Thursday, 27 April 2017

AAN2017. B cells remain in the brain after rituximab treatment

341 Persistent B lymphocytes in multiple sclerosis plaques after rituximab treatment S. esfandi (University of Colorado), S. Salimian (U of Colorado School of Medicine), J. Corboy (U of Colorado School of Medicine), E. Alvarez (University of Colorado).

To describe the persistence of inflammation lymphocytic infiltrates in plaques from a postmortem case of aggressive multiple sclerosis (MS) after treatment with Rituximab.

Background: B-cells are believed to be strong autoimmune effector cells in the pathogenesis of MS. Rituximab depletes B-cells in the peripheral blood and is an effective treatment for MS. However, this effect may not extend to the CNS as effectively. Spinal fluid analysis from multiple studies has shown the persistent presence of B-cells after rituximab treatment, despite elimination from peripheral blood. 

Design/Methods: Case report. Results: 30 year old man with aggressive multiple sclerosis was diagnosed in 2010 and presented to University of Colorado in 10/2013 in a wheelchair. He was treated with Tysabri from 10/2013 until 8/2014. He was JCV+ and was then treated with 1 gram of rituximab in 9/29/14. He was showing gradual improvement and was beginning to ambulate with a walker (leg strength went from 2/5 to 4/5) when he died on 1 November15. He had received two additional 500mg doses with the last dose on 15 September. His peripheral CD19/20 counts stayed undetectable. His last MRI Brain on 3 July 2015 was stable. 

CNS autopsy verified severe multifocal brainstem and cerebral periventricular white matter plaque burden. Microscopically, several plaques manifested conspicuous perivascular lymphocytic cuffs, predominantly CD3+ T cells (mixed CD4/8) and macrophages, but individual CD20+ cells could still be identified within the parenchyma and perivascular cuffs. 

Conclusions: This case underscores the fact that lymphocytic inflammation in plaques, including B-cells, is not completely abrogated following treatment with Rituximab, even with undetectable peripheral CD20+ B cell counts.

It is clear in arthritis that some people with arthritis relapse despite depletion of B cells in the blood and this case shows that the same is the case in MS, however it also shows us that these systemically adminsitered agents do not effectively deplete cells from the brain. 

#ClinicSpeak & #AAN2017: cognition and MS

Is it not time to start measuring cognition in routine clinical practice? #ClinicSpeak #AAN2017

As promised to several people who have come up to me at the AAN; the following are my slides from the satellite symposium on MS and cognition. In my talk, and slides, I make a strong case for measuring cognition in routine clinical practice. If you don't measure and monitor it how can you address it in clinical practice? 

To help I have also asked Biogen to make available their iPad based Processing Speed Test (PST), which is a 2 minute version of the SDMT (single digit modality test), which is rapidly becoming the mainstay of cognitive testing in MS. This could be the game changer we need. 

One commentator made the point that if you measure cognition and its getting worse what can you do about it? Several things; firstly you can assess whether or not it is related to MS disease activity, which may require starting or switching therapy. Secondly, it may be related to some reversible factor, for example a concomitant medications that affects cognition, e.g. anti-cholinergics, or even a cognitive relapse. Thirdly, if you do detect worsening cognition you can also counsel patients and offer them help, for example cognitive rehabilitation. People with MS who have worsening cognition may factor in this information into certain life choices, for example, whether or not to register for a particular educational course or not to apply for a specific job. Some patients may use the knowledge to change their work and life status. 

I also made the point that why should we treat cognition differently to other MS outcomes, for example the EDSS and walking speed. PwMS know that they are physically deteriorating, why shouldn't they have the option of knowing that their cognition is deteriorating? To make the latter point an Italian colleague of mine sent me the following quotes:

'Omnia metire quaecumque licet et immensa ad mensuram tempestive redige' or 'measure what is measurable and render measurable what is not', which has been attributed to Galileo. The phrase is the motto of Franz Halberg, the father of modern Chronobiology and sounds very similar to Lord Kelvin’s: 'When you can measure what you are speaking about, and express it in numbers, you know something about it, when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind; it may be the beginning of knowledge, but you have scarcely, in your thoughts advanced to the stage of science'

CoI: multiple

#PoliticalSpeak & #BrainHealth: can we shame MEPs?

The European Parliament sucks! #PoliticalSpeak #BrainHealth #MSBlog

The following is the EMSP report from our recent meeting at the European Parliament. The meeting was hosted by Cristian Busoi, an MEP from Romania, who was the only, and I really mean the only, MEP to attend. No other MEPs bothered to attend despite them being aware of the meeting and having many constituents in their countries with the disease. I wish we could name and shame them.

