Monday, 8 May 2017

#ClinicSpeak & #ResearchSpeak: Graves' eye disease in alemtuzumabers

Did you know that alemtuzumab can rarely affect your looks? #ClinicSpeak #ResearchSpeak #MSBlog

There are two core messages in this post today. 

  1. All alemtuzumabers (people who are treated with alemtuzumab) should know about Graves' eye disease 
  2. The unpacking of biology continues at a rapid pace with a new treatment for Graves' eye disease
Graves' ophthalmopathy, also known as thyroid eye disease (TED), dysthyroid/thyroid-associated orbitopathy (TAO) or Graves' orbitopathy, is an autoimmune inflammatory disorder affecting the orbit around the eye, characterised by retraction of the upper eyelid, swelling, redness, conjunctivitis and bulging eyes. 

Graves' Ophthalmopathy; image from Wikipedia
Graves' ophthalmopathy is caused by autoantibodies that bind to tissues in the eye socket and in general occurs with hyperthyroidism (overactive thyroid), most commonly as part of Graves' disease. Please note that approximately 10% of cases do not have Graves' disease, so you can get the eye problems without an overactive thyroid gland. The autoantibodies in Graves' ophthalmopathy stimulate the fibroblasts in the eye muscles to differentiate into fat cells, which expand and become inflamed. As the eye muscles swell the compress veins which are unable to drain fluid from the eye that causes swelling. Occasionally the swelling compresses the optic nerve leading to blindness. Severe cases are a medical emergency, and need to treated with steroids and occasionally radiation therapy and/or surgery to decompress the orbit.

Why is this topic important? Graves' eye disease is one of the secondary autoimmune complications of Alemtuzumab treatment. I have now had two patients who have developed Graves' eye disease post-alemtuzumab. Both have said to me 'if I knew I was going to develop this complication I would never have had the treatment in the first place'. Why? It is cosmetically unattractive and one patient calls herself a a goldfish, because of her bulging eyes.

The good news is we now have a new treatment for treating Graves' eye disease. It is a monoclonal antibody called teprotumumab that blocks insulin-like growth factor I receptor (IGF-IR) one of the targets for the auto-antibodies. IGF-1 stimulates fat cells and by blocking this receptor the fat cells regress in the eye. This for me is beautiful science and shows how fast we are unpacking biology to develop treatments for diseases that were untreatable in the past.  

I wonder how much this new treatment is going to cost? Add this on to what alemtuzumab already costs to treat MS and you begin to see why healthcare costs of treating MS and treating their complications are soaring. 

Smith et al. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med. 2017 May 4;376(18):1748-1761.

BACKGROUND: Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy.

METHODS: We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves' ophthalmopathy-specific quality-of-life questionnaire. Adverse events were assessed.

RESULTS: In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes.

CONCLUSIONS: In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; number, NCT01868997).

CoI: multiple


  1. When do you think this new treatment for graves eye disease will be available on prescription? A year or so? If a cost hasn't be set then it sounds it might be a while.

  2. Why didn't the Graves' disease get picked up via monitoring of your two patients?

    More generally, what is the end game here. You put up research showing how effective Alemtuzumab is (reduction in relapses, impact on brain atrophy etc.) and then put up posts like this which just puts the fear of god into patients and leads to more uncertainty. The neuros should be discussing pros / cons of treatment when running through treatment options with their patients. The main complications with Alemtuzumab can be picked up through monitoring. If a patient with RRMS came to you and wanted the best chance of not becoming disabled what is your advice? I know you will say that it depends what level of risk they are prepared to take, but this is a cop out. You have real world experience of treating hundreds of patients with different treatments. Last week you put a pin in the Ocrelezumab bubble by suggesting it didn't have much effect on reducing brain atrophy. I've enjoyed this blog but am now of the view that the future is Pender. He knows EBV causes MS and is doing something about it.

