Tuesday, 28 November 2017

Alemtuzumab hair today gone tommorrow

NeuroDoc Gnanapavan I didn't sign-up for this!


 I want my hair back ;-(



Front Neurol. 2017 Oct 30;8:569. doi: 10.3389/fneur.2017.00569. eCollection 2017.

Alopecia Universalis following Alemtuzumab Treatment in Multiple Sclerosis: A Barely Recognized Manifestation of Secondary Autoimmunity-Report of a Case and Review of the Literature.

Zimmermann J, Buhl T, Müller M.

Secondary autoimmunity is the most frequent adverse event occurring in almost every other alemtuzumab-treated multiple sclerosis patient. We report a case of a patient with relapsing-remitting multiple sclerosis who reported smooth, circular areas of complete hair loss on both thighs 6 months after the second treatment cycle with alemtuzumab. The patient was diagnosed as having alopecia areata (AA). Within 3 months, AA progressed to complete loss of all body hair (alopecia universalis). Current literature rarely connects alemtuzumab with the onset of alopecia of autoimmune origin. Here, we report a little-noticed autoimmune disease affecting the skin, very likely being associated with alemtuzumab. We emphasize the necessity of careful clinical surveillance of alemtuzumab-treated patients for yet undescribed autoimmune diseases.

Alopecia areata

Alemtuzumab (aka Campath-1H) is arguably one of the biggest early success stories in MS, but as with every cloud that has a silver lining, every silver lining also has a cloud - namely the autoimmune side effects. In the horizon, ocrelizumab and cladrabine loom as omnipresent threats; which makes acceptance of this very unpalatable cloud by the MS community essential. 

We know that reason for the autoimmune disorders following alemtuzumab is a consequence of B-cell hyper-population in the relative absence of a T cell regulation during the period of immune reconstitution. The ability to predict who develops what, however, have been largely unsuccessful to date, and yet with increased exposure to the drug, the types of autoimmune disorders described is expanding.

So what autoimmune disorders have been linked to alemtuzumab?
  • Autoimmune thyroid disease = 30%
  • Immune thrombocytopenic purpura (low platelets) = 1-2%
  • Goodpasture's disease (kidney disease) = <1%
  • Guillain-Barre syndrome (described in the cancer label)
Around 47% exposed to alemtuzumab develop another autoimmune disorder other than their MS. Zimmerman et al. now report a case of alopecia (or hair loss), which may possibly be linked to alemtuzumab. They also point out the alopecia is not unique to alemtuzumab, and has also been reported with teriflunomide and mitoxantrone. In their case, even after cessation of treatment, there was no regrowth of hair at the 6-month follow up.

The EMA (European Medicines Agency) label does report alopecia under side effects of >0.5% in alemtuzumab 12mg treated subjects. Alopecia areata is thought to be T cell (CD8+NKG2D+) mediated damage of the hair follicles, although there may be some B cell involvement here too and has been linked to thyroid autoimmunity.

The authors' advice that those receiving alemtuzumab examine themselves on regular basis for any early signs of hair loss so that prompt steroid treatment can be started.

55 comments:

  1. This is a very worrying development. How many more secondary autoimmune diseases are there yet to emerge?

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    1. So far they have all been treatable. Autoimmune disorders vary from different backgrounds, for example SLE (Indian subcontinent), Behçet's disease (Turkish). As the utilisation of alemtuzumab increases in those areas you may see more cases of the prevalent to those areas...

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    2. Yet I have seen reports from the UK of Alemtuzamab being used FOR Behcet's Disease.
      Also, Behcet's is worldwide now... so much intermarriage, wars, disasporas...it is also heavily seen in Japan and surrounding areas.

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    3. Ok, but it may not exclude the development of the most prevalent AI disorder in a population if the person is susceptible to it...

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    4. Interestingly, my daughter was on Rituxan (not Lemtrada) for her pediatric onset of MS, with marvelous results. At least for the MS.
      Two years into it, Behcet's emerged and reared it's very ugly head. Her case was even reviewed with doctors in Turkey, who confirmed this was NOT neuro-Behcet's, but MS and Behcet's separately.
      In fact, she passed away recently, only 1.5 years into the course of her BD, (total necrosis of uterus, with a what is presumed to be an extreme pathergy reaction days after surgery).
      Pathology showed her MS was totally not active, and there was no signs of BD in her brain, either.

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    5. Penina, I am very sorry for your loss. My condolences.

      There are two cases of Rituxan induced Crohns after lymphoma.
      https://www.ncbi.nlm.nih.gov/pubmed/28129697

      NDG Could there be a relation to RTX and autoimmunity too?

