Wednesday, 17 October 2012

Autoimmune hepatitis, daclizumab and MS

In response to several posts concerning the press release about autoimmune hepatitis as a complication of daclizumab treatment: Med Page Today 

"We must be careful not to throw the baby out with the bathwater. All DMTs have tolerance and safety issues. I agree serious or life threatening adverse events are worrying but we need to know how common they are, if they are predictable, can they be detected early and are they treatable. This knowledge then needs to balanced against how effective the drug is controlling MS disease activity. For Daclizumab we don't have this information; this is why there is a large ongoing phase 3 trial running. Another issue is ascribing a serious adverse event to a drug when it could have occurred by chance or is associated with MS rather than the drug treatment. Autoimmune hepatitis is just such an adverse event. I have personally seen two cases that occurred in MSers on interferon beta. In both cases they were considered by the hepatologist to be unrelated to the treatment. If you delve into the literature you will see that glatiramer acetate, interferon beta, steroids and natalizumab have all been associated with autoimmune hepatitis. In fact, MS itself seems to be associated with the disease."

"One swallow doesn't make a summer!"

"Daclizumab looks very promising ; it has a significant impact on disease progression, which is out of proportion to its apparent effect on relapse reduction. The drug boosts natural killer cells or NK cells, which are the cells that are know to fight viral infections. Could Daclizumab be the elusive anti-viral agent we are looking for? If yes, we need to be careful about prejudging something without all the information at hand." 

"We have just completed a meta-analysis, which we are about to submit to a journal, that shows MSers, and their first-degree, relatives are at increased risk of developing autoimmune thyroiditis and ulcerative colitis. It seems as if autoimmunity is a state that may be related to MS. Therefore these events could still have occurred by chance."

"I am still raw by the failure of cladribine. Cladribine is a very, very, effective drug that has failed due to a perceived excess risk of secondary malignancies and persistent lymphopaenia. The regulators wanted data that another phase 3 trial would be unlikely to deliver, i.e. long-term safety. I am hoping someone will resuscitate the cladribine programme; MSers deserve it."

"What the 'natalizumab and PML', and 'alemtuzumab and ITP (immune thrombocytopaenia)' stories have taught me is that MSers are comfortable with known risks. Knowledge is power is allows you to make informed decisions about the future. Please don't judge a promising emerging therapy on hearsay and a single journalists opinion. We need to give daclizumab, and all other emerging DMTs, a chance. Each trial is an experiment and until the experiment is over we need to reserve judgement. While  the trial or experiment is running the Data and Safety Monitoring Committee are responsible for making sure MSers in the trial are safe and that the benefits of continuing the trial outweigh the risks. This happens to be the case for daclizumab."

"Please note I have conflicts of interests."


References of interest

Subramaniam et al. Glatiramer acetate induced hepatotoxicity. Curr Drug Saf. 2012 Apr;7(2):186-8.

Arruti et al. Autoimmune hepatitis in a patient with multiple sclerosis under treatment with glatiramer acetate. Rev Neurol. 2012 Aug 1;55(3):190-2.

Deltenre et al. Acute hepatitis induced by glatiramer acetate. BMJ Case Rep. 2009;2009.

Neumann et al. Glatiramer acetate induced acute exacerbation of autoimmune hepatitis in a patient with multiple sclerosis. J Neurol. 2007 Jun;254(6):816-7.

Ramos-Casals et al. Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev. 2010 Jan;9(3):188-93.

Burdick et al. Type I IFNs and their role in the development of autoimmune diseases. Expert Opin Drug Saf. 2009 Jul;8(4):459-72.

