DMTsDetail

Interferon-beta

Summary

Interferon-beta (IFN-beta) preparations have been the workhorse of MS treatment for decades. They are moderately effective; only a minority of people with MS receiving IFN-beta achieve long-term NEIDA (no evident inflammatory disease activity). Their impact on preventing end-organ damage (brain volume loss) and reducing neurofilament levels (an indicator of damaged nerve fibres) is modest. In general, IFN-beta formulations are poorly tolerated in the short-term owing to injection site reactions and flu-like side effects, but both these side effects can be effectively managed in most people with MS. Monitoring requirements are not too onerous. Adherence has been a problem long-term owing to injection fatigue. IFN-beta is a biological so it can induce neutralising antibodies (NAbs), the rate of which varies according to the different formulations.

IFN-beta belongs to the class of cytokines and is produced by the body to help fight infections, particularly viral infections and possibly cancers. IFN-beta also plays a role in foetal bone development. I have long had concerns about the potential of anti-IFN-beta NAbs to neutralise one’s own IFN-beta and to cross the placenta and affect the role of IFN-beta in foetal development. Therefore, I have favoured the formulations with the lowest NAb rates. Given that more effective DMTs are now available, with more favourable attributes, most people with MS tend to choose other, non-injectable treatments. Despite this, there is still a role for IFN-beta preparations in the treatment of MS, particularly as they have now been shown to be safe in pregnancy.

Trade names

Avonex (IFN-beta-1a), Betaferon (IFN-beta-1b), Betaseron (IFN-beta-1b), Extavia (IFN-beta-1b), Plegridy (Peg-IFN-beta-1a), Rebif (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.

Dosing 

  • IFN-beta-1b (Betaseron, Betaferon, Extavia; continuous type 1 interferon receptor stimulation and downregulation), freeze-dried, 250 micrograms (µg) subcutaneous (SC) alternate days.
  • IFN-beta-1a (Avonex; pulsatile, type 1 interferon stimulation), prefilled syringe, 30 µg IM weekly.
  • IFN-beta-1a (Rebif; continuous type 1 interferon receptor stimulation and downregulation), prefilled syringe or cartridge, 22/44 µg SC three times a week.
  • Peg-IFN-beta-1a (Plegridy; pegylated hence long-circulating half-life with continuous type 1 interferon receptor stimulation), prefilled syringe 125 µg SC or IM 2-weekly.

Main adverse events

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

Rare adverse events of special interest

  • Thrombotic microangiopathy, which manifests as so-called thrombotic thrombocytopenic purpura or haemolytic ̶ uraemic syndrome (i.e. low platelet levels, blood clots, bruising and renal failure).
  • Liver failure or autoimmune hepatitis.
  • Pulmonary oedema, or capillary leak syndrome, in patients with a monoclonal gammopathy.
  • Severe bone marrow suppression.

Neutralising antibodies (NAbs)

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

Monitoring requirements

Baseline

  • Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum protein electrophoresis, renal protein.

Follow-up

  • 1-month, 3-months, 6-months and then 6-monthly while on the treatment: FBC, U&E and LFTs
  • 12-monthly: TFTs
  • 12- and 24-monthly: NAbs.

Rebaselining

A rebaseline MRI needs to be done after IFN-beta has had sufficient time to work, ideally 6 months after starting treatment. I recommend including Gd-enhancement as part of the MRI. The presence of Gd-enhancing lesions on the rebaseline scan is sufficient evidence at this stage to switch/escalate treatment to another DMT, that is, it tells you that the treatment is failing to suppress inflammatory disease activity.

Pregnancy

There is a small increased risk of spontaneous abortion in women who are on IFN-beta when they fall pregnant. Initiation of treatment is not recommended during pregnancy. In case of unplanned pregnancy while receiving IFN-beta, termination of the pregnancy is not necessary, and many neurologists recommend continuing IFN-beta treatment throughout pregnancy.

Breastfeeding

Safe, not contraindicated.

Male fertility

Safe.

Vaccination

Safe.

Summary of Product Characteristics (SmPC)

Betaferon (Europe), Betaseron (USA), Extavia (IFN-beta-1b); Avonex, Rebif, Plegridy (IFN-beta-1a); interferon-beta.

Switching-2-IFN-beta

IFN-beta to IFN-beta switch

The only reason to switch between IFN-beta preparations is for local, or systemic, intolerance. Many patients with local skin, or injection site, reactions move to intramuscular IFN-beta-1a (Avonex), which does not cause local skin reactions. In contrast, many patients move from IFN-beta-1a (Avonex) to IFN-beta-1a (Rebif) or -1b (Betaferon) because of 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. Betaferon is administered on alternate days; however, Rebif is given three times per week, and some patients experience mild flu-like side effects after the 2-day injection break (once each week) but not after a 1-day break (twice each week).

NAbs

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 a 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 will make sense to switch classes. I generally tend to escalate treatment to a more efficacious DMT rather than switch to another moderate efficacy DMT: vertical escalation rather than horizontal switching.

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 a different DMT predicts a lack of response to another IFN-beta. However, if you are switching due to a suboptimal response, I would recommend a potentially more efficacious DMT. There is reasonable 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/or abnormal LFTs, that can occur with several DMTs, are relative contraindications to IFN-beta. Similarly, the presence of a monoclonal gammopathy (abnormal protein in the blood) is a contraindication to IFN-beta due to the risk of capillary leak syndrome (fluid on the lungs).