Sunday, 27 March 2016

ClinicSpeak: frontloading risk; not one but two autoimmune diseases

Are you prepared to trade-in MS for one, or maybe two, other autoimmune diseases? #ClinicSpeak #MSBlog #MSResearch

"Are you prepared to trade in your MS, on the promise of long-term remission, for a second autoimmune disease? If not alemtuzumab is not for you. The two case reports below are of two MSers who developed both autoimmune thrombocytopenia and autoimmune thyroid disease after their first course of alemtuzumab. Interestingly, both these MSers had previously been treated with fingolimod with marked lymphopaenia. Is it possible previous fingolimod treatment predisposes you to secondary autoimmunity? We will learn very quickly as many MSers in our centre are transitioning from natalizumab to alemtuzumab via a fingolimod bridge."

"Please note that one of the selling points for alemtuzumab is pregnancy, i.e. you can fall pregnant ~4 months after having a course of treatment with no drug on board. However, if you develop autoimmunity whilst pregnant the auto-antibodies can cross the placenta and affect the unborn foetus. For thyroid disease this may not be such a big problem (transient neonatal hyperthyroidism), but this may be much more serious for autoimmune thrombocytopenia and kidney disease. Please note that the secondary autoimmune complications of alemtuzumab treatment are frontloaded; if you get through 5 years (4 years post last course) you are likely not to get the secondary autoimmune complications. However, the 4 year rule does not answer the other major outstanding question of delayed secondary malignancies post-alemtuzumab. The latter  question will only be answered after thousands of treated MSer go beyond 10, or even 20, years of follow-up; the same timeframe we require to see if the long-term remission becomes a cure in a proportion of MSers."

Frontloading Risk!

Obermann et al. Simultaneous early-onset immune thrombocytopenia and autoimmune thyroid disease following alemtuzumab treatment in relapsing-remitting multiple sclerosis. Mult Scler. 2016 Mar 15. pii: 1352458516638558.

OBJECTIVE: We report two cases of patients with relapsing-remitting multiple sclerosis with early-onset thrombocytopenia and autoimmune thyroid disease after the first treatment course with 60-mg alemtuzumab.

METHODS: Case series and review of the literature.

RESULTS: Both patients showed severe thrombocytopenia with platelet counts of 2 × 109 and 11 × 109/L, respectively, as well as increased thyroid antibodies within only a few months after initiating alemtuzumab treatment (11 and 9 months). Both patients responded considerably well to medical therapy including corticosteroids and intravenous immunoglobulins with slow platelet recovery over several weeks. Interestingly, both patients were previously treated with fingolimod and showed a marked lymphocytopenia that led to discontinuation.

CONCLUSION: These cases emphasize the necessity of careful clinical surveillance and proper education of patients treated with alemtuzumab as proposed by the safety-monitoring program. Previous severe lymphocytopenia under therapy with other disease-modifying therapies may be a risk factor for the development of immune thrombocytopenia.

CoI: multiple

19 comments:

  1. The simple answer is yes. My thyroid has not been stable since starting lemtrada. Does it worry me? No where near as much as MS. I'd happily lose a limb if I thought it would halt MS. Of course I wish there were safer treatments available but there isn't and that's life.

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  2. Prof G, the trouble with these case reports is that they do not give a sense of the number / proportion of MSers who have had alemtuzumab who are doing well. These researchers trawl through all the cases to find the extreme examples of those who developed other autoimmune diseases and /or side effects. 11 years from my first infusion and I am doing extremely well (long term remission). I am in contact with half a dozen others in a similar position (some of us developed thyroid issues, but these are well managed). Where are our statistics to balance out these case reports? There's a good news story here which isn't being reported. Scary stories such as these will put some people off which means they ate unlikely to see the benefits which the majority do see. From all your RRMS patients who have opted for alemtuzuamb, are you able to give a broad brush assessment of how they ate doing? From a clinicians perspective are the risks worth it given the benefits seen by many?

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    Replies
    1. I agree, very good comment!

