Wednesday, 20 September 2017

#ChariotMS: what do we need to do to convince the community that more advanced MS is modifiable?

What needs to be done to tackle 'progressive' or more correctly 'advanced' MS? #ClinicSpeak #ThinkHand #ChariotMS

Summary: This post summarises what needs to be done to tackle more advanced MS including people with MS using wheelchairs. It makes the case for making several changes in the way we study advanced MS. What is needed now is a large injection of money to kick-start a trial in wheelchair users to delay loss of upper limb function. This post is an essential read for anyone who cares about people with more advanced MS. 

Earlier this week I had a debate with a colleague about therapeutic targets and whether or not they are achievable. He thought NEDA was a crap target as most of our patients who achieve NEDA still have residual problems. Therein lies the rub. NEDA, or no evident disease activity, refers to evidence of ongoing inflammation. NEDA does not refer to previous damage, nor does it refer to the ongoing consequences of previous damage. You can only do so much with an anti-inflammatory agent, i.e. switch-off inflammation, and even then most anti-inflammatory agents we use don't switch-off innate immunity within the CNS (hot microglia), nor do they purge the nervous system of plasma cells and oligoclonal immunoglobulins. In reality, we can only ask so much of our current DMTs. This is why we need combination therapy strategies. 

The following are some points about progressive MS that needs repeating: 

