Thursday, 25 May 2017

#NewsSpeak: Jet-lag and the CMSC 2017 meeting in New Orleans

Jet-lagged, tired and MSed-out in New Orleans; time to take a break? #CMSC2017 #MSBlog #NewsSpeak

I arrived late last night in New Orleans and will be talking at a teaching session this morning. The main objectives of my talk are:
  1. MS is 1 and not 2, 3 or 4 diseases
  2. MS is a length-dependent axonopathy 
  3. Progressive MS is a tractable problem
  4. Neuro-repair is feasible and provides hope for the future
  5. Holistic management of MS#
I am very jet-lagged and tired. I have less than 3 hours sleep on top of several weeks of sleep deprivation. I was meant to be flying back this evening to travel to Scotland for a week's walking holiday doing the Cape Wrath trail. But had to pull out of the walk because of my hip problem; I simply can't do 100+ miles carrying a 20+ kg backpack. I was really looking forward to some time out, but instead my supposed week-off has already filled up rapidly with MS-related activities. I reopened my NHS clinic,  have scheduled several meetings including attending an important biomarker meeting.

The one positive thing about a long trans-Atlantic flight is that I managed to finish 9 writing tasks with plenty more to do. Hopefully, I will be able to maximise some of my free time in New Orleans and next week to complete some more tasks. The life of an academic is no different to any other; we are on a treadmill that seems to be going faster and faster.  

The following is my talk that I will be giving this morning, the programme for the CMSC meeting and a satellite I have been asked to chair are below. Regarding the latter  the previous chair was unable to attend the meeting. The satellite is being hosted by 'MS in the 21st Century' an initiative that focuses on patient engagement. It should be good so if you are in New Orleans please come along. In addition, I am presenting several abstracts and have done already done a Medscape panel discussion.  

CoI: multiple


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May 2017

Letter from the President

Welcome to the second ECTRIMS newsletter of 2017. Being already in the month of May, I begin by highlighting that this year's World MS Day is May 31st. World MS Day is an excellent initiative of the MS International Federation and its members to raise awareness of MS throughout the world. For further information see (

Plans continue to proceed well for this year's Congress (MSParis2017). As happens every three years, the meeting this year is being held jointly with ACTRIMS. It will be the 7th such joint meeting and will take place in Paris on October 25th - 28th. Comprehensive Scientific and Teaching Course Programmes have been established and further details of these are available on the website, along with other  information relevant to the meeting ( The deadline for abstract submission is May 31st. This year, ECTRIMS will be providing a limited number of rooms at a very reduced rate for non-profit, non-governmental specialty groups or organisations in the MS field that may want to hold a meeting at the time of the Congress. For further information, see (

ECTRIMS keeps busy with a number of regular activities other than the annual Congress. This year's Focused Workshop on the topic of "Advancing Trial design in MS" was held in Rome in March in association with the Progressive MS Alliance. It was a very successful, informative and interactive two-day meeting. This month (May 2017), the third ECTRIMS Regional Teaching Course was successfully held in Vilnius, in conjunction with the Baltic MS council. In June, the 5th ECTRIMS Annual Summer School, which is on "Rehabilitation and Symptomatic Treatment in MS", will take place in Santiago de Compostela. The summer school programme and faculty will provide an excellent educational experience for the attendees. Plans are already underway to hold further Regional Teaching Courses in 2018, along with a Focused Workshop and Summer School. Warmest thanks to all my Executive Committee colleagues for their leadership for taking forward these activities.

The 2017 round of ECTRIMS fellowship awards was recently decided. There were many very good applications this year and a total of 10 fellowships have been awarded as follows: Post-doctoral Research Exchange Fellowship (4), Clinical Training Fellowship (3), ECTRIMS-MAGNIMS Fellowship (2) and MS Nurse Training Fellowship (1). Elsewhere in the newsletter you will find reports from several previously awarded fellows.

