Tuesday, 29 November 2016

#ResearchSpeak: rise of the PIRTs

Are you pro-PIRTs or would you prefer to be maintained? #ResearchSpeak #MSBlog #MSResearch

You may agree, or disagree, that one of the major advantages of the PIRTs (pulsed immune reconstitution therapies) is that they front-load risk with the potential to induce long-term remission and hopefully in some pwMS a potential cure. At present we only have one licensed PIRT, alemtuzumab. The study below confirms what we see clinically, that despite the burden or using alemtuzumab (cost, infusion reactions, secondary infections, monthly monitoring and secondary autoimmunity) pwMS have markedly improved quality of life (QoL) compared to pwMS on interferon-beta-1a. 


It is quite remarkable how well pwMS feel post-alemtuzumab. I suspect having an inflammatory soup swishing around in your head, with active MS, makes you feel awful. Switching off inflammation and reducing the inflammatory mediators that drive so called 'sickness behaviour' clearly makes the difference. Sickness behaviour is the clinical syndrome associated with inflammation; i.e. fatigue, sleepiness, low mood, low energy, poor concentration, etc. If  you don't have MS you may relate to how you feel when you have flu or a viral infection; you simply feel awful. From an evolutionary perspective sickness behaviour evolved to force the sick individual to rest and recover from illness. It is clear from this study, and my personal observations, that the interferons are not effective in abrogating sickness behaviour. 

Another point that this study addresses is that the clinical effectiveness of alemtuzumab is mirrored by how pwMS feel and unction post-alemtuzumab. Please note improvements were noted in all QoL domains, i.e. physical, mental, and emotional. There are not many DMTs that do this. 


Other PIRTS include cladribine, HSCT, mitoxantrone and possibly the anti-CD20 therapies. I suspect that a lot of clinicians will use ocrelizumab in a similar way to how some neurologists are currently using rituximab, i.e. with a 2-year course and then to retreat when disease activity re-emerges. Who knows we may even find a response marker that informs us about the need to retreat with anti-CD20? Now wouldn't the latter be disruptive? 

Arroyo et al. Alemtuzumab improves quality-of-life outcomes compared with subcutaneous interferon beta-1a in patients with active relapsing-remitting multiple sclerosis. Mult Scler. 2016 Nov 24. pii: 1352458516677589.

BACKGROUND: Alemtuzumab was superior on clinical and magnetic resonance imaging (MRI) outcomes versus subcutaneous interferon beta-1a in phase 3 trials in patients with relapsing-remitting multiple sclerosis.


OBJECTIVE: To examine quality-of-life (QoL) outcomes in the alemtuzumab phase 3 trials.

METHODS: Patients who were treatment naive (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I [CARE-MS I]) or had an inadequate response to prior therapy (CARE-MS II) received annual courses of alemtuzumab 12 mg/day at baseline (5 days) and Month 12 (3 days) or subcutaneous interferon beta-1a 44 µg three times/week. QoL was measured every 6 or 12 months using Functional Assessment of Multiple Sclerosis (FAMS), European Quality of Life-5 Dimensions (EQ-5D) and its visual analog scale (EQ-VAS), and 36-Item Short-Form Survey (SF-36).

RESULTS: Statistically significant improvements from baseline with alemtuzumab were observed on all three QoL instruments at the earliest post-baseline assessment and sustained through Year 2. Statistically significant greater QoL improvements over subcutaneous interferon beta-1a were seen at all time points in CARE-MS II with FAMS, EQ-VAS and SF-36 physical component summary, and in CARE-MS I with FAMS.

CONCLUSION: Patients treated with alemtuzumab had improvements in physical, mental, and emotional QoL regardless of treatment history. Improvements were significantly greater with alemtuzumab versus subcutaneous interferon beta-1a on both disease-specific and general measures of QoL.

CoI: multiple, Prof G is a co-author on this paper. 

14 comments:

  1. > interferons are not effective in abrogating sickness behaviour

    Because interferons themselves are mediators of sickness behaviour ?

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  2. Prof G, I had my first Alemtuzumab infusions over ten years ago and the second infusions a year later. I have not had any further infusions or MS treatments. I have remained relapse free / annual MRI shows no activity or new lesions. My EDSS has remained stable. I did get a thyroid condition and take a tiny thyroxine tablet once a day. I know of three others who have had Alemtuzumab who have similar experiences (in terms of shutting down the disease). I feel the advice provided by neuros is too soft - either take an injectable / tablet which is very safe and reasonably effective or an induction therapy (Alemtuzumab) which is more effective but comes with higher risk of side effects. A patient needs a clearer steer from their neuro e.g. your best chance of not becoming more disabled over the next ten years is an induction therapy. The short term inconvenience of monthly blood tests, annual MRIs and six monthly clinic appointments {for the first 3 years after treatment) pales into insignificance if, by year ten, the patient who opted for the injectable has moved up a couple of points on the EDSS scale. Neuros must get tougher with their advice to patients. Patient choice is not the way to go if the choice they make results in a much worse outcome a decade later (and then keeps getting worse).