  1. We all need to accept that ‘progressive MS’ is a misnomer. Progression means improvement. At Barts-MS prefer the term ‘advanced MS’ this captures the associated disability that comes with this phase of the disease.
  2. We need to accept that the pathology that drives neuroaxonal loss, or neurodegeneration (the pathological substrate that underlies ‘advanced MS’) as being there from the beginning. This means the neurodegenerative phase of MS is present from the beginning before pwMS become physically disabled.
  3. MS is 1-disease and not 2-3-or-4-diseases. As I have said before the false division of MS into several diseases is not backed up by science, nor by philosophical arguments. This false division of MS into many diseases has become counter-productive to the field of MS. The division of MS into relapsing and progressive forms was Pharma-led to get MS defined as an orphan disease, which allowed interferon-beta-1b to get a license based on the results of one pivotal phase 3 study. It also allowed the company concerned to charge rather a lot of money for its product. Overall this has been good for MS in that it has attracted a lot of Pharma interest and has supercharged drug development in MS, but it is now slowing down drug development and making it very expensive. We need cheaper drugs for advanced MS; disability affects the cost-effectiveness models for reimbursement hence DMTs for advanced MS need to be priced lower than those for relapsing forms of MS.
  4. Following on the point above the division between SPMS and PPMS is false. There is no pathological, genetic, imaging or other data that suggests these are different entities. We, therefore, should be doing trials in both populations simultaneously.
  5. Slay the dogma that more advanced MS has reduced inflammation, or is non-inflammatory. There are clinical, imaging and pathological data that shows inflammation plays a big part in driving advanced MS. Therefore not to target more advanced MS with an anti-inflammatory is folly.
  6. Accept that reserve capacity in particular systems plays an important part in how MS worsens. Neuronal systems with reserve are more likely to be able to recover function and hence show a treatment effect compared to neuronal systems in which reserve capacity is exhausted. In the latter systems, it will simply take longer to show a treatment effect; we refer to this as therapeutic-lag. These observations are explained by the length-dependent axonopathy hypothesis. This means that we will need to focus more on the arm-and-hand function as a primary outcome in pwMS who have lost too much function in their lower limbs (EDSS>=6.0). This is what we are proposing to do in our CHARIOT study (parenteral cladribine).
  7. Challenge the dogma that once someone has lost lower limb function and is a wheelchair user that the disease is not modifiable. We have good data that DMTs can slow the worsening of upper limb function despite subjects being wheelchair-bound. We feel very strongly about this point and are very keen that future trials in advanced MS include wheelchair users. Why should we write-off people with MS who have lost leg function? What keeps pwMS independent and functioning in society is arm and hand function. We as a community have to think about that very carefully. We have rehearsed these arguments many times as part of our #ThinkHand campaign.
  8. Accept that we will need to use combination therapies to make a real difference to more advanced MS. We are not necessarily talking about two anti-inflammatories, but an anti-inflammatory targeting adaptive immune responses in combination with a neuroprotective therapy. I agree there is a good argument for combining an anti-inflammatory that targets innate immune mechanisms - for example, laquinimod which targets hot microglia - with a classic anti-inflammatory against targeting adaptive immune mechanisms.
  9. We need to ditch the EDSS as the primary outcome in advanced MS trials. The whole community knows that the EDSS is not fit for purpose in more advanced MS. We need to get the regulators to accept this. We also need to work on a set of outcome measures that capture the whole impact of MS on someone with the disease. We are getting there with the new rendition of the MS functional composite. But in my opinion, this is not enough. We need more PROMS in the battery, in particular, a better hand-and-arm function PROM. We are aware that there are several out there and some are in development, including one from Barts-MS.
  10. We need to think creatively about our trial design. I am not an expert here, but some in the community are pushing for adaptive trials, i.e. a multi-arm phase 2 trial with a seamless design allowing it to be converted into a phase 3 study. Pharma doesn't like adaptive designs nor do the regulators. I do think we do need two phases to trials in more advanced MS, i.e. the standard head-to-head phase with a robust primary outcome, say a multi-outcome composite, followed by an open-label extension where the study subjects remain blinded to their original treatment allocation. This will allow us to capture therapeutic lag. If we had done this we would have had licensed treatments for more advanced MS decades ago. The logic behind this trial design is explained in detail in our length-dependent axonopathy paper (see below).
  11. Acceptance of more sensitive biomarkers to get proof-of-concept trials done more quickly. I know I am biased, but I really think neurofilament level monitoring in the CSF and blood will provide us with this tool. This means we will be able to do phase 2 studies a lot quicker and more cheaply than we have done them in the past. We have fully recruited our PROXIMUS trial and we have learned a lot in the process. For those of you new to this blog the PROXIMUS trial was an add-on neuroprotective trial in which we add oxcarbazepine, a sodium channel blocker, on top of an existing DMT in subjects with ‘early SPMS’. Labelling eligible subjects as having early SPMS was a mistake. Nobody wants to be told they have SPMS, therefore their clinicians were reluctant to refer patients eligible for the study. My advice to anyone doing trials in this space is to avoid the term progressive.
  12. Political changes are needed to incentivise the repurposing of off-patent drugs. We have discussed this on this blog endlessly and have even written a paper on the so-called ‘Big Pharma Alternative’ to explain our thoughts on this.
  13. Regulatory changes are also required. We need to get the FDA and EMA to accept wheelchair users in trials. Some of my colleagues think this is a big issue; I don’t. If we do a trial and provide compelling data that drug x in combination with drug y delays, or stops, worsening disability in upper limb function in pwMS in wheelchairs they would be obliged to license the combination, provided it was safe. What we need from them, however, is to accept the need for combination therapies. MS is a complex disease and hence will need a complex solution to tackle it, i.e. combination therapies, this is not rocket science and happens all the time in other disease areas for example oncology.
  14. More detailed cost-effective models that focus on the loss of upper-limb function and bulbar function (swallowing and speech) are needed. It is clear from the recent EU cost of MS study that costs soar as pwMS lose arm function.
  15. We also need to tackle ageing and its impact on worsening MS. The evidence that early, or premature, ageing from the reduced brain, and cognitive, reserve drives worsening of MS in older pwMS, is beyond doubt. What we need is some way of dissecting-out premature ageing from MS-specific mechanisms. Another issue with ageing is the emergence of comorbidities as a driver of worsening MS, in particular, smoking, hypertension, hypercholesterolaemia, metabolic syndrome, diabetes and a sedentary lifestyle. I sit on many trial steering committees and we deal with this problem by simply putting an age cap on the trial population. This is the main reason why trials in advanced MS usually have a ceiling of say 55, or 60, years of age. This is ageist and we must develop better tools for dealing with this issue.
  16. We need to manage expectations. PwMS are expecting an effective treatment to restore function or return them to normal, similar to my colleague's expectations. The latter is not going to happen. The best we can expect is to slow down the rate of worsening disability, or flat-line their disability, with anti-inflammatory and neuroprotective strategies. I say this knowing that in pathways with reserve capacity there is a possibility of improvement in function, but not enough improvement for me to falsely raise their hopes. To get substantial and meaningful improvements in disability we need new treatment strategies, possibly remyelination therapies that work, but we will almost certainly need treatments that promote axonal sprouting, synaptogenesis and plasticity mechanisms to restore function. This is not rocket science. If you are coming to ECTRIMS I will be giving a talk on this exaxt topic in a satellite symposium. 

As you can see we are passionate about tackling more advanced MS. I personally think we have thrown-out many babies (DMTs) with the bathwater. Why? We haven’t thought deeply enough about some of the issues highlighted in the points above. We need to start a serious debate about these issues and get on with the job of protecting arm and hand function in pwMS. 

