Wednesday, 8 August 2018

Learning from others CD20 depletion do we need to deplete so often.

Kim SH, Kim Y, Kim G, Park NY, Jang HM, Shin HJ, Hyun JW, Kim HJ. Less frequent rituximab retreatment maintains remission of neuromyelitis optica spectrum disorder, following long-term rituximab treatment. J Neurol Neurosurg Psychiatry. 2018 Jun 21. pii: jnnp-2018-318465

Rituximab, a chimeric monoclonal antibody that selectively targets CD20+ B cells, has exhibited robust efficacy and an acceptable safety profile in neuromyelitis optica spectrum disorder (NMOSD). Previously, we reported that the therapeutic response of B cell depletion varied among 100 patients with NMOSD, which resulted from multiple factors including Fc gamma polymorphism, and that monitoring CD27+ memory B cell appears to improve treatment outcomes via individualised treatment. Our treatment strategy has also proven to effectively prevent relapse at a lower cumulative dose, compared with the fixed maintenance therapy every 6 months. Currently, we have a group of patients with NMOSD who have undergone long-term rituximab treatment for more than 7 years. We found that retreatment interval became significantly prolonged over time when we targeted depletion of memory B cells. Here, we analysed clinical outcomes and changes in B cell reconstitution over time, following long-term repeated rituximab treatment.

What's this got to do with MS, as NMO isn't MS. 


Yep, but both respond to CD20 depletion.

We know that there are antibodies to a number of CNS proteins in NMO , notably to a water channel expressed mainly by astrocytes and to a myelin protein. 

In MS, we know some people have antibodies to nerve proteins, but these are rare.

However in both NMO and MS, the dosing schedule is set at every 6 months. We have shown that this is probably too frequent for some people as in the ocrelizumab phase II extension study there was efficacy despite being on no drug for 18months

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.
Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017;16:41-50.

Perhaps Relapses in NMO than MS are more frequent but the authors have shown that if you dose according to memory B cell numbers, then you don't need to dose as frequently and being closer to once a year than once every 6 months

The annualised relapse rate was reduced by 97% and 62% patients became relapse-free after rituximab treatment. Disability improved or stabilised in 98% of patients.

This is likely to be the case with ocrelizumab too so can we learn something from other diseases
 

9 comments:

  1. Ok. I have just one problem with B depletion in MS. If you were 100% right why is Brain atrophy reduction superior in Alemtuzumab. End of the day. Reducing inflammation, reducing relapses, NEDa is Fanatastic. But if Brain atrophy is still high. You've only achieved cosmetic changes.

    ReplyDelete
    Replies
    1. OK it is likely that T cells are doing something because they do things like help B cells, but is this the reason for good effects on atrophy.

      I suspect that part of the effect is because the people in the alemtuzumab trials were entered soon after onset. I think in the MS-CARE I this was about 2.1 years but for OPERA it was 6.7 years, so people in the B cell depletion trial had had nearly 5 more years of damage. Therefore their reserve may have been used and their brains would be more susceptible to the artefacts of pseudo atrophy. I guess we need a head to head

      I think that if you look at the people in the CARE-MS 1 and CARE-MS 2 trails with alemtuzumab people were less than two years from diadgnosis

      Delete
    2. Thanks MD. By using this argument patients in Alem trial were early in their disease phase. However your are also implying the MS progression rate is the same. We know this is not true. Given B therapy has been used for many years in Sweden. If MS was only a B mediated disease then by this logic there should be no disease breakthrough in this cohort of patients. We both known this is not true. Has Bart become the same as the doctors they ridicule for being T enthusiast and not looking at the evidence?

      Delete
    3. I was not implying anything about progression rate..I dont know about progression rate, However De Stefano et al. 2010 found similar atrophy in CIS, PPMS, SPMS and RRMS.

      "If MS was only a B mediated disease then by this logic there should be no disease breakthrough".

      There is indeed breakthrough with B cell depletion, HSCT and alemtuzumab.

      No treatment is 100% effective, with aemtuzumab there is 50% breakthrough within two years and more if you look for the longer term there is more.

      No I am not the same as the Doctors I ridicule....(A) I look at the data and try and think rather than follow dogma (b) I am willing to admit I am wrong and (C) am willing to change my position and world view.

      Delete
    4. "Has Bart become the same as the doctors they ridicule for being T enthusiast and not looking at the evidence?"

      Yes.

      HSCT, Alem, HAART, ATA188, even intermittent fasting, all can fit smoothly under the idea of Tcell exhaustion.
      In contrast, you B cell theory struggles for connection with those. And the anti cd20 approach has already hit a wall and cannot move forward towards something that can look like a solution (no BTK inh. are not a solution).
      I wouldn't put my money on this horse.

      Delete
    5. HSCT, ALem deplete B cells, HAART and fasting have no reliable data which shows they work and ATA188 is a T cell therapy that attacks EBV infected B cells....even smoother

      You may not put your money on the B cell horse, but Pharma have already. Most MS companies have BTK inhibitors and there are a load looking at anti-CD20 too.

      T cell exhaustion...Don't you find it exhausting trying to disprove the B cell idea? :-)...But that's what science is about.

      Delete
    6. "Pharma have already"

      That's because pharma are not looking for a cure. They want a treatment that you take for life and make them money. Also a treatment that is not 100% effective to treat, so they make more money to treat the effects of MS. Double whammy for patients.

      Delete
  2. "ATA188 is a T cell therapy that attacks EBV infected B cells"
    That's more or less my point...

    BTK inhibitors have two failures in RA, so lets see.

    I was born exhausted :P

    ReplyDelete
  3. It might be useful to say that with constant immunosuppression with Rituxan, we see IGG issues and netropenia that might force patients to stop treatment. Usually the problems start after the 5-10 year. With Ocrevus these phenomena might come sooner.

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.