Alemtuzumab-a monoclonal antibody targeting the CD52 glycoprotein expressed by most mature leucocytes-effectively decreases relapse rate and disability progression in early, relapsing-remitting multiple sclerosis (MS). However, secondary autoimmune disorders complicate therapy in nearly 50% of treated patients, with Graves' disease being the most common. Rarely, thyroid eye disease (TED) ensues; only seven such cases have been reported. Our aim was to analyse the largest series of MS patients developing thyroid eye disease after alemtuzumab treatment. We performed a retrospective chart review of MS patients treated with alemtuzumab (1995-2018) and subsequently identified by their treating physicians as having developed TED and referred to our ophthalmology service.
As an original trial centre for alemtuzumab, our hospital has treated approximately 162 MS patients with this novel therapy. In total, 71 (44%) developed thyroid dysfunction, most of whom (87%) developed Graves' disease, with ten (16%) referred for ophthalmological evaluation. Two developed active orbitopathy following radioiodine treatment; one occurred after cessation of anti-thyroid drug treatment. Three developed sight-threatening disease requiring systemic immunosuppression, with one refractory to multiple immunosuppressants. The remaining patients were treated conservatively.
TSH-receptor antibody (TRAb) levels were significantly raised in all cases, when ascertained. We report sight-threatening as well as mild TED in MS patients after treatment with alemtuzumab. Endocrine instability, radioiodine treatment and positive TRAb are all likely risk factors. The data support at least 6-monthly biochemical and clinical assessment with a low threshold for referral to an ophthalmologist, particularly for those with higher TRAb levels who may be at greater risk of orbitopathy.
We all know that alemtuzumab cause antibody mediated, and possibily CD8-mediated, autoimmunities so why keep reporting them. Well alemtuzumab is a very effective drug and can be accessed first line in the UK.
You can be say the problems are mild and can be dealt with which is the case but it is also the case that some are more serious. In other countries they use it third line because of these risks. Anyway Cambridge who have the longest history of these cases have seen that on o fthe issues with thyroid disease is that it can be associated with eye problems . They are reporting this issue and suggesting that you add to your monitoring requirements and act if you are at risk of pathology to your orbit (eye).
Many autoimmunities have secondary complications. I suspect we will be seeing more of these as the list of secondary autoimmunities grow.
I was asked this week How do we we de-risk this?
I was sorry to say I think the time has passed. About 5-6 years ago ProfG went to the manufacturers with a proposed study to try and remove the risk based on the idea that the repopulating B cells and the regulatory environment were not properly alligned. The idea was dismissed, especially as there was not competitive alternative.
However when interferons can out it was found that they stopped working because of neutralizing antibody responses. We were working on immune tolerance and had shown that depleting T cells followed by tolerogenic antigen switched off EAE for good. So how would we translate it as there was not a known antigen....yeah right myelin basic protein..I think not.
So ProfG said where is there an autoimmunity where we know the antigen. The answer was a neutralizing response to beta interferon. If we could get rid of them then interferon would start working again. This time we found a company who actually recognised the problem and was willing to try do something about it.
At the time there was no source of T cell depleting antibody, and we spent months trying to find one, stupidly we didn't think about anti-thymocyte globulin, so we used mitoxtantrone we didn't think about.
So we dosed our first volunteer and their neutralizing antibodies eventually disappeared.....Yeah. The person could continue on beta interferon.
But along came natalizumab and then the double whammy occurred the risk of using mitoxantrone increased as it carried an increased cancer risk. Therefore it was not ethical to plough on, if you failed beta interferon you simply started natalizumab. We couldn't recruit and so we had to close the trial down. End of story.
Was it a fluke? Antibodies didn't disappear in other people, maybe not we will never know:-(
We really must report this...Maybe a Christmas project. Rather than the start of the MS cure, it was the end of the road :-(
Now we have cladribine as an immune reconstitution therapy alternative that does not cause the autoimmune side effects and if the phase II extension data is replicated and extended this may be may be a selective immune reconstitution therapy too.
The alemtuzumab data looks the dogs but as I said people went on drug within 2 years of diagnosis and they had good atrophy data, ocrelizumb it was 6-7 years post diagnosis and for cladribine about 9 years so a long time to loose brain before getting an effective treatment
The ocrelizumab extension study should be done, Prof Hauser should be made to hunt the subjects down to see how they did 4-5-10 years on. Maybe the company thinks it is not in their interest to have a limited pulse therapy, but clearing up the MS market will be lucrative. If infection issues show then maybe a rethink.
So what is the best way to avoid alemtuzumab issues...the answer is easy