scans have been stable for at least 24 months then chance of the MS inflammatory activity returning is low (~2%) according to this study. Of course the evidence for stopping a more highly active maintenance treatments is not there and will be more complicated than stopping a first-line MS treatment e.g. rebound activity. The pros and cons of stopping MS treatments in progressive MS therefore needs to be discussed carefully.

Abstract

Int J Environ Res Public Health 2022 May 17;19(10):6069.

Stopping Interferon Beta 1b Does Not Influence the Risk of Disability Accrual in Non-Active SPMS: Results from an Italian Real-World Study

Aurora Zanghì Emanuele D’Amico Francesco Patti Carlo Avolio 

Background: No consensus exists on the possibility to stop disease modifying therapies (DMTs) in Secondary Progressive Multiple Sclerosis (SPMS).

Methods: The primary outcome was the time to reach 24-weeks confirmed Expanded Disability Status Scale (EDSS) 7.0. We enrolled all patients with a confirmed diagnosis of non-active SPMS (here, absence of clinical or radiological activity for at least 24 months before the conversion) between 1 January 2010 and 31 December 2015, at MS centers of Catania and Foggia, Italy. Patients were divided into two groups, according to the shared decision to stop DMTs (group A) or to maintain/switch to licensed interferon beta 1b for SPMS (group B). A Cox model adjusted with an inverse probability weighted propensity score (IPTW-PS) was employed.

Results: A cohort of 311 patients was enrolled, 165 were in group A and 146 were in group B. Patients in the two groups were similar for baseline characteristics. The IPTW-PS adjusted Cox model for the event time to 24-weeks confirmed EDSS 7.0 did not show differences between the two groups (ExpB 0.96, CI 0.739-1.271, p = 0.819).

Conclusions: In a real-world setting, in patients with non-active SPMS, the maintaining or switching to the licensed interferon beta 1b did not reduce the risk of reaching confirmed EDSS 7.0.

About the author

Neuro Doc Gnanapavan

18 comments

  • Thank you. When do you personally ever feel it is the right time for someone who is radiologically stable to stop a DMT (regardless of what med they are on)? When do the risks associated with anti-CD20s outweigh the potential/theoretical benefits in an older, stable MS patient, particularly in the age of COVID? Thanks.

    • So I also work with other inflammatory disorders where I use the more traditional agents such as Azathioprine and mycophenolate mofetil – I wean these off after the age of 70 and watch for re-emergence. I have offered the same for MS patients that have remained stable for a number of years. This is individual practice so others have a different approach.

  • Except EDSS doesn’t measure hand function or cognition, which have way more of an impact on people’s ability to live independently than walking. And MS is inflammatory from beginning to end, as proven by pathology studies… Not only does no difference in EDSS outcome not imply no difference in disability outcome, it doesn’t even imply no difference in inflammatory activity. Bad methodology and bad conclusion. Really surprised to see a Bart’s contributor reporting this study so uncritically.

    • I think this is based on what you understand by the pathophysiology of inflammatory and progressive MS. Yes I agree that no upper limb function assessment is done, but you need to also assess that upper limb dysfunction is not always secondary to inflammation and is often on a continuum of neurodegeneration (I.e the legs are affected first, then the arms). Stopping anti-inflammatory drugs will not modify this trajectory. At an older age the predominant process in the brain is ageing I.e. neurodegenertion. Believe it or not time 25 foot walk is one of the more sensitive ways of measuring progression clinically and EDSS as it’s heaving weighted to leg function captures this. It is also performed routinely in clinics and something all MS physicians do regularly and regulatory bodies undesirable. It isn’t going to go away

      • “Stopping anti-inflammatory drugs will not modify this trajectory.”
        Not sure what you mean by this. The phase III trial of Tysabri in SPMS showed that it preserved hand function even though there were no differences in EDSS outcomes. It’s pretty clear that anti-inflammatory drugs modify the trajectory of the disease at all stages. Now you may argue that this was due to sub-clinical inflammatory activity and that is why Tysabri had an effect, but since neurologists have no way to detect that activity (as by definition it doesn’t show up as MRI changes or relapses) they should err on the side of caution, assume it’s there, and act aggressively to preserve every single neuron possible.

        “EDSS as it’s heaving weighted to leg function captures this.”
        Again, the phase III trial of Tysabri in SPMS showed that it preserved walking function despite no differences in EDSS, so obviously EDSS doesn’t even do a good job of capturing leg function.

  • Out of curiosity, roughly, what proportion of the entire MS cohort is still taking beta-interferon (or any of the CRAB drugs for that matter?) versus the more modern and efficacious treatments?

    We hear that the CRAB drugs are outmoded in the modern setting, I have heard several neurologists decrying their use and so on but I wonder if (except GA in those wanting to get pregnant) if in the UK/US people are still started on these as first-line therapies?