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    2. Re: "Where are our statistics to balance out these case reports?"

      http://multiple-sclerosis-research.blogspot.com/2014/05/alemtuzumab-long-term-follow-up-for-up.html

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  3. To prove your cure theory. Why not review some of the earliest treated Alemtuzumab trial patients and see if
    A) they have no clinical or sub clinical activity
    B) they haven't progressed to progressive disease
    If the earliest patients haven't been followed up then surely a quick email or phone call would give you a basis for your theory.
    You have also mentioned that c. 10% of your patients get Alemtuzumab, if our believed it was a cure that seems like a low number.
    Another thing is that prof Coles specifically doesn't call Alemtuzumab a cure, (seen on at least 2 interviews) yet you often refer to that being a possibility. Can you explain why you think that? Based on clinical observance or just a theory?
    This blog is a great source of information, but sometimes it feels when patients challenge your theories they can be dismissed with sarcasm or you feel 'patients just don't understand'
    Now I know you are all incredibly busy which is why all comments don't get responded to, but when you mention cure you have to remember the desperate MS'ers out there looking for that. So giving more basis to your theory would be a good thing rather than dangling a carrot.

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    Replies
    1. Also, does Alemtuzumab get rid of oligoclonal bands in the csf?

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    2. http://www.academia.edu/2393374/Long_term_lymphocyte_reconstitution_after_alemtuzumab_treatment_of_multiple_sclerosis
      To answer my question. alemtuzumab does not alter OCB in CSF.

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    3. Dr Coles is my neuro (excellent guy). He told me that some patients (c50%) had to be retreated, so it's not a cure in the sense that the disease is gone forever. I'm 10 years out with no retreatment and disease in long term remission / stable - I'm more that happy.

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    4. Re: "Defining a cure...."

      Yes, I talk about the potential of a cure. I don't make the claim that treatment X or Y is a cure. If we don't define what a cure looks like we won't find it. Please read these older posts on the topic.

      http://multiple-sclerosis-research.blogspot.com/2013/02/neda-defining-cure.html

      http://multiple-sclerosis-research.blogspot.com/2015/12/researchspeak-brainhealth-deep.html

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    5. Re: "To prove your cure theory. Why not review some of the earliest treated Alemtuzumab trial patients and see if
      A) they have no clinical or sub clinical activity
      B) they haven't progressed to progressive disease."

      http://multiple-sclerosis-research.blogspot.com/2014/05/alemtuzumab-long-term-follow-up-for-up.html

      http://multiple-sclerosis-research.blogspot.com/2015/12/researchspeak-brainhealth-deep.html

      Delete
  4. Prof G,
    What are the theoretical chances of secondary malignancies post Alemtuzumab, particularly in the younger population receiving this treatment?
    Thank you

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    Replies
    1. In the Welsh SE England follow-up there were 10% but as you indicate these are a product of age too.

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    2. Re: "Secondary malignancies..."

      All immunosuppressive drugs increase your risk of secondary malignancy. The greater the immunosuppression the higher the risk. Alemtuzumab is not that immunosuppressive long-term, however, it is still associated with long-term lymphopenia that varies from individual-to-individual hence the risks may vary. I don't think I should guess at this stage, but something in the order of a 50% increase would not surprise me. This is what I tell my patients.

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    3. Prof G,

      If patients have taken Alemtuzumab early with a low lesion load and no disability, remain stable but after many years still transition to SPMS... Do they not fair better considering they enter this phase with minimal damage & no disability?

      And if the theory that existing sites of damage provide the location for neurodegeneration later, could the patient expect to not experience debilitating symptoms if their initial symptoms were minor & sensory?

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  5. I think this raises a larger issue for all of the DMTs: we need to carefully document what therapies patients have been on and for how long along with lots of screening of blood counts, antibodies and anything else the doctors can think of to give a better picture and understanding of how these DMTs are changing and effecting the immune system.

    This is the exact issue I have raised numerous times. I have been on Tysabri for over 10 years and responded well. I am now JC+ and have been put on extending dosing. Changing to Fingolimod or and anti-CD20 therapy is so scary I just keep hoping my MRI stay stable.

    I look forward to learning more from your group as your patients transition.

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  6. The 12 year follow-up reported 5% to fulfill SPMS, some other cohord studies relate disease timevto SPMS with % reaching EDDS 6-7. From 1 report I can assume alemtuzumab is slowing or preventing conversion to progressive MS, and reaching progressive the older, the better

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  7. I think if we knew for certain that there's a chance to be cured and stopping ms in its tracks most of us will give it a try

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    Replies
    1. However the reality is you don't........ or you don't get given the option to try. If it was certain that it is a cure then there would be no chance in it.

      However, without pineers one will never know.

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