I hope you find this newsletter enjoyable and informative.
David Miller


World MS Day 2017

What is World MS Day?
World MS Day, which will occur on May 31st this year, brings the global MS community together to share stories, raise awareness and campaign with and for everyone affected by multiple sclerosis. World MS Day is the only global awareness raising campaign for MS. Every year, the MS movement comes together to provide public with information about MS and to raise awareness on how it affects the lives of more than 2.3 million people around the world.
In 2017, the theme for World MS Day is "Life with MS". As life with MS can be difficult and each day brings its new challenges, valuable tips for living well with MS will be made available.
Since its inception in 2009, the World MS Day has grown from strength to strength, reaching hundreds of thousands of people in more than 78 countries worldwide and continuing to grow every year.
How can you get involved?
Read more about World MS Day at and learn about how you can take part in the World MS Day.

ECTRIMS Focused Workshop 2017/ 9-10 March 2017 in Rome, Italy

The ECTRIMS 2017 Focused Workshop took place on March 9th and 10th in Rome. The topic was "Advancing Trial Design in Progressive MS" and it was held in association with the International Progressive MS Alliance. There were about 50 participants encompassing a broad range of expertise, including clinical neurology, neuropathology, trial design, statistical, pharmaceutical, regulatory and lay viewpoints. Themes included treatment targets; trials to date; clinical outcome measures; interim outcome measures focused on neuroprotection that included MRI, OCT, CSF, neurophysiology and PET;   trial designs and statistical analysis; insights from big datasets and ongoing phase 2 trials; and pharmaceutical and regulatory considerations. There were didactic presentations and ample time was allocated for round table and open discussions. The workshop covered a lot of ground and there were many lively discussions. It is proposed that the proceedings will be published as a series of short papers in a themed issue of the Multiple Sclerosis Journal with authors coming from amongst the workshop attendees. We thank Jeremy Chataway and Bob Fox for being the guest editors on this publication.

ECTRIMS Regional Teaching Course 2017/ 11-12 May 2017 in Vilnius, Lithuania

ECTRIMS regional teaching courses have been established in 2016. After two successful teaching courses in St.Petersburg/Russia and Dubai last year this educational activity continued this year with the third teaching course in Vilnius/Lithuania. The course was organized by the ECTRIMS Teaching Course Committee in close collaboration with the Baltic Neurological community. The programme covered basic aspects of MS like the involvement of genes and environmental factors in the pathogenesis of MS and the immunopathophysiology of MS. The main focus of the teaching course was practice relevant topics including differential diagnosis, treatment monitoring and discussions about the rationale for switching or escalating therapies. The teaching course was well attended with 90 participants. The active interaction and high quality of the presentations made this teaching course again a great success, which is also exemplified by a very positive feedback from the participants.
For further information on upcoming teaching courses and detailed programme please visit the ECTRIMS Website here.

ECTRIMS Summer School 2017 / 13 - 15 June 2017 in Santiago de Compostela, Spain

The 2017 ECTRIMS Summer School on "Rehabilitation and symptomatic treatment in multiple sclerosis", organized in collaboration with RIMS, will take place in Santiago de Compostela, Spain, on June 13th – 15th.
The target audience is represented  by high-potential young researchers and clinical experts from different backgrounds (neurologists, rehabilitation physicians and multi-disciplinary therapy team) who want to generate and implement best evidence-based treatment and rehabilitation care.
Through formal presentations delivered by international experts,  interactive, multidisciplinary group discussions and multi-disciplinary group work on research projects,  this course will provide an update on the framework of rehabilitation and available evidence for the effectiveness of motor and cognitive, as well as emotional symptomatic treatment and rehabilitation interventions in MS. Moreover, it will cover epidemiology, physiopathology, diagnosis and evidence base behind the various pharmacologic and non-pharmacologic approaches to the management of MS symptoms, which in most cases requires multidisciplinary input. The course will pursue as main learning objectives understanding the indications and concepts of symptomatic treatment and rehabilitation, and its effects on the patient everyday functioning, integrating evidence from multiple disciplines into clinical case management and identifying key research questions and challenges for clinical implementation of holistic symptomatic treatment and rehabilitation.

