Feb 6, 2022 • 3M

Is there still a role for interferon-beta in the management of MS?

I don’t think we as an MS community should give up on using interferon-beta just yet. Why?

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This is the first of a series of upcoming MS-Selfie Newsletters on specific disease-modifying therapies (DMTs) and is part of the series of questions you need to ask, and have answered, by either yourself or your HCP, before starting a DMT.

  1. What is multiple sclerosis (MS)?

  2. Am I sure that I have MS?

  3. What type of MS do I have?

  4. What prognostic group do I fall into? 

  5. What is the risk of not being treated with a disease-modifying therapy (DMT)? 

  6. Do I have active MS? 

  7. Am I eligible for treatment with a DMT? 

  8. What is the difference between a maintenance/escalation DMT and an IRT (immune reconstitution therapy)?

  9. Do I understand the difference between short-term intermittent and long-term continuous immunosuppression?

  10. Do I understand the concept of treat-2-target?

  11. What are the attributes of the specific DMTs or treatment strategies?

    1. Interferon-beta

    2. Glatiramer acetate

    3. Natalizumab

    4. S1P modulators

    5. Alemtuzumab

    6. Teriflunomide

    7. Fumarates

    8. Anti-CD20

    9. AHSCT

    10. Off-label therapies

  12. How can I derisk or reduce my chances of getting certain adverse events on specific DMTs?

  13. Will I be able to become a parent? What about pregnancy and breastfeeding?

Summary

The interferon-beta (IFN-beta) preparations have been the workhorse of MS treatment for decades and in many countries, in particular middle-income countries, they still are. 

As a class IFN-beta is moderately effective; only a minority of people with MS (pwMS) achieve long-term NEIDA (no evidence of inflammatory disease activity). IFN-beta’s impact on end-organ damage (brain volume loss and reduced neurofilament levels) is on average modest. 

In general IFN-beta formulations are poorly tolerated in the short term, due to injection site reactions and flu-like side effects. However, both the injection site reactions and flu-like side effects can be effectively managed so that the majority of pwMS starting on IFN-beta can continue on the treatment. The monitoring requirements IFN-beta are not too onerous and major life-threatening adverse events are rare on IFN-beta. 

Adherence to therapy has been a problem long-term, due to injection fatigue and lipoatrophy (loss of subcutaneous fat) at injection sites. As IFN-beta is a biological therapy it can induce anti-drug antibodies (ADAs), or neutralising antibodies (NABs), the rate of which varies according to the different formulations. I have always had concerns about the potential of anti-IFN-beta NABs to neutralise one's own IFN-beta and to potentially cross the placenta and affect the role of IFN-beta in fighting infections and in foetal development, respectively. Because of this, I have personally tended to favour the IFN-beta formulations with the lowest NAB rates. Please note that a lot of the biosimilar versions of IFN-beta in middle-income countries have not been adequately assessed regarding their immunogenicity, i.e. ability to induce NABs, and hence I don’t recommend their use. 

With more effective DMTs to choose from, with more favourable attributes, most pwMS when given a choice tend to choose a non-injectable DMT. Despite this, there is still a role for IFN-beta in the treatment of MS particularly as a legacy agent, i.e. in pwMS doing well on IFN-beta (why change if you are doing well?), women with MS planning to start and extend their families (IFN-beta is safe in pregnancy and does not impact breastfeeding), in pwMS with secondary cancers and in people who have active chronic infections. These latter two are the most common reasons in my current practice to consider an IFN-beta preparation. The important thing to note is that IFN-beta is not immunosuppressive and we have a lot of experience with using it over decades.

As a result of COVID-19, IFN-beta has had a resurgence in use in many parts of the world. IFN-beta does not blunt vaccine responses or affect one’s immune response to the coronavirus. In fact, pwMS on IFN-beta are less likely to get COVID-19 and severe COVID-19 presumably because IFN-beta works as an antiviral agent. 

The academic MS community has a good idea by using a relatively simple blood test who is going to be an IFN-beta responder or non-responder. One of the great tragedies of MS management is that this was never taken forward by the pharmaceutical industry. The blood test simply looks to see if there is already a type 1 interferon signature in the cells of the peripheral blood, i.e. evidence of your own body producing and responding to IFN-beta or interferon-alpha. Patients with a pre-existing type 1 interferon-response are likely not to respond to IFN-beta. 

I personally think we still have many things to learn about IFN-beta in relation to its mode of action and whether or not we can use it for studying the role of EBV and other viruses in MS.  

I don’t think we as an MS community should give up on using IFN-beta just yet. IFN-beta may still have a very important role in induction-maintenance strategies and as a safe DMT to derisk immunosuppression in older pwMS and those in whom immunosuppression is contraindicated, i.e. with comorbid cancer or infection. 

If relevant please read on for a more detailed profile of IFN-beta and on the issues around switching to or from an IFN-beta formulation.

Interferon beta-1a - Wikipedia
Interferon-beta by Nevit Dilmen - created from PDB entry with Cn3D Data Source: https://www.ncbi.nlm.nih.gov/Structure/

Please feel free to ask questions and share your experiences about your decision to start interferon-beta or another DMT. If your case illustrates an important issue I will then use it to do a separate case study on it so we can all learn from each other.