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  2. "with increased exposure to the drug, the types of autoimmune disorders described is expanding".

    When are people going to learn that DMDs are far worse than hsct in terms of long term (unpredictable) side effects.

    Dmd's are like the worst of both worlds. Long term suppression, but without the benefits of that surpression.

    The longer dmd's are out there, the worse than efficacy rates and the greater increase in reported side effects.

    Until just another pointless DMD rolls around.

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    1. "Dmd's are like the worst of both worlds. Long term suppression, but without the benefits of that surpression."
      What? You have evidence of NO benefit OF DMDs?

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    2. your credentials against theirs. Would you post your CV?

      http://www.msbrainhealth.org/long-term-management/article/stick-with-treatment-but-ask-about-switching-if-its-not-working-for-you

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    3. Depends what DMD is used as you're no doubt aware we're big fans of cladribine here. What is clear is there is a big problem with the development of secondary autoimmunity with Alemtuzumab, most treatable and some, though more rare are more serious.
      HSCT, though showing promise for some is not the sole answer.
      Baby, bathwater etc.

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    4. Yes, alemtuzumab has been combined with induction regimens in HSCT as part of the conditioning. Cyclophosphamide is the other alternative, which also has issues.

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    5. "HSCT, though showing promise for some"

      Lol. Some? This blog is getting further detached from what really benefits pwMS.

      It will only be so long before the numbers speak for themselves (they should already).

      Even DMD based studies support HSCT approach, even the science.

      In not so long, the views expressed in this blog and the medicine pushed, will be shameful.

      The disregard for pwMS. The blind dogmatism funding low efficacy poisonous drugs, it actually is nasty.

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    6. HSCt is not immune from these secondary autoimmunity and occurs in people not conditioned by alemtuzumab.lol

      Evangelists of all forms are tedious.

      HSCT is an extreme variant of a DMD

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    7. I agree. But its this very 'extreme' that is required to beat MS. Stop seeing the extreme as 'extreme'. Start seeing it as the very measure, the exact opponent to beat MS.

      MS is extreme. The cracking a nut with a sledgehammer, reversing the pyramid... Whatever you want to call it.

      It is precisely that, that is required. It's that approach that knocks MS into dormancy.

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    8. lol keep arguing and calling each other names, eventually time will tell.

      the only reason my partner made the choice for hsct is because it seemed a better/more comfortable risk profile than lemtrada: efficacy did not come into the debate too much.

      she went from a very unfavourable progressive ms diagnosis nothing is going to help, to here have the best drug available now because we think it's rrms and aggressive.

      we just figured, her being relatively young and otherwise healthy, if ever hsct was going to be part of the equation it would be now not later. if she has to risk the autoimmunity levels associated with lemtrada (as opposed to non myelo hsct without lemtrada) then she as well have lemtrada later if she needs to (or something better if it comes along) and at least hedge her bets that way.

      with the advent of indefinitive ocrelizumab for now and maybe we'll figure out inductive regimes later, a history of aggressive breast cancer at young age stats wise, she is still appreciating her choice.

      she was offered and accepted a one off rituximab infusion roughly based on her weight with ms practices in mind, with the view of extending any possible hsct benefit by re-killing those memory b cells which may be emerging with ms if they haven't been killed off already.

      i want to say she is part of an experiment 15 years in making (regardless whether her choices are regarded as brave or foolish) - but the truth is no one is registering her progress for those purposes lol.

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    9. This is where registries are important eg msbase ms register if people chose such treatments it is important that the benefit or not is documented.

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  3. Need to put all these risks into perspective. 11 years since my first of two Alemtuzumab rounds - no relapses, no MRI activity and stable EDSS. I had agressive RRMS with very disabling relapses. I did get the thyroid side efect and now take one small tablet a day. The side effects can lok worrying but are way better than the humiliation of ocupational health fitting a support around my toilet or m kids seeing me using a zimmer frame around the house after a bad relapse. Baldness did Yul Brynner no harm, but MS killed Jacqueline du Pru. This site keeps posting stuff on the side effects of Alemtuzumab without presenting the benefits - it's beginning to look like a sales plug for Cladribine! Prof G and NDG must be treating patients with Alemtuzumab - what are their views on it's effectiveness (as unbiased professionals rather that Clabriibine pushers)?

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    1. Alemtuzumab is a highly efficacious drug in the treatment of MS with good NEDA and brain atrophy outcomes. With such induction treatments the risk of SE is front loaded with better safety profile after this, as opposed to long term immunosuppression with the maintenance drugs.