ECTRIMS Fellowship 2017

ECTRIMS offers a comprehensive range of fellowship programmes for different target groups.
In 2017 10 new fellowships were awarded:
Dr. Gloria Castellazzi (Italy): 2-year fellowship at UCL Institute of Neurology, Queen Square MS Centre, Department of Neuroinflammation, London, United Kingdom, under mentorship of Prof. Claudia Gandini Wheeler-Kingshott. Project: Developing a clinical decision system based on characterising shared and specific functional features of MS subtypes.
Dr. Joanna Marczynska (Poland): 2-year fellowship at University of Southern Denmark, Neurobiology, Odense C, Denmark, under the mentorship of Prof. Trevor Owens. Project: Mechanisms suppressing autoimmune responses in the central nervous system.
Dr. Kyla McKay (Canada): 2-year fellowship at the Karolinska Institutet, Clinical Neuroscience, Stockholm, Sweden, under the mentorship of Prof. Jan Hillert. Project: The causes and consequences of paediatric multiple sclerosis: A population-based study.
Dr. Emanuela Oldoni (Italy): 2-year fellowship at KU Leuven, Department of Neurosciences, Leuven, Belgium, under the mentorship of Prof. An Goris and Prof. Bénédicte Dubois. Project: Multiple sclerosis heterogeneity: patient-to-patient variation in cerebrospinal fluid biomarkers
Dr. Nuria Cerdà Fuertes (Spain): 1-year clinical training fellowship at the University Hospital Basel, Neurologisch-Neurochirurgische Poliklinik, Basel, Switzerland, under the mentorship of Prof. Tobias Derfuss. Project: Evaluation of clinical bedside tests (primitive reflexes e.g. palmomental reflex) of MS patients in correlation with neuropsychological tests.
Dr. Giordani dos Passos (Brazil): 1-year clinical training fellowship at the University of Oxford, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, United Kingdom, under the mentorship of Prof. Jacqueline Palace. Project: Are there differences in MS severity, as assessed by MRI and clinical parameters, between different racial and ethnic groups?
Dr. Pietro Maggi (Belgium): 1-year clinical training fellowship at the Lausanne University Hospital, Department of Neurology, Lausanne, Switzerland, under the mentorship of Prof. Renaud Du Pasquier. Project: High field gradient echo MRI enhances the differentiation between multiple sclerosis and other inflamatory disorders: a further step beyond the concept of "no better explanation".
Macarena Rus Hidalgo (Spain): 6-months fellowship at the IRCCS Foundation Carlo Besta Neurological Institute, Neurology 4 Unit-neuroimmunology and neuromuscular disorders, Milan, Italy, under the mentorship of Prof. Prof. Silvia Rossi. Project: A multicentric randomized PRAGmatic trial to compare the effectiveness of fingolimod versus
dimethyl‐ fumarate on patient overall disease experience in relapsing remitting Multiple
Sclerosis: novel data to inform decision‐makers – (PRAG‐MS).
Dr. Soheil Damangir (Sweden): 1-year fellowship at the VU University Medical Center, Amsterdam, Netherlands, with collaboration at the Vall d'Hebron University Hospital, Barcelona, Spain under the mentorship of Dr. Vrenken and Prof. Barkhof. Project: Optimizing crowd-sourced solutions toward generating large reference datasets for WM lesion segmentation in MS.
Dr. Marcello Moccia (Italy): 1-year fellowship at the UCL Institute of Neurology, National Hospital for Neurology & Neurosurgery, Queen Square, London, United Kingdom under the mentorship of Prof. Ciccarelli and Prof. Barkhof. Project: Improving longitudinal spinal cord atrophy measurements for clinical trials in multiple sclerosis by using the Generalised Boundary Shift Integral (GBSI).

