ResearchSpeak: Does interferon-beta still have a role in the treatment of MS?

Is interferon-beta dead, or not? #ResearchSpeak #MSBlog #MSResearch

“On our last Barts-MS Preceptorship one of the delegates asked if I thought there was still a place for interferon-beta in the treatment of MS? I answered yes. Firstly, if  you are on an interferon and you are NEDA, and are tolerating the therapy well, why would you want to change? Maybe NEDA is not sufficient and you would want to know if you had smouldering MS or not. If we had done serial MRI studies on you, and were able to show that over a 3-4 year period your rate of brain volume loss was within the normal range, and your spinal fluid analysis showed normal neurofilament levels, would you be satisfied? You need to remember that interferon-beta is a safe drug and is not associated with any major long-term risks so if you happen to be in the 20-40% of pwMS who respond why change? Remember that being a responder to interferon-beta does not necessarily mean you will respond to another class of DMT.”
“What about naive patients, would I ever start interferon-beta in someone who has active MS? Yes, I would if that is what they choose when given the choice the available 1st-line therapies available on the NHS. In addition to interferon beta the other options are glatiramer acetate, terflunomide, dimethyl fumarate, alemtuzumab and shortly daclizumab. In price sensitive markets interferon-beta is still being widely prescribed; local guidelines state that you have to fail an injectable DMT first to be able to access one of the newer DMTs. Another factor is the emergence of cheaper biosimilars; these are forcing payers to demand that they be used first-line.”
“Another factor that may drive the ongoing use of interferon-beta may be the re-emergence of the so-called induction-maintenance paradigm. This is when interferon-beta is used after an induction therapy; orginally interferon-beta was used in this way after mitoxantrone. May be using interferon-beta after an initial course of alemtuzumab, cladribine or HSCT may re-emerge as a viable and safe long-term treatment option. However, we would need data to support this.”
“Finally, we are in discussion with one of the interferon-beta manufacturers of making their product available in resource-poor settings, on humanitarian grounds, to help treat pwMS who can’t afford to pay for commercial product. We hope to start by running a pilot scheme so as to address all the local regulatory and logistical issues about making this happen. I was surprised at how difficult it is to provide a biological therapy in resource poor settings. However, I am confident we will be able to make this happen; where there is a will there is a way.”

“Please note the study below showing that relapses and MRI activity on interferon-beta predicted failure in terms of disease progression on the EDSS. I note they set their threshold on 3 or more new T2 lesions for predicting failure on treatment. I don’t buy into the concept of MEDA (minimal evident disease activity). Why would you allow some inflammation (MEDA) in your brain when you could have none (NEDA as measured using MRI)? I will need to analyse this paper in more detail to see if the investigators had enough power to assess whether or not patients with zero new T2 lesions did better than patients with one, or more, new T2 lesions. In the past when I attempted this I calculated that thousands of study participants would be needed to address this question.”

“One final point. If you have been reading this blog for some time you will be aware that relapses and MRI activity in natural history studies, or on placebo drug, don’t predict long-term disease outcome in MS. In contrast, relapse and MRI activity on a DMT do predict disease outcome. These observations tell us that relapses and MRI activity are not the disease. If they were the disease they would predict disease outcome regardless of whether you were on a treatment or not! Please think about these observations carefully. These observations challenge the current dogma about what is causing MS. Based on these insights alone it is important to find-out how interferon-beta changes the natural history of MS. Therefore there is another reason why we need to continue to use interferon-beta to treat MS, to pin down the cause of the disease.”

Epub: Sormani et al. Assessing response to interferon-β in a multicenter dataset of patients with MS. Neurology. 2016. pii: 10.1212/WNL.0000000000002830.

OBJECTIVE: To provide new insights into the role of markers of response to interferon-β therapy in multiple sclerosis (MS) in a multicenter setting, focusing on the relevance of MRI lesions in combination with clinical variables.

METHODS: A large multicenter clinical dataset was collected within the Magnetic Resonance Imaging in MS (MAGNIMS) network. This included a large cohort of patients with relapsing-remitting MS on interferon-β treatment, MRI and clinical assessments during the first year of treatment, and clinical follow-up of at least 2 additional years. Heterogeneity among centers was assessed before pooling the data. The association of 1-year MRI or clinical relapses with the risk of treatment failure (defined as Expanded Disability Status Scale [EDSS] worsening or treatment switch for inefficacy) and of EDSS worsening alone was evaluated using multivariate Cox models.

RESULTS: A pooled dataset of 1,280 patients with relapsing-remitting MS from 9 MAGNIMS centers was analyzed. The risk of failure had a relevant increase with 1 relapse (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.39-2.44, p < 0.001) and ≥3 new T2 lesions (HR 1.55, 95% CI 0.92-2.60, p = 0.09). In patients without relapses and less than 3 new T2 lesions, the 3-year risk of failure and EDSS worsening were 17% and 15%; in patients with 1 relapse or ≥3 new T2 lesions, the risks were 27% and 22%; in patients with both conditions or more than 1 relapse, the risks were 48% (p < 0.001) and 29% (p < 0.001).