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    1. Dear Anonymous Tuesday, November 29, 2016 9:24:00 am

      I feel I know you very well, but as there are a lot of very happy and satisfied alemtuzumabers' out there I won't linger to long on this.

      I don't necessarily disagree with you, which is why I did a post on unshared decision-making several months back:

      http://multiple-sclerosis-research.blogspot.com/2015/08/clinicspeak-unshared-decision-making.html

      What prompted this post was a particular case who was paralysed by the choices I have given her. When I realised her predicament I made the call and I recommended alemtuzumab. However, despite the need for unshared decision making I think the default in the modern era needs to be shared-decision making. The art of being a doctor is deciding which call is the correct one for a particular patient. This is personalised medicine.

      You will disagree with me, but then I suspect you are a highly-educated, knowledgeable, empowered individual and would have no difficulty standing-up to your neurologist if you disagreed with her/him. Your position is not the default position, but the learnt position; and it is a privileged place to be.

      Yours sincerely

      Gavin Giovannoni

      Delete
    2. "Neuros must get tougher with their advice to patients. Patient choice is not the way to go if the choice they make results in a much worse outcome a decade later (and then keeps getting worse)."

      There are many theories about happiness, our purpose in life and our need to have control over our own lives and destinies, for better or for worse.

      I don't know what the world would look like if patient choice was regularly eroded by doctors in favour of potent meds. I do know that our world is not based on such an idea: and in order to receive Tysabri, Lemtrada and a host of other meds one has to sign a form acknowledging they consent despite the risks.

      I don't smoke but I support the right of all human beings to engage in activities they choose, even if those activities are harmful.

      Otherwise where do we draw the line? Anonymous, do you cross the street sometimes even though there is no crossing? Should you be allowed? Should we have police monitoring you to make sure you don't make choices which could harmful to you?

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    3. There should be a caveat to this... "... I support the right of all human beings to engage in activities they choose, even if those activities are harmful."
      Do those activities inpact others and in a positive or negative way? We live under a social contract and so those who do as they wish could also be seen as selfish in some circumstances . I guess taking (or not taking) DMTs may require some thought around ethis (maybe a back seat in the car, but still in the car). If we don't try and stop this what impact does it have on family, lived ones and society?

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  3. Another 'maintained' therapies also could reduce this 'sickness behavior' couldn't those? (nat & fingo)

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    1. Yes, we see pwMS on both fingolimnod and natalizumab coming back and saying I feel great, my brain fog has lifted and my energy levels are back.

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  4. Had PIRT
    Was told it could kill me by neuros and not to worry that it wouldn’t kill me by the haemo.
    Didn’t kill me.
    Feel great. 6 months after PIRT felt significantly better than immediately before PIRT, and that has maintained at 12 months post now. Climbed a volcano 5 months after PIRT. Spending Christmas skiing in the Swiss Alps.
    Have had no post PIRT complications so far.
    Had a horrible time on Tysabri, including infusion reactions and infections. Don’t hate Tysabri but wasn’t for me.

    Not hard to guess my stance on PIRTs.

    Had hell of a time getting neurologists to support my decisions. I'm sure my old main neuro thought me irrational.

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    1. Maybe MS is a disease of the blood that is manifest in the CNS and is better off treated by a haematologist with corresponding visits to a neuro? It seems the most effective treatments I.e. PIRTS and HSCT are best understood by haematologists. Nothing against neuros per se.

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  5. I'm finishing my studies at the hospital and I'm able to play rugby on a competitive level again, all 1 year post alemtuzumab, ya I'm a pro PIRTs, going for round 2 in a month time, hope to have a similar story to anon 9:24 in 9 years time.

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  6. Another post on induction...
    100,000+ patients are JCV- and good respondent to natalizumab.

    Shall they switch or not? (ceteris paribus or all other factors like lifestyle, family planning...)

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    1. In the context of 2 meds which have significantly different loaded risks and frequencies of administration, whose efficacy is difficult to compare side by side and which came on market at different periods of time, how could 'all other things' ever be equal?

      Delete

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