MSIF-ECTRIMS McDonald Fellowship

Starting in 2016, MSIF (Multiple Sclerosis International Federation) and ECTRIMS jointly support a 2-year McDonald fellowship every year. This fellowship is offered to young researchers from emerging countries and enables the recipient to travel to an established research institution anywhere in the world to work with leading researchers in the field of MS. It is intended that these fellows return to their home countries after finishing the fellowship program to establish their own research using the newly learned techniques.
For more information regarding the fellowship program and for application please visit the MSIF webpage:
Application deadline: 30 June 2017

Reports of ECTRIMS Fellows


Ana Luisa Falcão PhD – 2015 Awardee
Research Topic
Epigenetic states underlying oligodendrocyte precursor differentiation in Multiple Sclerosis
Fellowship Institution
Karolinska Institute, Department of Medical Biochemistry and Biophysics, Stockholm, Sweden
Dr. Gonçalo Caselo-Branco
Fellowship Duration
2 years
Summary as ECTRIMS Postdoctoral Research Exchange Fellow 2015 - 2017
The research objective of this fellowship project was to understand the epigenetic mechanisms underlying oligodendrocyte precursor cell (OPC) differentiation during development and in Multiple Sclerosis (MS). In the first part of the project we investigated the role of citrullination in oligodendrocyte (OL) differentiation and myelin maintenance. Citrullination is the conversion of an arginine to the neutral citrulline, a process mediated by Peptdidylarginine Deiminases (Padi) and found induced in MS. We have uncovered the PADI2-mediated citrullination targets in OLs and found that both cytoplasmic and nuclear proteins are citrullinated, such as myelin proteins and histones. Our study shows that PADI2 citrullination impacts on proper OL development acting as an epigenetic regulator through histone citrullination, but also displays other functions in the cytoplasm and myelin as observed by its interaction with several myelin proteins. In a second part of the project we have performed single cell sequencing profiling in OL lineage cells isolated from the brain and spinal cord of the MS mouse model EAE, and from healthy controls. We observed a remarkable segregation between cell populations from controls and diseased animals that discloses many targets of the disease.
We are currently preparing the 2 manuscripts describing the findings from these projects and we have recently published part of the results from the single cell RNA-seq profiling in OLs (Marques et al, Science).


María Isabel Zuluaga MD – 2015 Awardee
Research Topic
The effect of hormonal changes on women MS risk and prognosis
Fellowship Institution
Centro de Esclerosis Mútiple de Catalunya – CEMCat, Barcelona, Spain
Dr. Mar Tintoré 
Fellowship Duration
6 months
Summary as ECTRIMS Clinical Training Fellowship Programme Fellow 2015
I developed my ECTRIMS Clinical training fellowship at the CEMCat. During these months, I participated in activities of patient care and clinical research. My project was to investigate the possible association of reproductive background, hormonal changes and environmental factors in the risk and prognosis of MS. We found that age at menarche was not associated with an early CIS, neither with the risk of second attack or accrual disability. We also found that pregnancy before or after CIS did not modify the risk of CDMS or accrual disability. Regarding environmental factors, we found that vitamin D deficiency and smoking are risk factors for disability progression in the BARCELONA CIS cohort.
I´m very thankful with ECTRIMS, my mentors and co-workers at CEMCat; this experience had enriched my professional and personal life, and also will positively impact the care of MS patients back in my country.


