Wednesday, 29 October 2014

ClinicSpeak: macrophages infiltrates after alemtuzumab in a patient with NMO

What does the pathology of a case of NMO teach us about alemtuzumab? #MSResearch #MSBlog #ClinicSpeak

"The case report below is of a patient with anti-aquaporin-4 NMO who was treated with alemtuzumab. Unfortunately the patient died and at post-mortem the pathology showed extensive innate immune activation, i.e. extensive macrophage infiltration, with very little lymphocytes. It is clear this patient did not respond to alemtuzumab in that she had a recurrent attack and died from a large lesion and extensive lesion involving the brain stem and brain. The brain MRI lesions of this patient are very atypical for NMO and I wonder if she may have succumbed to another condition, for example progressive multifocal leukoencephalopathy or PML; the pathological description does not mention tests to exclude PML. Outside the context of MS alemtuzumab has been linked to PML, typically in patients with leukaemias and lymphomas. This poor woman had a very stormy course with multiple urinary tract infections, septicaemia, herpes zoster, a deep venous thrombosis in the leg, haematomas following plasma exchange, a broken femur after falling out of her wheelchair and an episode of Clostridium difficile colitis. She finally required a tube inserted for feeding directly into her stomach; i.e. a so called gastrostomy tube, before being discharged home."


"The interesting question is did alemtuzumab work in this patient and dos it work in NMO?  We have previously reported on the association between thyroid autoimmunity and the MS mimics, NMO (neuromyelitis optica) and TM (transverse myelitis), compared to MS in the past and I have speculated that alemtuzumab may not suitable for treating autoantibody mediated conditions such as NMO. This may relate to how alemtuzumab works and its complications; i.e. it may trigger and stimulate autoantibody production."

"Alemtuzumab's putative mode of action is via depleting your immune system and allowing it to recover spontaneously. Alemtuzumab kills or bursts open white blood cells, or leukocytes, by binding to a specific protein CD52 on the surface of the cell. When alemtuzumab binds to the cells it attracts a large number of other proteins, called complement, to the surface of the cells and these proteins pierce a hole in the cell causing it to burst. Complement is the family of proteins the immune system uses to kill damaged or cancerous cells and invading organisms. When the white cells burst they release their contents into the bloodstream; some of these substances are proteins that mediate the effects of inflammation on the body, which is why alemtuzumab causes an infusion reaction with a raised temperature, chills, rigors and a skin rash in most treated patients. To dampen down the infusion reactions we pretreat patients who are about to receive alemtuzumab with steroids, paracetamol and anti-histamines."

"Alemtuzumab is given as short courses on a yearly basis; daily for 5 days in the first year and then daily for 3 days in the second and subsequent years. Subsequent courses are only given if your MS has been shown to reactivate, i.e. you have relapses or develop new or enhancing lesions on MRI. The majority of MSers (two-thirds) only require 2 courses to go into long-term remission. A minority of MSers will require 3, 4 or very rarely 5 courses of alemtuzumab. Please note that reactivation of your MS after alemtuzumab does not mean that you have failed to respond to alemtuzumab it simply means you need another course, this is different to maintenance therapies (give continuously) were disease reactivation is an indication of non or suboptimal response."

"After each course the white cells recover by dividing or proliferating. When the immune system recovers there have been questions about whether or not it is competent to fight infections, cancers and whether or not it can remember the vaccines you have had in the past. A small study has shown that when the immune system recovers post-alemtuzumab it is competent and does remember the vaccinations you have had in the past. Another observation that tells us the immune system post-alemtuzumab is competent, or nearly competent, is the lack of so called opportunistic infections in alemtuzumab-treated MSers."

"There is one major caveat; when the white blood cell counts post-alemtuzumab are very low, or have not yet fully recovered MSers are at risk of herpes virus reactivation. Unfortunately, the lady below had herpes zoster. Once infected with herpes viruses they persist in the body in a dormant state and can reactivate when the immune system is stressed or compromised. To prevent this from occurring we prescribe prophylactic anti-viral drugs for about 6 weeks to prevent herpes virus reactivation. Despite doing this there is an approximately 1 in 50 chance of developing shingles after alemtuzumab treatment. In the clinical trials the majority of shingles cases were mild or moderate. It is also reassuring to know that shingles can be treated with anti-viral drugs."