CONCLUSIONS: Substantial MRI activity, particularly if in combination with clinical relapses, during the first year of treatment with interferon-β indicates significant risk of treatment failure and EDSS worsening in the short term.

CoI: multiple

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.


  • Is there any ongoing trial for induction-maintenance scheme? How can you get interferon or ga prescribed after getting an induction therapy? I've been NEDA since I got alemtuzumab but I try to do my best stay that way, if interferon gives an edge against MS after alemtuzumab prolly many will want to have it… is there any data to support this?

    • Re: "… induction-maintenance scheme …."

      I have broached the subject with Genzyme-Sanofi already and want to use teriflunomide post-alemtuzumab. Two reasons for this; (1) to try and prevent secondary auto-immunity and (2) to try and target intrathecal plasma cells.

      I have also suggested the same to Merck regarding cladribine. For them we would probably need to go with Rebif. Merck would only contemplate a induction-maintenance trial if and when oral cladribine gets a license. Hopefully, this will happen soon.

    • Thanks prof G., I think this makes sense, also combination therapy needs to happen. Probably pharma can see business here, and also patients like myself are interested, i can see this happening soon now that we have very efficient treatment, hope it lift off, count me in.

    • I can's see anyone post cladribine wanting to go back to inject themselves with Rebif again as a maintenance scheme. It's difficult enough getting long term compliance when it is the only DMT and MSer is on

    • RE: "… I can's see anyone post cladribine wanting to go back to inject themselves with Rebif…"

      I agree, but we would need to see the data before making a call on this. I think pwMS would do it if it maintained the majority in remission long-term. Unfortunately, we don't know how good cladribine is on its own in inducing long-term remission.

    • Do we know anything about the people who were in the trial – how long did their remissions last?

      And if any former cladribine users in Australia or Russia read the blog, please share your experience.

    • The major problem of using Interferons as maintenance therapy are it's side effects. I am very interested in this type of treatment, use strong and effective DMT as Cladribine and then use a maintenance therapy.
      Interferon would be out, at least for my case, because I got to have suicidal ideations with him…

      Glatiramer could come as a maintenance therapy ?!

  • "If you are on an interferon and you are NEDA, and are tolerating the therapy well, why would you want to change?"

    This was me. 33 year old female dx March 2014. Commenced Rebif whilst deciding which induction treatment or monoclonal antibody I wanted to pursue. You're always on about treating aggressively early. Why wait for the horse to bolt when it could have been prevented?

    I was diagnosed with zero disability. I was aware I had a window of opportunity and I certainly wasn't going to risk realising in hindsight that I should have pursued aggressive treatment earlier.

    CRAB drugs have a place for risk adverse patients or those reassured by long term safety data. I certainly wasn't inspired by the long term disability and brain atrophy data associated with interferons. Alemtuzumab became available in Australia and exactly 2 years post dx (& still NEDA, although we don't measure neurofilament levels here), I had my first course of Alemtuzumab. I feel the risks are largely mitigated with regular monitoring, so they are likely to be responsive to timely treatment.

    My question is, wouldn't an aggressive and hard hitting immunosuppressive treatment be more effective at achieving NEDA, in the same patient, as a weaker immunosuppressive treatment? Aren't they both working on the same principle, albeit with a different mechanism of action? So in reality, what patients really need to consider is how much and what particular risks they are willing to accept. HSCT comes with the highest success rate, but arguably the most risk.

    • I imagine Prof G is speaking to people like me. I started on GA 5 years ago, and have watched anxiously as better therapies have come online, wondering if I was missing the chance to protect myself from future decline. But the truth is, I've had zero disease activity on MRI or clinically. And the side effects are relatively manageable (some weight gain, and painful injections). Since I know it's working, why change? I seem to be getting disease protection, don't have to worry about PML, plus I get to keep my thyroid!

    • Of course, there is the possibility that this has nothing to do with GA and just the luck of the draw (everyone's MS is different) but if you feel it's working for you then great.

    • RE: "…but if you feel it's working for you then great."

      It is not enough to feel its working; you need you have your MS monitored with annual MRI studies and if there is any concerns we would do a lumbar puncture and measure your neurofilament levels.

      There is little doubt in my mind that about 20-40% of patients do very well on injectable therapies. The only problem is that finding the minority who respond means putting the majority at risk of ongoing disease activity. This is why we try an profile patients at baseline and those with a poor prognostic profile we would tend to steer them to one of the more effective treatments.