If there are any wealthy philanthropists out there? DrK (@KlausSchmierer) is looking for a large donation to support his application to the NIHR for the CHARIOT study. He needs to bring the NIHR costs down to under £2.5M to have any chance of getting this trial funded. 

DrK with a smile

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

CoI: multiple

HSCT in the News

Yesterday in the mail we had another news story on HSCT, 

This is Haematopoetic Stem Cell Therapy, which I'm sure you have all heard of as some of our commenters ensure the topic of conversation steers that way every day ......Yawn.

You don't need a neuro to do it and if you have the you go.

Whilst this modus operandi is consistent with most fad treatments that you feel compelled to try, and use to suggest there is some pharma conspiracy about why it is not investigated.

However, the difference here is that there is solid data that it works.
As we all know neuros in grey-suits are a conservative bunch and if they get the willies with the thought of using something like alemtuzumab, is it surprising that they positively tremble with the fear of using HSCT and its consequences (which used to be mortality). However, it is your risk but it is usually reserved for the treatment of last resort.

Based on the data presented is it probably the most effective DMT, it should be as in one form HSCT (ablative) removes and replaces your immune system. Yet it is not widely used. Why not...

The conspiracy theorists suggest we are a biased bunch supporting pharma to the detriment of HSCT..

In the article by the Mail (as Newspaper) will fuel that clamour. It says "About 60 patients have now been treated as part of the ongoing study at London’s King’s College Hospital and Imperial College Healthcare and doctors say that the effect has been dramatic for some".

Reading the other direction it therefore says "there are no dramatic effects for many" .....So go into this with your eyes wide open as it may not be the cure you are hoping for.

If you are going to do this ensure you sign up to the MS register?Narcoms etc

Sign up here (CLICK), as it is vital that the magical effect, or not, is recorded somewhere. Imagine in the hundred/thousands of people who have taken a trip to Mexico/Russia has been followed there would be massive anecdote and information to help inform choice would be available.

At a cost of £35,000 per patient, the price is comparable to a single year of MS drugs....well not really for some as £35K is 6 years worth. However if the NHS took up the slack when haematology clinics have spaces, it would certainly be cost-effective in the long term, as alemtuzumab costs about £60,000 + the rest for monitoring.

The procedure is described and importantly the Doc leading the study says "For those with significant disability, we don’t expect a dramatic transformation" I say again 

"For those with significant disability, we don’t expect a dramatic transformation"....Do this with your eyes wide-open.

‘If they "are in wheelchair, they are likely to stay in one. But they may not get worse. And there have been very good results with patients with earlier-stage MS"

Then they say the study was published a year ago, we reported on it a year ago, and not much has happened since then....Yawn

Read more: 

ProfG has been writing that there is a UK application in progress.                                                                                           

Tuesday, 19 September 2017

#ClinicSpeak: post-menopausal hormone replacement therapy in women with MS

HRT has shown not increase mortality in postmenopausal women. #ClinicSpeak #WomenPower #BrainHealth

Summary: A long-term, follow-up, study of hormone replacement therapy in post-menopausal women shows that HRT does not increase mortality (death). If your GP has refused you HRT in the past based on the assumption that HRT is unsafe you can now challenge this position armed with this new data. 

There is a reasonable scientific rationale why women with MS who are post-menopausal should consider hormone replacement therapy (HRT). It helps with bone health, a well-defined problem in MS, and HRT is possibly neuroprotective. In addition, HRT addresses troubling menopausal symptoms that may, or may not, exacerbate MS-related symptoms. These include mood disorders, poor sleep, fatigue, low libido and weight gain. Over the last few years, there has been an increasing trend for GPs (general practitioners or family doctors) to refuse HRT to several of my patients based on the fact that it increases your risk of cardiovascular events and breast cancer, albeit by a very small amount. Despite several of my patients stating that they are prepared to take these risks their GPs have refused to prescribe them HRT. It is clear that paternalistic medicine is alive and kicking. 

The following paper on all-cause mortality shows that among postmenopausal women HRT for ~ 6-7 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. If you are brave and feel like taking on your GP you can now go armed with this information back to your GP and demand them to reconsider their previous decision. 

I also want to state that a lot of GPs view HRT as being a lifestyle therapy, which is one of the reasons why they are so reluctant to prescribe it. In short, HRT is an anti-aging drug and a lot of women take HRT to fight back the ravages of aging. So what, if that is the reason why women want HRT who am I, or their GPs, to say no? I now think there is a very strong case for HRT becoming available as an over-the-counter (OTC) medication so that women can make their own decisions about their health. What do you think? 