"Whether or not MSers treated with alemtuzumab are at increased risk of developing secondary cancers is at present unknown. There have been too few MSers treated with alemtuzumab, and the ones who have been treated have been followed for too short a time, to answer this question. Therefore the increased cancer risk is a theoretical risk at present. In my opinion the cancer risk is low as we have not seen many of the so called indicator cancers, i.e. those cancers associated with drugs that target the immune system, in any of the MSers treated with alemtuzumab in the phase 3 trials. But on balance it is too early to make any judgement on this."

"The one risk from being treated with alemtuzumab is the development of secondary antibody-mediated autoimmune diseases that occur months to years after the last course of alemtuzumab. Autoimmune thyroid disease is the commonest disease and occurs in ~30% of treated MSers. The second most common is immune mediated thrombocytopenia, or ITP, that occurs in 2-3% of treated subjects. In ITP the immune system destroys the platelets or cells that help stop bleeding. A much more rare disease is so called Goodpasture's disease when the immune system makes antibodies that can damage the kidney. This last two diseases can be serious, but if detected early and treated most people make a good recovery. These autoimmune complications of alemtuzumab are why MSers who have been treated with the drug need to be monitored with monthly blood and urine tests for at least 4 years after the last course of treatment. Therefore if you are eligible for alemtuzumab and you want to be treated with this drug you are going to have to be adherent to the monitoring programme. If not and MSers die, or have near-death experiences, from these treatable complications the regulatory authorities may restrict alemtuzumab's use in the future. This would be unfair on those MSers who may wish to be treated with the drug in the future."

"The real advantage of alemtuzumab is the fact that it is an induction therapy; i.e. you get treated with the drug and you don't have to have it continuously. This has advantages for MSers who can't tolerate daily injection or oral therapies. Another advantage is the long-term remission that the majority of MSers go into after a two courses. Woman wanting to fall pregnant and start a family will find this attribute of the drug very appealing. What has been played down is that a large number of MSers who have disabilities find that they improve spontaneously after alemtuzumab. I don't think this is because alemtuzumab is a neurorestorative drug, but it simply reflects that when you suppress and stop inflammation in the brain and spinal cord you allow spontaneous recovery to occur. This is why I don't believe we need drugs to promote remyelination in MS; remyelination will occur spontaneously if we suppress inflammation with sufficiently effective therapies early in the disease course; a similar observation occurs with natalizumab or Tysabri. An important point regarding the spontaneous improvement post-alemtuzumab is the observation that it is more likely to occur early in the course of the disease, before the demyelinated axons die and there is sufficient reserve capacity to allow recovery. You can't remyelinate an axon that is not there; and this is why alemtuzumab has not be as effective in MSers in with secondary progressive MS."

Gelfand et al. Massive CNS monocytic infiltration at autopsy in an alemtuzumab-treated patient with NMO.Neurol Neuroimmunol Neuroinflamm. 2014 Oct 9;1(3):e34.

OBJECTIVES: To describe the clinical course and neuropathology at autopsy of a patient with neuromyelitis optica (NMO) treated with alemtuzumab.

RESULTS: A 61-year-old woman with aquaporin-4 immunoglobulin G antibody seropositive NMO had 10 clinical relapses in 4 years despite treatment with multiple immunosuppressive therapies. Alemtuzumab was administered and was redosed 15 months later. For the first 19 months after the initial alemtuzumab infusion, the patient did not experience discrete clinical relapses or have evidence of abnormally enhancing lesions on brain or spinal cord MRI. However, she experienced insidiously progressive nausea, vomiting, and vision loss, and her brain MRI revealed marked extension of cortical, subcortical, and brainstem T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities. She died 20 months after the initial alemtuzumab infusion. Acute, subacute, and chronic demyelinating lesions were found at autopsy. Many of the lesions showed marked macrophage infiltration with a paucity of lymphocytes.