    • Anon 4:50pm
      I sincerely hope GA has given you good disease control. I too was the same as you after two years on Rebif, so I do feel Prof G's comment is relevant to myself also. Statistically however, GA does nothing for brain atrophy (which correlates with long term disability). Are you having brain atrophy and neurofilament levels monitored? If not then you may be NEDA-3. Personally I wanted at least NEDA-4 and even without measuring for brain atrophy there is evidence to suggest it will normalise post Alemtuzumab. Hopefully I too will get to keep my thyroid! If not, I'd rather manage it with medication that I know and can easily test to be doing the job.

  • Maybe laquinimod would work it's a weak DMT and neuroprotective, it depends on what happens in their trial

  • "is not associated with any major long-term risks"

    NABs are a potentially serious long-term risk, are they not?

    • Re: "NABs are a potentially serious long-term risk, are they not?"

      I am glad to see someone reads the blog.

  • '…relapses and MRI activity in natural history studies, or on placebo drug, don't predict long-term disease outcome in MS. In contrast, relapse and MRI activity on a DMT do predict disease outcome…'

    Does this mean that if you are on a DMT and show disease activity either in terms of subclinical activity or clinical relapses that you are less likely to well in terms of disability?

    • Re: "Does this mean that if you are on a DMT and show disease activity either in terms of subclinical activity or clinical relapses that you are less likely to well in terms of disability?"


  • This post has confused me. I thought CRAB drugs are not neuroprotective. Then why should patients continue to stay on them? I am on tecfidera at thr moment. I started on Copaxone because I was planning on having a child. It was clear that it wasn't working at all. Switched to Tysabri after delivery, but had an anaphylactic reaction. We tried to get Rituxan approved but it was denied. I have been on Tecfidera since. I would say that I have been MEDA since, not NEDA. According to this study it seems like I would be fine on Tecfidera. I disagree. I would prefer to either get Rituxan or ocrelizumab.

  • … you will be aware that relapses and MRI activity in natural history studies, or on placebo drug, don't predict long-term disease outcome in MS. In contrast, relapse and MRI activity on a DMT do predict disease outcome. These observations tell us that relapses and MRI activity are not the disease. If they were the disease they would predict disease outcome regardless of whether you were on a treatment or not! …

    Please can you in more detail explain this important part, why in the case of DMT relapses and MRI activity have "different" impact on the decease progression?

    • RW: "….What factors (if any) predict long-term outcome in untreated MS?"

      The answer to this question is on the blog. In short older age at onset, male sex, race (African or Asia), baseline lesion load, presence of Gd-enhancing lesions at baseline, posterior fossa lesions, spinal cord lesions, relapse rate in first two years, motor attacks, early bladder involvement, brain atrophy at baseline, cognitive impairment at baseline, smoking, presence of comorbidities, nulliparity (if you are a woman not having children), positive CSF OCBs, raised spinal fluid neurofilament levels, etc.

    • I was thinking here, "Nulliparity and being male" are among the long-term indicators for MS. Sexual hormones ?! Cholesterol?!

      And positive OCBs, I know several MSers that are negative OCBs in repeated tests and have disease progression and higher relapse, this fact sometimes confuses me …

      MD has published here on the Blog a study that indicated that if properly searched actually all MSers has positive OCBs…

    • Not sure I understand how the factors anyone can predict the outcome of untreated MS. Not when a lot of untreated pwMS even see a neurologist. Are they included in the factors?

  • My problem with any of the drugs is the lack of evidence in managing conversion to SPMS. The CRAB drugs don't stop this from happening otherwise you would have seen those results now. I have my doubts that the induction therapy will either but they may slow the conversion rate down. (E.g – U treatment RRMS converts on average after 10 years – maybe that is 12//15 if treated early with the mabs)

    But I still believe that is where we have a gap in the treatment schedule (excusing the PPMS'er for a moment) I think there is treatments that manage RRMS but don't stop SPMS, and then like PPMS no obvious treatment (unless you still have enhancing lesions)

    • See the post regarding Dr. Freedman and aHSCT trial results. Although the number of patients was just 24, there were no new enhancing lesions, T2 lesions or increased brain atrophy at 13 years post therapy. Alemtuzumab therapy is a less aggressive form of mature lymphocyte depletion. Many researchers and clinicians are reluctant to call aHSCT a cure for MS and because of the risks involved with the procedure it is not a first line therapy. But this aggressive treatment may be a cure for MS even though most neuros are unwilling to recommend first line aHSCT. "Wait and see" approach is still in effect.

    • How long is that follow up? Would you say it needs to reach 20 years before we can say it has been successful? At the moment I'm guessing the data is c.10 years. Which is the average conversion untreated?
      I have asked 4 Neuros and none of them have any patients over 10 years who are both NEDA AND NOT converted to SPMS after Alum treatment.
      I feel the reason the long term data is not followed up my initial trials is because of fears it won't stop conversion to SPMS, which is ashame.

    • You have to remember that many treated with alemtuzumab will have been treated when their MS was already well established. Treating earlier=better outcome.

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