    Thanks.

    Dominic

    • Ok you may ask why then even do this study. It is because we all have patients who started interferons in the 1990’s who are now approaching the age where we need to have this discussion imminently.

  • It sometimes takes my breath away how little has really been achieved in improving patient outcomes froth MSers. Interferon Beta has been approved for c.25 years, is regarded as limited effectiveness, yet is still being prescribed! Are there any other diseases where this happens? Even the highly effective DMTs don’t have a massive impact in slowing down the accrual of disability caused by neurodegeneration / progression. Given time even those on treatments such as Natalizumab get reclassified as Secondary Progressive. I thought the field was shifting in terms of now recognising that Progression is there from the very start and relapses are a response to the neurodegeneration taking place in the CNS. What’s shocking is that as patients we can follow our inevitable decline (sometimes slowly, sometimes quickly) along the EDSS scale. 10 clearly states death from MS, but the lethargic MS websites claim that MS is not a terminal disease and is only rarely fatal! As patients what we want are treatments to stop the neurodegeneration and provide stability ie you’re at EDSS 4, but won’t get any worse. Surely neuros also want this! My neuro said to me “you’re now SPMS and there’s no treatment as there’s no activity on your MRI”. In 2022 you’d think we’d be in a better position than this. The ineffective CRAB drugs should have been removed from the prescribing list years ago.

    • Entirely agree. The continuing complacency and inertia in still a significant proportion of the neurology community is both astonishing and deeply vexatious.

      • You agree MS is a neurodegenerative disease and relapses are just responses? I thought MD’s would lean towards autoimmune with subsequent neurodegeneration as a result of immune.

        • I’m still undecided on that, it certainly is in the mice but I keep an open mind in MS, however I am certain that neuroinflammation is important and so is treating it but so is the degeneration which needs an entirely different treatment strategy in my opinion and it is here that pwMS are being let down badly.

        • That is my take at the moment. Relapses a response to degeneration so why don’t they occur in Alzheimers

          • Thanks for replies both MD’s – also sorry this is little off-topic for this post.

          • Because ALZ are diagnosed at old age.
            Relapses in ms are mostly in the younger.

          • You can have young onset Alzheimer’s too and lots of other neurodegenerative conditions can manifest at a younger age, so this doesn’t make sense.

  • OK, this sounds like me and my experience may run counter than some of what I am reading here.

    MS in 1989. Beta 1b (the 1st MS treatment) started in 1995. Essentially no MRI or clinical evidence of relapse for me since around 2002, and greatly reduced at 1995. I own a wheel chair (in mothballs). Bladder dysfunction and other lingering deficits (wear a diaper and be extra aware of when to hit the toilet ahead of time- NO procrastination as if things were normal). Have always walked a bit different and no running, since a relapse in 1995.

    In 2016 my leg started to slowly become painful. Assumption was “MS”. Switched to Ocrevus. What a relief in terms of no more injections after 20+ years! Then COVID came along. Doctor on sabbatical and I decided on my own “nope”, not gonna risk it. So since 2020 or so, no more treatment (unless you consider Alpha Lipoic Acid, Swank diet 6 days per week; and prior amalgam removal and IV steroid use concurrent with relapse [<5 days]).

    But the leg got worse. Excruciatingly painful and mobility therefore challenged. Long story short- Was it MS? Was I progressing? No, pain and function is improving now, 3 years later, on its own. It is a structural problem probably brought on by MS back in ’95. But not any kind of current neurodegeneration. Went to seven different specialists and spent a lot of money with little to show for it. Could have just sat down in my wheel chair too. But the leg thing now is a whole other essay.

    Conclusion- I stopped Betaseron after 23 years. A year on Ocrevus. Nothing seems to be changing now (MS wise), at least not in any noticeable way. I am OK. Maybe I’ll be worse when I’m 80, but let’s be realistic here about that whole thing- the “final exit”.

    MS is very scary at the onset. Life as you know it is gone, although many will struggle in one way or another to deny that and even be led on inadvertently to do so. B cell depletion may be a favorable trade-off for early active relapsing disease form, but when you get to your 60’s, you really have to give it some thought. The B-cells are there for good reason. I didn’t worry that much yesterday (for example), in line at the grocery store, 6 feet behind the maskless constantly coughing idiot.

    But I have MS and I don’t know still, what the future holds for me in that context. Right now, I am OK and no longer on a DMT.

  • ‘The reality of the matter is that we do not know in a clinically meaningful way when the inflammatory phase of MS stops.’

    In which case why risk stopping medication? Aaron Boster made recent reference to a study with results showing that those who has their DMT stopped did worse than those who remained on treatment – so what are we to be confident of?

    The argument could be that with a degenerative disease better to continue to try and undermine/slow it down than risk adding progression.

    CRABS should be hailed as a significant breakthrough that has since been resigned to the annals of history!

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