ClinicSpeak: predicting response to beta interferon

Why didn’t Pharma commercialise an interferon response marker? They will pay for it. #MSBlog #MSResearch #ClinicSpeak

“The study below confirms what has been established by several other groups that if you have a signature in your blood that your own immune system is churning out interferon you are unlikely to be a responder to interferon-beta treatment. You are probably aware that interferon-beta is a natural anti-viral cytokine that is produced as part of the inflammatory reaction. Interferon binds to receptors on cells and stimulates cells to make anti-viral proteins. One anti-viral protein that is specific for interferon-beta is myxovirus resistance protein A  or MxA. If your MxA levels are high in your blood it indicates that your body is producing your own interferon-beta. In the study below MSers with a high baseline level of MxA, i.e. before starting treatment with interferon-beta, were more likely to be non-responders to treatment. In comparison, those MSers without raised MxA levels were more likely to respond to treatment. Unfortunately when the researchers ran a so called receiver-operating curve, or ROC, analysis the test did not quite cut the muster as being useful clinically. In general, for a test to be clinically useful it has to have a sensitivity and specificity of greater than 80%; however, there are exceptions to the rule.”

“I an convinced by this data as this finding has been confirmed by several other groups. I only wish the Pharma companies had validated this data as part of their phase 4 programmes so that we could use this test in clinical practice. A test like this is what we need to select MSers who are more likely to respond to a treatment than not. However, things have now moved on an most MSer when given a choice between an injectable DMT such as interferon-beta or an oral (teriflunomide or DMF) go for the latter. Please note in the UK we can’t offer fingolimod 1st-line, unlike in many other countries.”

“One of the problems with selecting a 1st-line therapy that only a minority of MSers will respond to (<50%), such as interferon-beta, is that the majority (>60%) will need to be monitored and switched to another therapy under our treat-2-target of NEDA strategy. Depending on your monitoring frequency, and whether or not you use MRI activity to guide treatment, it can take 1, 2, 3 or even 4 years to classify a MSer as a non-responder to interferon-beta. During this time MS can cause a lot of irreversible damage. So at a population level using moderately effective therapies 1st-line disadvantages the majority with and advantage of finding a safe treatment for the minority or responders. In comparison, using a highly-effective 1st-line treatment strategy benefits the majority at a cost of safety issues for a minority of MSers. If I was a population health doctor it would be no-brainer; I would go for the latter option; let the majority benefit at the cost of the minority. The latter is what underpins population vaccine programmes. This is probably why New Zealand have stopped their neurologists prescribing interferon-beta and GA as first-line therapies; they are now limiting the 1st-line treatment options to fingolimod and natalizumab. The New Zealanders have clearly seen the light and over the next 10 years you will see New Zealand MSers shoot-up the national league tables in terms of MS outcomes. I hope NICE and NHS England are watching this space.”

Matas et al. Baseline MxA mRNA Expression Predicts Interferon Beta Response in Multiple Sclerosis Patients.PLoS One. 2014 Nov 14;9(11):e112758.

BACKGROUND: Myxovirus resistance protein A (MxA) is a molecule induced after interferon-beta injection, mostly used to evaluate its bioactivity. There is little available data on clinical utility of baseline MxA mRNA status. The objective of the study is to investigate whether baseline MxA mRNA expression can predict relapse and disease progression in multiple sclerosis patients treated with interferon-beta.

METHODS: Baseline blood samples were obtained before the first interferon-beta dose was administered to evaluate MxA mRNA expression using real-time polymerase chain reaction (PCR). Demographic and clinical variables were prospectively recorded to define treatment responder and non responder groups.

RESULTS:104 patients were included in the study. Baseline MxA mRNA expression was significantly lower in the group of patients who met the definition of responders (1.07 vs 1.95, Student t test, p<0.0001). A threshold of 1.096 was established using Receiver Operating Characteristic analysis to differentiate between responders and non-responders (sensitivity 73.9%, specificity 69.0%). Survival analysis using this threshold showed that time to next relapse (p<0.0001) and to EDSS progression (p = 0.01) were significantly higher in patients with lower MxA titers.

CONCLUSION: The results suggest that baseline MxA mRNA levels may be useful for predicting whether multiple sclerosis patients will respond or not to interferon-beta treatment.

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.


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  • So for interferon the NHS is wasting 50 per cent of the amount they are spending on this drug i.e.the 50 per cent of patients given this drug do not benefit. This is a big chunk of wasted money. If I was ruling this country I'd give RRMS patients the options of alemtuzumab, natilizumab or gilenia. All drugs which could not reduce relapse by more than 50 per cent would be taken off the list. Giving patients a choice (which is not always a good thing) means that a large number will always opt for the least effective / safest drug. In the long run, this is not in their best interest. I take my hat off to New Zealand. What we need is a ten years study of RRMS patients – say 100 on interferon, 100 on copaxone, 100 on natilizumab, and 100 on alemtuzumab. The number of relapses would be counted over the ten years, the change in MRI, the change in brain volume, the number who have converted to SPMS, the number who have died, the number who have experienced serious side-effects (PML, ITP…). It's simple and should show what works best in the long run, what are the real risks etc. This sort of real life research would be much more useful to patients than some of the garbage pumped out by the MS research world.

  • It seems to me that exploration and development of tests for potential non-responders to ANY of the MS meds should be part of the testing and trials conducted in the first place. Why waste time, money, and neurons taking a drug which you are unlikely to respond to? Not to mention putting up with side-effects from a drug which may be achieving nothing positive for you? And this also goes for what Prof G advises are now the 1st line treatments in New Zealand – I would not be happy being forced into taking fingolimod or natalizumab with all of their own attendant potential impacts etc and not having other options available to me. However, I acknowledge there are others who would be equally unhappy having to take interferon or glatiramer acetate when they would prefer to be offered a wider choice. And there needs to be an element of choice for the patient – it’s our MS and our bodies that we have to live with, as well as the side effects and risks of each medication.

    However, it still comes back to what I see as the absolutely critical missing link – what are the causes of MS? If this were known then drug treatments offered could be selected/recommended which have been "proven" to work on your own particular version of MS. Having said that, I need to mention that I personally don't think there is a single cause of MS – I think there is probably a number of different causes, and that MS is an "outcome" of whatever triggers an individual’s MS. A simple analogy – your car stops running – cause may be fuel blockage, blown up engine, wiring fault, etc etc – but the end result is the same – the car won’t go. I suspect that this is possibly why the different “types of MS (i.e. RRMS, SPMS, PPMS etc) exist, and why some people respond to one drug and not another. I’m not knocking Team’s G work on EBV as a possible cause (and I had EBV in my teens), but just throwing a pebble in the pond of causative theories………

By Prof G



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