Manson et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-SpecificMortality: The Women's Health Initiative Randomized Trials. JAMA. 2017 Sep 12;318(10):927-938.

IMPORTANCE: Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality.

OBJECTIVE: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials.

DESIGN, SETTING, AND PARTICIPANTS: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014.

INTERVENTIONS: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median).

MAIN OUTCOMES AND MEASURES: All-cause mortality (primary outcome) and cause-specific mortality(cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization.

RESULTS: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-causemortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.

CONCLUSIONS AND RELEVANCE: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years.

CoI: none in relation to this post.

Social cognition in MS

Eur J Neurol. 2017 Sep 12. doi: 10.1111/ene.13457. [Epub ahead of print]

Characterization of social cognition impairment in multiple sclerosis.

Neuhaus M, Bagutti S, Yaldizli Ö, Zwahlen D, Schaub S, Frey B, Fischer-Barnicol B, Burgunder JM, Martory MD, Pöttgen J, Annoni JM, Penner IK.


Multiple sclerosis (MS) has been associated with deficits in social cognition. However, little is known about which domains of social cognition are predominantly affected and what other factors are associated with it.


1) To characterize social cognition deficit in a group of MS outpatients. 2) To relate impairment in social cognition to overall cognitive status, depression and fatigue.


Thirty-five MS patients (mean disease duration 12.9 years, median EDSS 3) and thirty-four healthy controls (HCs) were examined using the German version of the Geneva Social Cognition Scale to measure different domains of social cognition. Standard neuropsychological testing was applied to all patients and to 20 HCs. Patient-reported outcomes included questionnaires for fatigue, depression, anxiety and executive-behavioural disturbances.


The mean social cognition raw score was lower in the MS patients compared to the HCs (86.5±8.7 vs. 91.2±5.9 p=0.005; d=0.6) and did not correlate with EDSS or disease duration. The difference was driven by facial affect recognition and the understanding of complex social situations (14% and 23% of patients under the cut-off, respectively). The impairment in these two tasks did not correlate with general cognitive performance or depression but with fatigue.


The impairment in our group was restricted to high order and affective social cognition tasks and independent of general cognitive performance, EDSS, disease duration and depression. Fatigue correlated with social cognition performance, which might be due to common underlying neuronal networks.

Critiques would have you believe that emotional intelligence (EQ) is fundamental to the survival of the human race, based on pretext that EQ provides the necessary models of cooperation to drive evolution in our favour. In my opinion EQ is overrated; part 'fru fru' and part new-age, a qualitative vision for the emotional chasers, an emergent probability. If the current state of global affairs was anything to go by, and say the EQ of the human race was a business, it would surely be either bankrupt by now, or at least leveraged to the teeth??? Frankly, most of us don't talk for our health...and least of all for show. And, so why care to listen? I believe, for the small things - relationships and such, and may be also for our own sanity.

Social cognition (SC) is defined as 'the processing of information that influences our behavior towards other people'. It is heavily reliant on set of unwritten social rules, and guess work on what others might be feeling, and if you're in the UK an uncanny ability to read between the lines. The cognitive and affective alterations that result from having a neurological disorder are clearly going to affect this.

Neuhaus et al. wanted to study the factors that influence SC performance in MS. In PwMS and controls they tested both the Geneva social cognition scale and the standard neuropsychological battery.

They found SC impairment in 9% of PwMS tested, reaching 24% for facial affect recognition (the ability to detect emotion from facial expressions). There was no association with SC score and EDSS (the level of disability) or disease duration. The global SC score was moderately correlated with verbal memory, visuospatial memory (a visual map for things) and verbal fluency (information retrieval from memory). Although, fatigue and depression scores were higher in MS, there was no correlation between SC and depression. On the other hand, there was a correlation of SC with cognitive fatigue. When the authors controlled for fatigue in their analysis, the differences between PwMS and controls in SC scores were no longer significant, i.e. they disappeared.

It is therefore likely that both fatigue and SC share the same pathophysiological mechanisms, caused by widespread network dysfunction in the intricate brain connections rather than abnormalities in specific brain domains per se. Heldner et al. (Front. Neurol.) found that behavioral changes, including depression, lability, irritability, impatience, apathy, were commoner in MS (with a lifetime prevalence of ~50%), and occurred largely independent of physical disability and cognitive functioning but correlated with both fatigue and depressive symptoms. Clearly, the whole thing is a bit complicated,  but the next time you strike up an important conversation or a relationship, make sure you're well rested!