The report: 

My presentation:

The peogramme:

Wednesday, 26 April 2017

AAN Targeting EBV with CD8 specific T cells

Symptomatic and Objective Clinical Improvement in Progressive Multiple Sclerosis Patients Treated with Autologous Epstein-Barr Virus-specific T Cell Therapy: Interim Results of a Phase I Trial

Michael Pender, MD, PhD; Peter Csurhes; Corey Smith; Nanette Douglas; Michelle Neller, PhD; Leone Beagley, PhD; Sweera Rehan, PhD; Tracey Hopkins, PhD; Kate Thompson, PhD; Stefan Blum, MD; Kerryn Green, MBBS; Zara Ioannides, MD; Alan Coulthard, PhD; Kaye Hooper, PhD; Scott Burrows, PhD; Rajiv Khanna, PhD

Objective: To determine the safety of treating progressive multiple sclerosis (MS) patients with autologous Epstein–Barr virus (EBV)-specific T cells. Background: Mounting evidence indicates a role for EBV in MS pathogenesis. EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T-cell immunity.
Design/Methods: In this trial we administer autologous EBV-specific T cells to patients with progressive MS (EDSS 5.0–8.0). Each patient receives their own T cells stimulated ex vivo to enhance reactivity to EBV nuclear antigen-1, latent membrane protein 1 (LMP1) and LMP2A, and is followed through 26 weeks. Four escalating dose infusions are administered biweekly.
Results: To date, four SPMS patients and one PPMS patient have been treated. No significant adverse events have been observed. Three patients experienced symptomatic and objective clinical improvement, which commenced 2–8 weeks after the first infusion and was most marked in the two patients receiving T cells with the highest EBV reactivity. Striking improvement occurred in one SPMS patient, with normalization of lower extremity tone and plantar (Babinski) responses for the first time in 16 years, increased walking distance with walker from 100 metres at baseline and for the previous 5 years to 1200 metres, marked reduction in fatigue, increased manual dexterity, and improvements in lower extremity power, reflexes and sensation. A second SPMS patient had reduced fatigue, increased productivity and improved balance. The third responder (PPMS) had improved colour vision, visual acuity and manual dexterity and reduced fatigue, lower extremity spasms and urinary urgency. These data are consistent with prior data from the first patient ever treated (SPMS compassionate use) who experienced reduced fatigue and lower extremity spasms, and improved cognition, hand function and productivity.
Conclusions: This is the first report of clinical improvement in a prospective trial of autologous EBV-specific T cells to treat progressive MS patients. Further studies are planned.

Study Supported By: Multiple Sclerosis Society of Queensland, Multiple Sclerosis Research Australia and Perpetual Trustee Company Limited

This isa safety study designed to test whether vaccination against EBV could impact on MS. They have made viral reactive CD8 T cells and transfer them in to kill the EBV infected (B) cells. This will be of interest, so maybe ProfG may have time to tweet or report on the presentation.

In the AAN press release it said the trial was designed to look at ten people and have found it should have been five with PPMS and five with SPMS. In the trial, the volunteers received four escalating doses of cytotoxic CD8 T cells over six weeks and were followed for an additional twenty weeks after the last dose. 

Here the abstract above it says five people were looked but in the press release from the AAN, it says six. These results are encouraging, but the study is seemingly unblinded and is reporting symptomatic improvements and this is not what a trial in progression may go for. But being a phase I it is designed to say it is safe. 

This study used autologous cells, so they were generated from the same people who they were later received the cells back after they were expanded. 

However, this data is now being reported as company data. It appears the company has got some rights from the University in Queensland. 

Anyway according to the company website. They are planning to use their product as allogenic cells, i.e. made in one person to be used in another person. Whilst this will help in production of a standardised cell this, without more data on the technology, makes little immunological sense as to get proper engagement of cells you need your antigen presenting cells to present to your own T cells.

An allogenic cell may not recognize the B cells infected with EBV in another person, but they can recognize a large percentage of other peoples major histocompatibility complexes (transplantation antigens) as a target, so you could be injecting cells that that can potential kill every cell in the recipient. I hope not. 

More likely the injected cells will last about 5 days and then the recipient will destroy them as being invaders.  

#NeuroSpeak & #ClinicSpeak: fingolimod rebound is a yellow-carder

Another thing for HCPs to lookout for: rebound post-fingolimod. #ClinicSpeak #NeuroSpeak 

An emerging and very important differentiator in the MS space is rebound activity that occurs when stopping a therapy. The MHRA have now made this a reportable, or yellow-card, event. It is good to see the regulators taking such a keen interest in such an important issue. Maybe they are begging to flex their muscles before the EMA departs after Brexit. 

MHRA: Multiple sclerosis therapies: signal of rebound effect after stopping or switching therapy. April 2017.

Healthcare professionals should report any suspected adverse effects relating to fingolimod (Gilenya▼) or other treatments for multiple sclerosis, including suspected adverse effects occurring after discontinuation, via the Yellow Card Scheme.

We are aware of two recently published articles1 2 describing a suspected rebound syndrome (clinical and radiological signs of severe exacerbation beyond what was expected for that patient prior to discontinuation or treatment change) in patients with multiple sclerosis after treatment with fingolimod (Gilenya▼) was stopped, some of whom were switched to other treatments.

In conjunction with other European national regulatory authorities and the European Medicines Agency, we are evaluating all available evidence on this safety signal. Further information on the outcome of the review and any relevant new guidance will be issued as soon as it is available.

Healthcare professionals are reminded to be vigilant for such events and report any suspected adverse effects relating to fingolimod or other treatments for multiple sclerosis via the Yellow Card Scheme.

For any reports of suspected rebound effect, please provide as much detail as possible. This could include any clinical, imaging and other test details; along with a description of disease activity prior to and during therapy.

Article citation: Drug Safety Update volume 10, issue 9, April 2017: 3.

Hatcher SE et al. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol 2016; 73: 790–94.

Willis M et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2017; 4: e320. 

CoI: multiple