    1. I disagree monitoring finds the problems after they have occurred and then it is a fire fight.It does not stop the problem occuring. Over active thyroid/underactive thyroid can be dealt with and perhaps this is brushed off as in-significant. It occurs in about 40% of people on the drug within 5 years, but is a question of life-long dealing with the problem. Then there are other 10% diseases. If it is kidney disease and it doesn't respond to treatment that may be dialysis for life. I don't know of this being needed but is a theoretical possibility. Nothing has been done to de-risk these issues. I believe a plausible soultion could have been tried, I know ProfG has suggested this but no interest.

    2. I should have said - I am an Alemtuzumab receipt (first infusion 7 years ago). I got Graves' disease but it was picked up and dealt with. I take a small thyroxine pill once a day. This is very insignificant as I had aggressive RRMS and was accruing disability rapidly. Alemtuzumab has been a life changer / life saver for me. You are spinning a line which is leaving MS patients between a rock and a hard place: (i) do nothing and your brain will be shredded; (ii) take a safe first line injectible / pill, but it won't do much for progression / brain atrophy; (iv) take a highly effective treatment which will do more to slow / prevent progression, but this comes with the risk of PML / Graves disease... It's all so academic for your guys - lots of stats / weighing up the risks / claims that data has not been disclosed. People like me have to actually make the choice - real life choice. I didn't want to die young in a care home so it wasn't that difficult. The risk of ending up looking like Marty Feldman was worth taking compared to ending up like Stephen Hawking. What are you guys like ordering a Chinese takeaway? You'd all have starved to death or developed a random number system to make the order. Academic pontificating is all very well, but sometimes choices have to be made.

    3. Re " pill, but it won't do much for progression / brain atrophy;"

      Anon at 12:36 how do you know this? I am taking a pill DMT for over two years and I'm not progressing or any getting significant brain atrophy.

    4. Anon 12.36
      Yes, choices have to be made but the more information you have, the better able you are to make an informed decision. Surely that's a good thing?

  3. Is it time to do a head to head with ocrelizumab and sort of if alemtuzumab is any better in terms of efficacy, and safety, but should we not test to see if ocrellit has PIRT activity first, as the data may suggest. Although it could be repopulation of the pathogenic cells are slow? Without the published data it is impossible to know that is going on.

    Or maybe a head to head of oral cladrinine

  4. The patient and the goldfish were just told the price of Alemtuzumab.;-)

  5. Is this to create balance as your past few posts have should like sales pitches for one company's products?

    1. Maybe, apparently we been accused of doing the same with cladribine. Note I did use generic cladribine as this available. The oral is hypothetical unless it gets approved. If it does it can be part of our impact statement for Giovannoni et al 2010. :-)

  6. No end-game, just reminding people of the risks associated with DMTs, in this case alemtuzumab.

    To put things in perspective: at the AAN we were told that 13,000 pwMS have been treated with alemtuzumab. This will result in ~3,900 (30%) news cases of Graves Disease and between 3-5% of these will develop severe Graves' eye disease*, i.e. 120-200 cases.

    The point of this post is the good news that we now have a licensed treatment for Graves' eye disease. I call this derisking alemtuzumab.

    Should we stop posting on topics such as this?

    * Reference: Smith & Hegedüs. Graves’ Disease. N Engl J Med 2016; 375:1552-1565

    1. No, keep posting. Information is information. Facts are facts. How an individual decides to react to or utilise that information is their choice.

    2. lol of course you shouldn't stop posting on topics such as this.

      yes it's good news, but even ms patients on lemtrada are a bit tired of good news which involve 'just another pill' added to their daily regime.

      Plus your ms readership is facing difficult decisions between lemtrada and ocrelizumab and perhaps your cryptic posts over the last week or so have unsettled them. Your unsettling posts about ocrelizumab are welcome and informative and I rely on them, but cryptic they are.

      On top of that, I know I am - and I suspect other readers are also - waiting a response from Prof G to this heart-wrenching plea:

      "AnonymousFriday, May 05, 2017 2:54:00 am
      Professor Giovannoni, I appreciate you raising this possible theory and truly appreciate everything you do, but I just don't understand how this squares with the observed data.