Takahashi et al. Development of autoimmune hepatitis type 1 after pulsed methylprednisolone therapy for multiple sclerosis: a case report. World J Gastroenterol. 2008 Sep 21;14(35):5474-7.
von Kalckreuth et al. Unmasking autoimmune hepatitis under immunomodulatory treatment of multiple sclerosis--not only beta interferon. Am J Gastroenterol. 2008 Aug;103(8):2147-8;

Ferrò et al. A case of multiple sclerosis with atypical onset associated with autoimmune hepatitis and silent coeliac disease. Neurol Sci. 2008 Feb;29(1):29-31.

Pulicken et al. Unmasking of autoimmune hepatitis in a patient with MS following interferon beta therapy. Neurology. 2006 Jun 27;66(12):1954-5.

de Seze et al. Autoimmune hepatitis and multiple sclerosis: a coincidental association? Mult Scler. 2005 Dec;11(6):691-3.

Martínez-Lapiscina et al. Natalizumab-induced autoimmune hepatitis in a patient with multiple sclerosis. Mult Scler 1352458512463485, first published on October 15, 2012 as doi:10.1177/1352458512463485

Etc......

CoI: Multiple, I sit on the steering committee for the Select and Selection Daclizumab trials and the Royal London Hospital is participating in the phase 3 trial.

18 comments:

  1. Couldn't agree more with the above.

    My only concern if the safety profile IS risky is, on the face of it, this looks less effective than Alemtuzumab but with potentially even more dangerous side-effects. I hope that doesn't prove to be the case and that the phase III studies are successful.

    Equally, re: Cladribine - is there nothing that we/you can do to try and find a way to move that on? It's a shambles that such an effective potential therapy, that would be cheap, is just sat and not being developed (dare I say, whilst millions is being spent on CCSVI?!).

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  2. Agree with your point about 'known risks' but the two patient stories in response to the Oct 2011 post were very scary.
    Based on current state of MS, if the chance of reactions like that turns out to be (suppose) 1-in-100, then I'll say no to daclizumab. But if progression speeded up I'll agree to anything that stops it

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  3. All DMTs are poison. They do much more harm than good. More money should be spent on holistic management of disease activity. You may say that there's no proof that will stop progression, but there's no proof that DMTs do that either.

    MSers are just desperate to take something rather than nothing.

    Is this blog in any way part-funded by Big Pharma?

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  4. Anonymous 11.45.
    You are quite wrong about DMTs having no effect on progression. I agree that holistic management of MS is important but it will be an adjunct with effective therapy.

    "The key disability data that was presented at the American Academy Of Neurology's 64th Annual Meeting included that the average EDSS score for patients in the alemtuzumab group decreased over a period of 2 years to 0.17, suggesting an improvement in physical disability, whilst that of the Rebif group increased to 0.24, suggesting that their disability got worse. (p < 0.0001).

    29% of patients in the alemtuzumab group experienced a six-month sustained reduction in disability in comparison, with just 13% in the Rebif group (p=0.0002) at 2-years. Over a 2-year study period, EDSS measured that those in the alemtuzumab group had a 42% reduction in the risk of six-month sustained accumulation (worsening) of disability (SAD) as compared with Rebif (p=0.0084), which represents a highly important statistical outcome for this co-primary endpoint."

    This is 2 year data, it will be interesting to see whether this is maintained or increases over a longer time-frame.

    This blog is entirely free of any funding from Big Pharma.

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  5. Today
    Natalizumab-induced autoimmune hepatitis in a patient with multiple sclerosis
    Mult Scler. 2012 Oct 15. [Epub ahead of print]

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  6. Checkout the blog there is 5 year data for alemtuzumab

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    1. Quite right MD.

      http://multiple-sclerosis-research.blogspot.co.uk/2012/03/alemtuzumab-5-year-follow-up.html

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  7. The so-called impressive data provided for alemtuzumab is slight to say the least. Any moderate improvements was only in less than half of patients. That's pathetic.

    A drug like alemtuzumab delivers a serious body blow to the human body, and to only benefit a tiny amount is terrible. It's almost irresponssible for a clinician to prescribe it. In a choice between alemtuzumab and CCSVI, I know which one I'd choose: Neither.