Monday, 18 September 2017

Plasma blasts are the problem

Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis 

Brain, Volume 128, Issue 7, 1 July 2005, Pages 1667–1676,

Multiple sclerosis is a chronic inflammatory and demyelinating disorder of the CNS with an unknown aetiology. Although intrathecal immunoglobulin G (IgG) synthesis is a key feature of the disease, little is still known about the B cell response in the CNS of multiple sclerosis patients. We analysed the phenotype and kinetics of different B cell subsets in patients with multiple sclerosis, infectious disease (IND) and non-inflammatory neurological disease (NIND). B cells were detected in the CSF of multiple sclerosis and IND patients, but were largely absent in NIND patients. In the CSF, the majority of B cells had a phenotype of memory B cells and short-lived plasma blasts (PB); plasma cells were absent from the compartment. The proportion of PB was highest in multiple sclerosis patients and patients with acute CNS infection. While PB disappeared rapidly from the CSF after resolution of infection in IND patients, these cells were present at high numbers throughout the disease course in multiple sclerosis patients. CSF PB numbers in multiple sclerosis patients strongly correlated with intrathecal IgG synthesis and inflammatory parenchymal disease activity as disclosed by MRI. This study identifies short-lived plasma blasts as the main effector B cell population involved in ongoing active inflammation in multiple sclerosis patients

As ProfG has gone AWOL today I post this,

I was reading a paper by a student and they had some references that I was not aware of one by the Cambridge group talking about the lymphocyte phenotyping data from the MS CARE studies and another about plasmablasts.

I was getting ready to make blog post apology, because I had said the data was unpublished in our paper, but then I found out that the Cambridge report was a meetings abstract not a publication. So they had not published the data.Just like we are still missing data from the trial where the thymus is stimulated:-(

Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K.Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol. 2017;74(8):961-969.

So I remain unrepentant about publishing the data and will not make the apology for exposing an issue that should have been exposed years ago.....namely neutralizing antibodies occur after alemtuzumab and that they......can be a problem for alemtuzumab.

It of course obvious as any protein can cause neutralizing antibodies to form. However it is the scale of the occurrence that is unusual. Had they been mentioned years ago it would be a non issue 

However, now we will see a number of papers appear about them. 

We can already see examples at ECTRIMS based on the programme....but in hindsight have we been told about this for years. 

CAMPATH-1H was the first humanised antibody and was designed to inhibit anti-globulin responses and did this to some extent, but it looks like it was the worse in class, as we can see about 80% of people treated with alemtuzumab make neutralizing antibodies.

Cambridge examined ways to get rid of the binding antibodies. 

Somerfield J et al. A novel strategy to reduce the immunogenicity of biological therapies.J Immunol. 2010 ;185(1):763-8.

Why do this unless you know about the issues they cause.

Next why choose the dosing schedule that was done...two doses a year apart and if you fail you have to wait to the end of the year to be redosed. 

Was it the neutralizing antibodies that drove this schedule? 

Why because by the time the third dose comes along 30% of people will have pre-existing antibodies ready to stop the next dose of alemtuzumab working compared to less than 1% before the second cycle. 

Of those 30% the titre (amount of antibody) of the antibody will be too low to do this, for most I suspect, but treatment failures were not mentioned in the literature. Anaphylactoid responses have not been mentioned. Do they occur as about 75% of people have binding antibodies 12 months after the second cycle. How common is this issue. I have asked numerous times.

Do you have to wait to the end of the year before the the next dose, because if you did it as disease reactivates there would be still neutralizing antibodies in the system waiting to stop the drug working as it takes a long time for them to wane..

Any way, I digress, the paper above caught my eye the take home message does not say memory B cells are the main problem. It say plasma blasts are the problem.  I said I would look at papers that challenge the role of memory B cells.

Plasmablasts are the fore-runner to a plasma cell and making antibody and in this study they saw that plasmablast numbers correlate with antibody secretion. 

But does this kill the memory B cell idea?

Not really as the first thing you ask is whether the memory cells are the fore-runner that change into the plasma blasts. 

The answer is you cannot say that this is not the sequence. 

Next why study the plasmablasts? 

Because if you look at the figure above you can see that the memory B cell is the main B cell subset in the spinal fluid (there are more red dots in group 2 than group 3. But because group 3 appeared the cells in group 2 were ignored for the rest of the paper. 

So the memory idea is not dead yet.