      I feel like the argument presented thus far, Prof G, is based on theory without data showing why it's true. This is frankly worrying me that neurologists like yourself have information that is not being shared with the public and causing these cryptic warnings that ocrelizumab will not be as effective as we hoped. I haven't known you as someone who would jump to conclusions, and you seem pretty convinced of this argument.

      Just know that there are hundreds if not thousands of your patients (I see you as just as much of an advisor as the neurologist whose office I visit) who are thinking about or in the process of moving to ocrelizumab. We've put our trust in you to give us the right information, so if you truly believe that picking alemtuzumab versus ocrelizumab is literally a matter of brain-survival or death, you owe it to us to lay out the case!"

    3. Re: "I feel like the argument presented thus far, Prof G, is based on theory without data showing why it's true."

      Can I suggest we wait to see the ocrelizumab brain atrophy data before jumping to conclusions. In addition, the alemtuzumab brain atrophy data is also not being presented the way I want to see it. A significant proportion of subjects treated with alemtuzumab have recurrent MS disease activity, which almost certainly cause their brains to swell. I refer to the latter as reversal of pseudo-atrophy. I would therefore like to see alemtuzumab brain atrophy data presented according to NEDA status. I would predict that subjects who are non-NEDA will have less brain atrophy than subjects with cumulative NEDA. I have asked Genzyme on numerous occasions for this data, but they have not done the analysis.

      This however does not answer the question of whether or not B-cell depletion on its own is sufficient to control MS or do we need T-cell depletion as well. For this we need to head-2-head study.

      Against the Pender hypothesis is how well patients do on natalizumab. If there was a virus causing damage within the CNS you would expect them to get worse despite being on natalizumab. In general this is not the case and suggests that trafficking of pathogenic cells is required for driving MS pathology. So there are many more questions than answers. Hopefully, time will allow us to answer these questions.

  7. Absolutely not! Keep em coming! This post has finally prompted me to move my butt and make my first opticians appointment in 6 years. After your previous posts on conditions those of us receiving Alemtuzumab are vulnerable to, my husband, son and I all have lists on our phones, identifying the risks. As MD says problems aren't prevented. However, swift and appropriate intervention can only be of benefit.
    Hope I don't offend though ProfG when I say some of your posts put a wry smile on my face as I find myself thinking that they're rather dramatic and that you're quite the showman - image of a bug eyed fish in this one - really?!!?!

    1. The fish is not my analogy, but my patient's. She calls herself a goldfish. I am just sharing it with you and telling you what she told me.

  8. I greatly respect you for not painting idealized pictures of MS drugs. The decision of whether to take them is often not black and white. There is an awful lot of grey involved, unknowns, unnpredictables, and every single person's experience of any given drug will be different. I can think of nothing worse than not being told of all the possible side effects and complications of a drug before making an _informed_ decision on whether to take it. I'm not interested in having medics lie to me and hide the truth from me.

  9. The point being made by anon (I think) is that all these risks and benefits are impossible to reconcile. For a long term this blog has been a supporter of PIRT- hit hard and early. I totally agree and know a number of Alemtuzumab patients who are 10 years post first infusion and doing well e.g. still working. Surely all of us want that. Alemtuzumab has side effects e.g. thyroid issues. Many of these problems are detectable and treatable = good. A few patients experience graves disease eye issues = bad. But there may be a treatment for graves disease = good. But NICE may not fund it = bad....... I would prefer a neuro to share their experience e.g. 90 patients treated, x% doing well... On the basis of my MRI scan, relapse rate etc. I would want the neuro to set out clearly what I should be doing to maximise my brain health. In considering Alemtuzumab I found the 10 year analysis of patient outcomes very helpful.

    1. I respect your very valid outlook. But I'd like to mention that I have never had any drugs or medications for my PPMS whatsoever, and I was still working 10 years after it set in, doing pretty well. It is all so complicated, variable. It takes so long to know outcomes...


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