Arman Eshaghi MD, PhD – 2015 Awardee
Research Topic
"To explore imaging phenotypes of patients with multiple sclerosis using 4-dimensional voxel-based morphometry"
Fellowship Institution
UCL Institute of Neurology, National Hospital for Neurology & Neurosurgery, Queen Square, London, United Kingdom
Prof. Olga Ciccarelli
Fellowship Duration
1 year
Summary as ECTRIMS MAGNIMS Fellowship in Magnetic Resonance Imaging in MS Fellow 2015 - 2016
During my ECTRIMS-MAGNIMS fellowship, I collected a big dataset of more than a thousand patients with multiple sclerosis, who have been followed longitudinally. I looked at the temporal and spatial evolution of brain atrophy. I looked at the differences of atrophy across neuroanatomical regions in multiple sclerosis phenotypes, and baseline imaging markers to predict disability accumulation in advance of time. This fellowship allowed me to work in a truly multidisciplinary environment, where I worked in between the UCL Institute of Neurology and UCL Department of Computer Science to learn computational methods and apply them in neurology. I presented my work as a platform presentation during ECTRIMS 2016 in London and was awarded "the Best Oral Presentation Given by a Young Investigator". I have prepared the results of my fellowship as a manuscript, which is now submitted and is under peer review.

Meeting Dates

ECTRIMS Summer School 2017
Santiago de Compostela / Spain: 13 – 15 June 2017
MSParis2017 - 7th Joint ECTRIMS - ACTRIMS Meeting
Paris / France: 25 – 28 October 2017
Berlin / Germany: 10 - 12 October 2018
We are looking forward to seeing you in Paris!

Please be aware of fraudulent organisations!

There are an increasing number of fraudulent websites that impersonate MSParis2017. We would like to alert all participants to be aware of possible scams and to strongly advise you to only use the official MSParis2017 registration and ECTRIMS accommodation agency Congrex Travel.
ECTRIMS Executive Committee
D. Miller, London/UK, President
B. Hemmer, Munich/DE, Vice President
M. P. Amato, Florence/IT, Secretary
T. Derfuss, Basel/CH, Treasurer & Newsletter Editor
M. Tintoré, Barcelona/ES
S. Vikusic, Lyon/FR
L. Brundin, Stockholm/SE

A reason for thyroid problems

Greer JM, Broadley S, Pender MP. Reactivity to Novel Autoantigens in Patients with Coexisting Central Nervous System Demyelinating Disease and Autoimmune Thyroid Disease. Front Immunol. 2017 May 8;8:514.

Several lines of evidence suggest a definite and unique link between CNS demyelinating diseases and autoimmune thyroid disease (AITD). The aim of the current study was to systematically compare the clinical and laboratory features of patients with co-existent AITD and CNS demyelinating disease with those of patients with just CNS demyelinating disease. Forty-four patients with co-existing CNS demyelinating disease and AITD were identified and their clinical and radiological features were recorded. Blood and DNA were collected and tested for HLA type and for the response of T cells and antibodies to a variety of antigens. Patients with multiple sclerosis (MS) without AITD and healthy individuals were included as controls. Patients with co-existing AITD and CNS demyelinating disease were almost exclusively female (43/44) and had prominent spinal cord involvement as the main neurological finding. The HLA molecules carried by individuals with CNS demyelinating disease and AITD differed from both other MS patients and healthy individuals. Furthermore, patients with both CNS disease and AITD showed less T cell reactivity than patients with MS alone to myelin proteolipid protein, but, compared to other groups, showed elevated levels of T cell reactivity to the calcitonin gene-related peptide, which is present in both the CNS and the thyroid, and elevated levels of T cell and antibody to the leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4), a molecule that is expressed in the brainstem and spinal cord, and which is a homolog of the thyroid-stimulating hormone receptor. We suggest that reactivity of autoreactive immune cells in these patients against antigens present in both the thyroid and the spinal cord is a potential mechanism underlying the pattern of lesion development in the CNS in patients with coexisting AITD and MS and might indicate a novel mechanism of disease pathogenesis in these patients.

Thyroid disease occurs in people with MS. Notably it is a common occurrence in people with MS, notably in those treated with alemtuzumab. In this study they suggest there is a common target in both tissues to explain the finding that MS and thyroid disease can co-exist and maybe this is why the thyroid problems occur. Reactivity to  Calcitonin gene-related peptide occurred ,which is a nerve transmitter found in nerves all over the body. Leucine-rich repeat-containing G-protein coupled receptor 4 is found in a number of organs. So it can be a cross-reactivity, but why the common occurence of MS and thyroid verses MS other things.
There are other explanations

Wednesday, 24 May 2017

Targeting the “virus factory” to stop MS activity

This is a #PlainEnglish version of this post.
We are trying out 'translating' some of the posts on the blog so they're accessible and understandable to a wider audience.