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  4. If barts hypothesis is correct that caldribine and ocrelizumab is as effective as alemtuzumab and the brain atrophy difference is due to different patient selection hmmmm. Then alemtuzumab is on its way out. I suspect caldribine will become first choice treatment for all.

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  5. Can short course of tecfidera at 6 months after 1st infusion of Alemtuzumab stunt the b cell population enough on rebound to prevent 2nd autoimmunity?

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    1. Short course of Rituximab might do the trick.

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    2. Yes. I am aware of ritximab. There's no way a neurologist in UK will give me a prescription for it on basis of a unproven theory. Even if the science behind it is solid. So in absence is there anything patients can do to reduce their risk of 2nd autoimmunity?

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    3. If going in with DMF afterwards you need to consider the prolonged lymphopenia. You need to pick an agent which is immunomodulatory but not immunosuppressive. Lymphodepletion with DMF may take an year to recover!

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    4. You mean something like aubagio? I remember reading about a off label version on this blog. Ok got it.

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    5. Aubagio might be of potential use here.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656406/

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    6. I am on Tysabri and already bold (like many men). I shave my head to hide it.

      Shall I switch to Campath in the hope of loosing all my hair and stop wasting my time shaving head and beard daily?

      Delete
  6. A little off topic, but since ocrelizumab was mentioned…

    Any insights/comments on the rumored deaths attributed to ocrelizumab due to opportunistic infections and infusion reactions? Apparently, Roche/Genentech have launched a review. If true, these "events" could be a harbinger of very bad things to come regarding Ocrevus… Frankly, this drug makes me very nervous.

    http://www.biopharminsight.com/roche-initiates-ocrevus-review-after-multiple-reported-patient-deaths-multiple-sclerosis-leave-usage

    In regards to HSCT, aren't the risks of secondary autoimmunity quite high, almost as great as with Alemtuzumab? It sure would be nice if some late stage HSCT trials would get going, lots of questions need to be answered, and the amount of anecdotal evidence out there is creating a tidal wave. I personally think HSCT will be considered a front-line treatment in the future, but without the proper trials it will take a long time to get there.

    Must the drug companies dictate the entire medical landscape these days? The medical journals rely on pharmaceutical company money, the studies printed in those journals are largely conducted by researchers paid by the pharmaceutical company whose drug they are testing, and the physicians prescribing the medications studied are on the pharmaceutical company dole as well. Seems like a tremendous ball of conflict of interest…

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    1. Based on the FDA side effects dashboard in 2017 there were 6 deaths in the infections and infestations and they will be investigated. But to put into perspective there are more in the adverse reporting data base for other MS drugs.

      Secondary autoimmunity after HSCT occurs I dont thin it is quite as high as with alemtuzumab.

      Must the drug companies doinate...at present they do but once patents have gone there is less enthusiasm.

      Conflicts of interest have to be declared

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    2. Adding to MDs comment, there needs to proper confirmation of these figures. All immunosuppressants report infections etc, but it will take time before a pattern emerges. My concern stands the cancer risk. And maybe those with family history of breast cancer should abstain or have regular check ups.

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    3. Thanks for the responses, doctors.

      Are the rumored deaths included in the FDA database? My understanding was that they were still under investigation, so had not yet been reported. Of course, my understanding could be wrong. Also, while other meds may have more deaths, Ocrevus has only been in use for part of the year… I agree with NDG about the cancer risk. Fearful what we might see in a year or two…

      It would be interesting to study secondary autoimmunity's in HSCT, or at least see some kind of retrospective look. I don't think I've run across anything like this.

      Seems that the drug companies have almost total control over the MS universe, from the journals to the studies to the treating physicians to the conferences. One MS neurologist friend of mine refers to conferences like ECTRIMS and the ANA meetings as "pharmaceutical company carnivals". This, of course, is why efforts like your "Big Pharma Alternative" are so important. But there are far too few…

      Regarding conflicts of interest, physicians receiving monies from the pharmaceutical companies for any purpose other than pure research (in other words, specious speaking and consulting fees, which in effect turn them into paid spokespeople) should be forced by law to wear patches with the logos of the companies they receive money from on their white coats. Kind of like NASCAR and Formula One drivers.

