Wednesday, 9 April 2014

Mitigating Lemtrada Risks with a Biomarker

Predicting Autoimmunity after Alemtuzumab

Jones JL, Phuah CL, Cox AL, Thompson SA, Ban M, Shawcross J, Walton A, Sawcer SJ, Compston A,Coles AJ. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest;119(7):2052-61

Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21than the non-autoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity.



Azzopardi L, Thompson SA, Harding KE, Cossburn M, Robertson N, Compston A, Coles AJ, Jones JL. Predicting autoimmunity after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry:: 10.1136/jnnp-2013-307042. [Epub ahead of print]

OBJECTIVE:We have previously shown that autoimmunity following alemtuzumab treatment of multiple sclerosis can be predicted by high baseline serum interleukin IL-21 (IL-21), as measured using a now 'redundant' enzyme linked immunosorbent assay (ELISA). Here we ask whether currently available ELISAs have similar prognostic value.


DESIGN:Serum IL-21 from 141 individuals with relapsing remitting multiple sclerosis was measured using the now 'redundant' IL-21 ELISA and five further currently available kits. All patients had been treated with alemtuzumab; 61/141 had developed secondary autoimmunity.


RESULTS:The 'redundant kit', and one current kit, confirmed higher baseline serum IL-21 in patients with autoimmunity (542 pg/mL vs. 222 pg/mL and 53.1 pg/mL vs. 9.3 pg/mL respectively) and showed positive correlation. However, only the 'redundant' kit had predictive utility.


CONCLUSIONS: Currently available IL-21 ELISA kits should not be used to counsel individuals with multiple sclerosis considering treatment with alemtuzumab.




The risk of Lemtrada is that is going to cause (a) neutralizing antibodies that can stop it working and (b) unwanted and sometimes life-threatening (if not detected quick enough) autoimmunities. This occurs in 20-40% of MSers within a few years of treatment. The docs at Cambridge have been investigating this and have ways to stop the neutralising antibodies and have found a marker they think shows your risk of developing autoimmunity. This type of study has not been reported of the phase III trials....With a large sample one could have seen if this had mileage as a pre screen to mitigate risk...

What do the manufacturers do about this?.....well apparently nothing!

They just make you get checked up every month for 5 years to check for the autoimmunities notably a platelet disease and thyroid disease. Heaven forbid that you don't take their drug because they can deal with the autoimmunities. 

What did the interferon manufacturers do to sort out who was one the 30% responders......well nothing as they could sell the inactive drug to 70% others. Some call it Bad Pharma others call it Phamacoeconomics.

In the second pape an ELISA that detected soluble interleukin 21 was used and was suggested to predict, in part, whether autoimmunity may develop after alemtuzumab treatment. An ELISA against interleukin 21 is may contain a capture IL-21 antibody that is stuck to plastic and a detect anti-body that has a dye attached to it. So you add blood which contains IL-21 that is bound to the capture antibody and then you add the detect antibody that can now bind to the captured IL-21 and the more IL-21 in the blood the more that is captured the more detection signal you get. You then take a known amount of IL-21 and put this in the assay and then you can work out how much is in the blood. You can make these ELISAs up or eventually a company will make a kit, which is easier to do and generally gives more consistent results. This study tests a few commercial kits and none of them performed as well as the original ELISA and they had n predictive value. There are clearly problems with the ELISAs as they are not accurately detecting the levels in the blood ~500pg/ml in one verses 50pg/ml. 

The New mantra from academia is personalised medicine...however are pharma going to invest much to work out   who will not benefit from drugs and who will not?....Is not phamacoenconomics to not sell drug. Likewise who will benefit from the drug. 

One would think that people early in disease have most to gain, but may not take the risk. But those with disability may be be more willing to take the risk......but will it work. The manufacturer could I guess work this out in relation to say ability to induce NEDA and prior disease duration. 

Whilst IL-21 may make a prediction of who will get autoimmunity as can be seen it is not predictive of who will and who will not get autoimmunity as there is a lot of overlap(seen in the graph). This is an example were you could test sensitivity and specificity.

3 comments:

  1. The publication you refer to is pretty old: from 2009. This screening would have helped Genzyme to get alemtuzumab approved in the US. So does this screening work? Or is it extremely impractical to do? Any idea why patients are not screened before treatment?

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    Replies
    1. Not impractical at all.

      and answer to second question is probably cash for the company.

      In their defence I say the test in that format is not absolute because there is too much overlap in the two groups for it to be predictive but maybe for people in very high bracket it may have been less well advised.

      I believe Dr. Coles is very keen on sorting this out

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  2. this auto immunity business is one of the key reasons my partner opted against lemtrada and decided to have non myeloablative hsct. she accepts hsct has its own risks and can lead to autoimmune issues also - but the autoimmune percentages associated with non myeloablative hsct which doesn't use lemtrada as part of the protocol are more favourable than with lemtrada. she has a family history of autoimmunity and for her it felt like almost a certainty. she felt like post hsct care and infection risks were somewhat within her control, whether post lemtrada autoimmunity is completely outside of her control. and if hsct works for 3 to 5 years, there will always be lemtrada (or something else) after it should the need arise. she didn't feel like adding co-morbidities to her list, notwithstanding the lack of gold standard clinical trials in the context of hsct.

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