Memory B cells and MS
We have been saying that the MS drugs which seem to work the best, appear to deplete memory B cells the most.

Memory B cells are cells that have helped your body to fight infection. A number of them stay dormant in the body and remember the infection. They can fight it off when the infection returns to the body. The problem is that they can sometimes attack the body, instead of attacking infections. They can create cytokines, “baddies” that can help other cells to create MS, or stimulate T cells to do the business.

In the past Prof G has called this idea the ‘Black Swan Theory’ (here, here and here). It’s when something unusual or highly improbable occurs, and has the potential to have an enormous impact. For MS, that means that instead of MS treatments targeting T-cells, they should instead target Memory B cells. It’s a game-changer, because it suggests MS may be caused by a virus that hides in the memory B cells. Although some treatments currently do deplete Memory B cells, MS is still primarily thought of as a T-cell disease.

Is MS caused by a virus?
Epstein Barr Virus (EBV) hides in Memory B cells. It shows itself every so often, when the T cells can kick its butt.

We’ve suggested that ocrelizumab - in targeting B cells, may actually be destroying a "virus factory". Indeed we’ve said that all active MS drugs may be doing this. Is there evidence for this?

In a study done on treating EBV with rituximab patients in a DIFFERENT disease, those with the highest level of EBV showed the best response to therapy, compared to people who were so-called EBV negative.

But the results didn’t show 100% response to the drug. Why? And why is it that some B-cell-targeting drugs don’t stop MS activity fully? The treatment failure may be because the cells causing the failure are already in the brain and it is too late. In the study, the bone marrow was also not emptied by rituximab. Other studies show rituximab does not effectively deplete EBV in the lymph glands.

What does this mean for MS treatments?

Earlier in the week we suggested alemtuzumab may fail in many people after switching from fingolimod, this is because it traps white blood cells in the lymph glands and bone marrow and because alemtuzumab does not clear out the bone marrow (this is based on an animal study). Is the level of purging of the bone marrow and lymph glands by ocrelizumab going to be enough so it doesn't to suffer the same fate as alemtuzumab after fingolimod treatment?

CD20 antibodies deplete EBV

If you haven’t been living under a rock for the past few months :-),
you will have noticed that we have been saying that MS drugs that work the best, seem to deplete the memory B cells the most.

What! You are a ground hog and have just come out of hibernation.

Ok… go on have a read. Its free (Click Here). Let’s get that altmetric up:-0

Centre stage is the memory B cells. According to the Immunologist they can turn into antibody making machines to help create MS, they can make goodies (cytokines) or should I say baddies that can help other cells to create MS and for the die-hards stuck in the mud, they can stimulate T cells to do the business. 

However, we can see ProfG’s Black swan perched on a Roche-inspired B cell. Don’t understand have a read of past posts.

Search on "Black Swan"

But ProfG’s swan may be laying a big egg. The dots may not be CD20 the target for Ocrelizumab as Roche intended, 
but seeds of discontent for alternative thought and the blobs of budding virus.

my favorite

Epstein Bar Virus infects via a B cell marker and hides in memory B cells. This shows itself every so often, when the T cells can kick it's butt.

So we suggested rather than depleting B cells to treat MS, ocrelizumab may be destroying a virus factory. Indeed we said that all active MS drugs may be doing this.
Is there evidence for this? 

Do we do some work or just a bit of reading?

The following was not done in MS (I have removed the disease)

Magnusson M et al. Epstein–Barr virus in bone marrow of patients predicts response to rituximab treatment.
Objectives. Viruses may contribute to disease. This prompted us to monitor viral load and response to anti-CD20 therapy in patients.