      Of course, here in the states a patient can look up their own or any other physician on the Dollars for Docs website to find out how much pharmaceutical money they are pocketing. Not true for other countries, I think. And the Dollars for Docs website will probably be targeted for shutdown by the Trump administration any day now…

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    4. DrK found an interesting paper about B cells and breast cancer
      but it is complex are B cells the bad guys or the good guys

      https://www.ncbi.nlm.nih.gov/pubmed/28429331

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    5. NDG, I am curious if is this a knee jerk reaction or did you rationally think about it? Here is an earlier blog post on this topic -

      http://multiple-sclerosis-research.blogspot.com/2017/07/teachspeak-reverse-causation.html?m=1

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    6. You may find the post I did on B cells and breast cancer from July of interest:

      http://multiple-sclerosis-research.blogspot.com/2017/07/researchspeak-b-cells-and-breast-cancer.html

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    7. Thank you for your reply. I have read both the posts several times during the last few months. I am curious about the rationale behind the comment "My concern stands the cancer risk. And maybe those with family history of breast cancer should abstain or have regular check ups". Women with family history of breast cancer should get regular check ups regardless. But why are you recommending these women to abstain from ocrevus?

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    8. "DrK found an interesting paper about B cells and breast cancer
      but it is complex are B cells the bad guys or the good guys

      https://www.ncbi.nlm.nih.gov/pubmed/28429331"

      Does this mean that RTX is also dangerous for b.c.? There must be a lot of data about RTX, as an older drug, but I guess that we would know by now if it was a red flug for b.c., wouldn't we? Does this come down again to potency?

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    9. I haven't researched this but potencyay be an issue

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    10. "personally think HSCT will be considered a front-line treatment in the future"

      ... absolutely. Just as chemotherapy is used for cancer. Hsct will be first port of call for autoimmune issues.

      Hsct isn't new. It's been used for decades, very safely.

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    11. A frontline.....

      I think you will need to wait for a generation of neuroscience to retire.

      Many neuros are reluctant to escalate past the CRAB drugs so to think they will take the HSCt option from onset...think again.

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    12. Neuroscience = neuros. Predictive text :-(

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    13. Sure, if neuroscience (and this blog too) considers becoming bedridden a "nut" it would consider HSCT a sledgehummer and would not recommend it, even if they have no other suggestion for PMS. La, la, la...

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    14. You are so wrong about what we will and will not consider but we do ask what is the evidence base, is it good enough does more need to be done about it, can we do something about it.

      However also remember there are only so many hours in a day

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    15. And personally, I wouldn't like it if HSCT -as it is-, is the future first-line. It needs to be today a first-line, as it is the most effective solution we have, yet a desperate one. Hopefully in the future, with the safer immune-depleting drugs that are being made for cancer, it could be a very good therapy, if our knowledge of autoimmunity (and pharma will unfortunately) will not bring better ideas...

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    16. BearMS. Post sounds too much like an advert.sorry.

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  7. Started to loss head hair the year I had alemz. But not in pattern depicted above, more like like typical male-type baldness and this was reversible by use of minoxidil.
    Coincidence?

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    Replies
    1. Male pattern hair loss unlike alopecia areata or universalis is hormonal rather than autoimmune. It's more likely drugs that affect rapidly dividing cells may lead to more hair thinning but overall if genetically you're supposed to loose your hair the final result may not change unless you intervene.

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  8. So here the next unusual autoimmune disease for alemtuzumab

    The pwMS first got Graves after first infusion and anti-factor VIII on second infusion and so developed haemophilia.

    Acquired haemophilia A complicating alemtuzumab therapy for multiple sclerosis. McCaughan G, Massey J, Sutton I, Curnow J.
    BMJ Case Rep. 2017 Dec 5;2017.

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    Replies
    1. This is encouraging... ehm... I have developed Graves with blocking antibodies (so I am hypothyroid now) + severe hair loss after the first round of alemtuzumab. Shall I give the second round a miss? maybe enough is enough.

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  9. So here the next unusual autoimmune disease for alemtuzumab

    The pwMS first got Graves after first infusion and anti-factor VIII on second infusion and so developed haemophilia as factor VIII is a blood clotting factor.

    Acquired haemophilia A complicating alemtuzumab therapy for multiple sclerosis. McCaughan G, Massey J, Sutton I, Curnow J.
    BMJ Case Rep. 2017 Dec 5;2017.

    This person developed spontaneous intramuscular and subcutaneous haemorrhage

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  10. Could this AA have happened due to EBV reactivation after Alem.? EBV reactivates after HSCT too.

    https://www.ncbi.nlm.nih.gov/pubmed/18329131

    https://www.medicoebambino.com/?id=CL9908_10.html

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    Replies
    1. Nice bit of detective work

      If there is EBV in the system maybe the memory B cells would expand following infection of mature B cells, which I think would be possible

      Delete

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