CONCLUSIONS: Following alemtuzumab treatment, there appeared to be ongoing innate immune activation associated with tissue destruction that correlated with nonenhancing T2/FLAIR hyperintensities on MRI. We interpret the cessation of clinical relapses, absence of contrast-enhancing lesions, and scarcity of lymphocytes at autopsy to be indicative of suppression of adaptive immunity by alemtuzumab. This case illustrates that progressive worsening in NMO can occur as a consequence of tissue injury associated with monocytic infiltration. This observation may be relevant to multiple sclerosis (MS) as well as NMO and might explain why in previous studies of secondary progressive MS alemtuzumab did not seem to inhibit disability progression despite a dramatic decline in contrast-enhancing lesions.

CoI: multiple

18 comments:

  1. Sad to hear that you don't think remyelination therapies will be of much use. I've had a highly effective treatment and have some remaining deficits. I was hoping that a future remyelination therapy would provide some benefit to me.

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  2. Thank you for the comprehensive review of Alemtuzumab mechanism of action and sequela that may result. The etiology of infusion related reactions is enlightening. I think this post will be very helpful to MSers in the UK as they now have this treatment option.

    I think this clinical case is not helpful in evaluation of Alemtuzumab in MS. This poor woman obviously should not have npbeen given one dose of Alemtuzumab, much less two. Her urinary bacteria, let alone septicemia should have been contraindications to any immune therapy. Although all the case details are unknown, it should come as no surprise that someone with extreme infections who is then given altmetuzumab (malpractice based on these details) subsequently died.

    I think the case will scare more people than it informs.

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  3. “Doctors put drugs of which they know little, into bodies of which they know less, for diseases of which they know nothing at all.”

    ― Voltaire


    Cool quote, huh, Don Giovannoni? Methinks it may become a feature for future PowerPoint lectures of yours whereby you attempt to convince the converted into believing that massively toxic concoctions will alleviate their incurable diseases. It’s funny because the latest data published by the UK MS Register shows that its cohort of participants who were SPMS was at 9% at the start (three years ago) and is now at 28% in 2014. This suggests that MSers are still becoming progressive despite the avalanche of expensive neo-DMTs.

    It seems that MS is still a seriously bad disease. Your story of a young woman dying post- alemtuzumab treatment is scary and disturbing. One can’t help but think that alemtuzumab related mortalities will increase if my beloved NHS agrees to fund this infernal medication, which I still hope never happens. Alemtuzumab sounds like the equivalent of playing Russian roulette in a clinical setting. Any responsible health body ought to shun such a lethal proposition.

    Our modern culture of entitlement is harming everyone. We’re not thinking about the consequences of our choices, we just want instant gratification. Get smart, bredrins. You can’t cure a disease when no-one knows why it’s happening. Just deal with it and accept your destinies, however bad that seems. To absorb life’s body blows is to be truly alive, man.

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    1. Long time no hear Dre but still the same old material. It's getting a bit stale old son.
      The Voltaire quote is a good one but I suggest things have moved on a tad since the 18th century. He was a champion of the enlightenment and would probably not support your apparent nihilism.
      Anyway, welcome back.

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    2. Dre's Voltaire quote seems most pertinent. Modern medicine has been hopeless at curing diseases. At least in the eighteenth century pharmacological experimentation and progress was at its most best pace, whereas nowadays we're still using treatments invented fifty years ago to try and fix things. There's nothing brand new on the market.


      Welcome back, Dre. Don't leave it so long next time, mate.

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    3. But then, Voltaire never had HIV in the 21st century.

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    4. "Modern medicine has been hopeless at curing diseases."
      Really? Antibiotics, vaccination, vastly improved cancer outcomes. I could go on but what's the point?

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    5. "We’re not thinking about the consequences of our choices, we just want instant gratification."

      So true. The moment that statisticians were needed to decide if a drug is effective for a disease, the blinders went on about trying to figure out what is an appropriate treatment. At this point it is just throw everything at it and see how it fairs in a two year trial. Long term consequences be dammed.

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    6. MD2, all of your citations are ancient. Give me something new. Give me a 21st century product. Science has not cured anything since polio. It's shameful.

      Dr. Dre is the man! That is a wonderful quote.