Methods. Blood and bone marrow from 35 patients were analysed for CMV, EBV, HSV-1, HSV-2,parvovirus B19 and polyomavirus using real-time PCR before and 3 months after rituximab (RTX) treatment and related to the levels of autoantibodies and B-cell depletion. Clinical response to RTX was defined as decrease in the disease activity score (DAS) >1.3 at 6 months.

Results. Before RTX treatment, EBV was identified in 15 out of 35 patients (EBV-positive group), of which 4 expressed parvovirus. Parvovirus was further detected in eight patients (parvo-positive group). Twelve patients were negative for the analysed viruses. Following RTX, EBV was cleared, whereas parvovirus was unaffected. Eighteen patients were responders, of which 12 were EBV positive. The decrease in the DAS was significantly higher in EBV-positive group compared with parvo-positive group (P = 0.002) and virus-negative patients (P = 0.04). Most of EBV-negative patients that responded to RTX (75%) required retreatment within the following 11 months compared with only 8% of responding EBV-positive patients. A decrease of  Ig-producing cells and CD19+ B cells was observed following RTX but did not distinguish between viral infections. However, EBV-infected patients had significantly higher levels of Fas (Suicide molecule) -expressing B cells at baseline as compared with EBV-negative groups.
Conclusions. EBV and parvovirus genomes are frequently found in bone marrow of patients. The presence of EBV genome was associated with a better clinical response to RTX. Thus, presence of EBV genome may predict clinical response to RTX.

So what does this study show. You can have a look at a few graphs from the paper.
EBV was eliminated from by the treatment of rituximab. This would be consistent with the B cells being infected by EBV being depleted. 

Those with the highest level of EBV showed the best response to therapy, compared to people who were so-called EBV negative (This proportion is too low compared to what we know of the normal population). 

Anyway, I have suggested that looking at memory B cells may be able to predict response to therapy, but this shows a hole in the argument because you can see that rituximab emptied the blood of B cells and as memory B cells make up about 30% of the CD19 population they are emptied from the blood too, and in this case there was not a 100% response to therapy.

However, if we drive from London (Bone Marrow/Lymph gland) to Leeds (Brain) along the M1 motorway (blood) and we can see a car (B cell) if we have a look for a minute from a bridge over the motorway (blood test). If I drive my car (Pathogenic B cell) to York (Centre of Gods own Country about 200miles north) to cause the problem (MS), if you look at 3 in the afternoon you might see loads of cars but do it at 3 in the morning and you might not see any although the problem is indeed a car driving to York (a few miles from Leeds) along the M1 motorway. 

So we may have to look outside of the blood to get the answer

The other problem is the treatment failure may be because the cells causing the failure are already in the brain and it is too late. In the ocrelizumab trials they re-baselined their results to allow 3 months
for the drug to work. A sensible thing to do if you are looking for efficacy.

However, you can also see that the bone marrow was not emptied by rituximab. If we look at other posts of rituximab, we can see that the lymph glands are not effectively depleted.

Subcutaneous versus Intravenous Administration of Rituximab: Pharmacokinetics, CD20 Target Coverage and B-Cell Depletion in Cynomolgus Monkeys Cheng-Ping Mao, Martin R. Brovarney, Karim Dabbagh, Herbert F. Birnböck, Wolfgang F. Richter, Christopher J. Del Nagro PLoS One. 2013; 8(11): e80533

Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing.  B-cell levels were decreased by 57% (subcutaneous) and 42% ( not that great) respectively. Yes this is in monkies but I could be bothered to go through 4000 references to pick a relevant human one.

Looks like ocrelizumab does something similar 

where it was suggested that alemtuzumab may fail in many people after switching from fingolimod 

This is because it traps white blood cells in the lymph glands and bone marrow and because alemtuzumab does not clear out the bone marrow (at least in animals expresing human CD52). Is the level of purging of the bone marrow and lymph glands by ocrelizumab going to be enough so it doesn't to suffer the same fate as alemtuzumab after fingolimod treatment?