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  8. It seems there's varios sub-cultures emerging on yhis blog: Those that belive in CCSVI, others that support DMTs and a vocal minority that has no time for any of it - rather choosing a purer, holistic, hippie approach to dealing with MS.

    All of them are pretty extremist groups in terms of their ideology. We need a more balanced fourth group.

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    1. The content of the BLOG is dictated by current research, there is not much of the fluffy stuff because no-one really supports that type of research. The DMT is the current trend in a few years it will be more and more progressive stuff and move forward again and it will be more and more repair stuff.

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  9. You forgot the Progressive MSers, we should not forget them

    I think the CCSVIers are probably also a vocal minority, based on the result so far on the poll on CCSVI. Otherwise they are too busy commenting to vote perhaps:-)

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  10. I think that those that are strong belivers in CCSVI got the wrong end of the stick if they think this i a blog for them and I do not quite get your point regarding DMT. Because that`s what this blog is all about for me.Seroius research regarding what`s causing MS, and different therapies. Education about different aspects of MS and scientific stuff that I as a layman have difficulties in understanding.
    So if you you think this is a battleground I`m not with you... For me this blog has served as a beacon. a light int the dark. Where I live you don`t often get to meet your neuro and as I Iive in a small community my neuro isn`t even a specialist in MS.
    I`m very grestful to those like Prof G and all the MDs that give some much of their time to this blog. It`s very frustrating to have MS but it doesn`t get better by bashing those trying their best to help us.
    //Swedish Sara

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  11. You’re raw about the discontinuation of Cladribine? I am livid! I was one of 150 people here in Australia prescribed Cladribine as part of Merck’s Product Familiarisation Program and had just completed the second of the first ear’s doses when Merck pulled the drug from the market here. I was left high and dry half way through my treatment program.

    Cladribine is the only DMD I have been able to take successfully as I had severe allergic reactions to the Interferons with hives and airway swelling and after a year on Copaxone with ever increasing sizes of welts I ended up with hives and airway swelling again. I can’t take Gilenya due to idiopathic bradychardia and I don’t meet the MRI protocol required for Tysabri here in Australia.

    I had been having back to back relapses prior to starting Cladribine and in the year following the initial dose I was relapse free and am only now dealing with my first relapse15 months after stopping it. It makes me wonder how well I may have remained had I been able to complete the full course. I had no side effects with Cladribine apart from some very, very mild nausea in the first 24 hours of starting it and the lymphopenia settled back to within normal levels very quickly. I loved that DMD.

    I will be in the first cohort of patients to take BG-12 as soon as it is approved by the Therapeutic Goods Administration here and I can’t wait.

    The meta-analysis you have undertaken into other autoimmune diseases is really interesting. This is anecdotal only but for what it is worth I was diagnosed with IgA nephropathy15 years before I was diagnosed with MS. I have always thought it was just rotten luck to have two autoimmune diseases, that or I am greedy ☺ but it seems there may be a link after all. I hope your paper gets published, I want to read it.

    Cheers and thanks for the blog, love reading it,

    Belinda




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    1. Belinda, You should ask your neurologists to treat you off-license with the oncology preparation. In Sweden they give this orally; this is despite it being a liquid made for injection.

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  12. That is a great idea :) The only problem with that would be the cost. I was getting Cladribine for free under Merck's Product Familiarisation Program. The cost of chemo without subsidy would be prohibitive I'm afraid.

    But thanks for the suggestion.

    B

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    1. Cost of 10mg on British National Formulary is £165

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  13. In Australia it would cost me $1321.56 but I wouldn't be able to get it anyway irrespective of the fact I can't afford it as it is an Authority only prescription which means the Dr has to ring Canberra for permission and it will only be prescribed for Hairy Cell Leukaemia. No mechanism with this drug for off-label prescribing. But thanks for your idea. It was worth chasing up.

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