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    7. Well if you believe science hasn't cured anything since polio, you're beyond help.
      It's an old quote that has little relevance today,I prefer his "There is no greater sorrow than to recall in misery the time when we were happy".
      Think on little acolyte.

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    8. Dre is like a bear, only he disappears during the summer only to wake up from his hibernation in winter.

      But MD2, won't you say that the situation is still pretty bleak? I think that Voltaire quote does hold great relevance today, and certainly in the case outlined in this post where a young woman died despite being given Alemtuzumab.

      I mean, look at the crisis we're having right now in medicine whereby antibiotics are losing their potency, diseases like Ebola are returning in pandemic proportions, and dementia looks set to seriously cripple our future wellbeing because we don't know what to do about it.

      I'm thankful that a voice like Dre's exists out there because he/ she almost echoes my shock and frustrations when you say that science is curing bad diseases. It's not, and I think that this is the big disconnect between you scientists working in labs and us sufferers living with awful ailments.

      Big Pharma is losing interest in diseases that require bespoke medication because that affects their bottom line and they just want to dish out outdated rubbish sat in their shelves. That is what repurposing is all about, MD2, is it not?

      Dre speaks for people like me. I honestly think that this rush to repurpose old stock rather than push for new medicines typifies the crisis of modern pharmacology. They are not interested in helping us, they just was dollars. They work to take care of shareholders, not people.

      Thank goodness for Dre. Stick with us, pal, and welcome back.

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    9. Is Dre a member of Team G by any chance? Is he a junior scientist at Barts who've you recruited to provoke debate? This guy is unreal and totally provocative for provocation's sake.

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    10. Where have you been Dre? We were worried but it only lasted 20 minutes.

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    11. Anon 6;02 (I wish you people would use a name/nickname)
      No, I wouldn't say the situation is bleak, it is hugely improved since i started researching in this field nearly 30 years ago and the pace of improvement is increasing.
      it's pretty clear this patient maybe shouldn't have been given alemtuzumab given her history of recurrent infections but it may have been a last throw of the dice for what was an extremely aggressive disease course. Hindsight is of course 20:20.
      Again you say science isn't curing bad diseases. Of course it is but there are some, like MS where we still have some way to go.
      Repurposing is not dishing out outdated rubbish, Thalidomide for example is now repurposed Thalidomide for a number of conditions including: erythema nodosum leprosum, multiple myeloma and a number of other cancers, for some symptoms of HIV/AIDS, Crohn's disease, sarcoidosis, graft-versus-host disease, rheumatoid arthritis and a number of skin conditions that have not responded to usual treatment and can be extremely effective.
      I like Dre and am certainly in the same camp politically but some of his "There's no hope, nothing works" schtick merely comes across as nihilistic and unhelpful but he certainly stimulates debate.
      There's nothing wrong with repurposing an old drug for a new condition if and only if it is shown to be very effective and comes with less risk of harmful side-effects. I would suggest that Cladribine for MS more than fits these criteria but we'll see. it would also be so cheap that everyone who wanted it could get it. A win win win in my opinion.

      Anon 6.15 pm Dre is certainly not a member of Team G or if he is he's in deep cover!

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    12. This might sum up Dre's philosophy? :-)
      https://www.youtube.com/watch?v=9foi342LXQE

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  4. Now I'm confused, Emma. Did she die from unmanageable infections or from lesions on the brainstem? Or do we know one caused the other? Anyway, I agree with you. This story frightens me. The only thing scarier to me than taking these highly effective treatments is not taking a highly effective treatment.

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    1. I couldn't agree more Anon 4.44. You're damned if you do and damned if you don't. Personally I'll probably take my chances with the treatment and hope for the best. Thanks for the information Prof G.

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    2. Anon 4:44, I think we, as MS patients, cannot compare our disease with this very sickly NMO patient. She did not have MS and was not otherwise healthy, as most of us MSers are.

      I think this previous post has much better information for MSers to compare and evaluate Alemtuzumab for themselves:
      http://multiple-sclerosis-research.blogspot.com/2014/05/alemtuzumab-long-term-follow-up-for-up.html

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