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Interferon-beta

Trade Names: Betaseron, Betaferon, Extavia (IFN-beta-1b) and Avonex, Rebif, Plegridy (IFN-beta-1a).

Mode of action: Immunomodulatory; with many different effects on the immune system. In general, IFN-beta is not immunosuppressive. 

Efficacy: Moderate

Class: Maintenance, immunomodulatory

Immunosuppression: No

Posology:  

  • IFN-beta-1b (Betaseron, Betaferon, Extavia; continuous type 1 interferon receptor stimulation and downregulation), freeze-dried, 250ug s.c. alt. day

  • IFN-beta-1a (Avonex; pulsatile, type 1 interferon stimulation), prefilled syringe, 30ug IM weekly

  • IFN-beta-1a (Rebif; continuous type 1 interferon receptor stimulation and downregulation), prefilled syringe or cartridge, 22/44ug sc TIW

  • Peg-IFN-beta-1a (Plegridy; pegylated hence long-circulating half-life with continuous type 1 interferon receptor stimulation, prefilled syringe 125ug sc 2-weekly or 125ug im 2-weekly )

Main adverse events: Injection site reactions, flu-like symptoms, abnormal liver function tests (LFTs), low lymphocyte counts (lymphopaenia), low white cell counts (leukopaenia).

Rare adverse events of special interest

  • Thrombotic microangiopathy manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS)

  • Liver failure or autoimmune hepatitis

  • Pulmonary oedema, or capillary leak syndrome, in pwMS with a monoclonal gammopathy

  • Severe bone marrow suppression

Neutralizing Antibodies (NAbs): Yes; ~30% IFN-beta-1b (Betaseron, Betaferon, Extavia), <5% IFN-beta-1a (Avonex), 12-25% IFN-beta-1a (Rebif) and <2% Peg-IFN-beta-1a (Plegridy).

Monitoring requirements

  • Baseline: FBC, U&E, LFTs, TFTs, serum protein electrophoresis, renal protein. Please note the presence of a monoclonal gammopathy (abnormal immunoglobulin protein) is a contraindication to starting IFN-beta due to the potential to develop a capillary leak syndrome in the lung, which can be life-threatening.

  • Follow-up: 1-month, 3-month, 6-month and 6-monthly FBC, U&E and LFTs. TFTs 12 monthly. NAbs 12 & 24 months

Rebaselining: A rebaseline MRI needs to be done after IFN-beta has had sufficient time to work. I recommend 6 months after starting treatment and to include Gd-enhancement as part of the baseline MRI. The presence of Gd-enhancing lesions on the rebaseline scan is sufficient evidence at this stage to switch/escalate treatment to another DMT.

Pregnancy: A possible higher risk of spontaneous abortion. Initiation of treatment is not recommended during pregnancy. In case of unplanned pregnancy on IFN-beta termination is not necessary and many neurologists, including me, are recommending continuing IFN-beta treatment throughout pregnancy.

Breastfeeding: Safe, not contraindicated.

Male Fertility: Safe

Vaccination: Safe

Summary of Product Characteristics (SmPC):  Betaseron, Betaferon, Extavia (IFN-beta-1b) and Avonex, Rebif, Plegridy (IFN-beta-1a)

Switching

IFN-beta to IFN-beta switch: The only reason to switch between IFN-beta preparations is for local, or systemic, intolerance. I have had many patients with local skin, or injection site, reactions who have moved to intramuscular IFN-beta-1a (Avonex) that does not have local skin reactions. In contrast, I have had many patients move from IFN-beta-1a (Avonex) to IFN-beta-1a (Rebif) or -1b (Betaferon) due to persistent flu-like reactions. Because Avonex allows the interferon receptors to regenerate before the next injections mild flu-like symptoms can persist; this does not happen with Rebif and Betaferon. However, as Rebif is given 3x per week some patients experience mild flu-like side effects after the 2-day injection break and not after the 1-day break.

NAbs: Please note that if you have developed NAbs to one IFN-beta preparation these cross-react with the other preparations. In this situation, NABs would simply neutralise the effect of the new IFN-beta formulation.

Lack of efficacy: I would not recommend switching between IFN-beta preparations because of lack of efficacy or perceived lack of efficacy. If you have had a suboptimal response to one IFN-beta preparation it would make sense to switch to a new class of treatment. In general, I tend to escalate treatment rather than switch to another moderate efficacy DMT.

Other DMTs: Provided the baseline screening blood tests are fine and there are no specific contraindications I see no reason why IFN-beta can't be used after any of the other licensed DMTs. Apart from NABs inhibiting the action of other IFN-beta formulations, I am not aware that a failure to respond to any of the other DMTs predicts a lack of response to other IFN-beta. However, if you are switching due to a suboptimal response I would recommend a more efficacious IFN-beta. There is good real-life data that shows switching upwards (escalation) gives a better overall response rate than switching to a similar efficacy DMT (horizontal switching).

Special circumstances: The presence of some specific comorbidities or adverse events may make it difficult to switch from one DMT to IFN-beta. For example, a persistent low lymphocyte count (<800), low neutrophil count (<1,000), low total white cell count (<1,500) and abnormal LFTs, which can occur with several DMTs, are relative contraindications to IFN-beta. Similarly, the presence of a monoclonal gammopathy (abnormal immunoglobulin protein) is a contraindication to IFN-beta due to the risk of capillary leak syndrome.

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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 Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.