Gavin Giovannoni

Guest Post: DrMaria from Spain explains about relapses

Hello everybody

First of all, I would like to introduce myself. I am Maria Mateo, I am a Neurology registrar from Spain and I have the pleasure of spending three months at Barts-MS to learn about MS.

As a part of my stay here, I have been attending MS clinics. As we know, MS patients can experience a broad variety of symptoms during their disease that can be difficult to explain. Thus, I have noticed that some MS patients have difficulties interpreting whether their symptoms are due to a new relapse or not, or if their symptoms are related to something else. Therefore, I have thought that it would be useful to clarify some main concepts around MS relapses.

What is a relapse?

Relapses are episodes of relatively sudden onset (over hours or days) new symptoms or worsening of existing MS symptoms. They usually get gradually worse over a period of time, normally a few days. Then, they remain for a period of time and later on (typically after some weeks) the symptoms start to gradually improve, either partially or completely. Relapses reflect disease activity and they must be detected an assessed properly. Steroids are the most common therapy used to treat relapses in order to shorten the symptoms and accelerate the recovery.

There are some considerations that can help us to distinguish real relapses from other conditions:

They must last at least 24 hours. As you know, MS patients experience many clinical issues over time. You can notice mild variations in these symptoms that are not related to new disease activity, so they should remain relatively stable. For this reason, at some point, this temporary worsening of symptoms can be misunderstood as a relapse. Thus, this time requirement can help us to distinguish relapses (more than 24h) from fluctuations symptoms (shorter, more variable).
Symptoms must occur at least 30 days from the start of the last relapse. Otherwise, the clinical change can be secondary to the same relapse or cluster of lesions causing multiple new symptoms. Neurologists refer to this a multifocal (many sites) relapse.
Other causes need to be ruled out. Frequently, other conditions can worsen existing symptoms or even produce new ones and mimic a relapse. For instance, hot weather or more frequently fever and infections can cause relatively sudden clinical changes over hours or days (pseudo-relapse, see below). Thus, these conditions must be assessed and ruled out when a relapse is suspected. The most frequent infections associated with pseudo-relapses are viral upper respiratory tract or urinary tract infections.

What kind of symptoms can you notice?

Any MS symptom can be a relapse, but the clue is that they should appear relatively suddenly. You must notice a change from your previous clinical state. For instance, you can notice one or several of these symptoms:

Weakness in a leg or an arm
Sensory disturbances: areas of numbness, pins and needles or pain
Visual loss, double vision
Bladder or bowel issues
Dizziness, balance and coordination impairment
Mobility or gait disturbances
Fatigue
Memory and concentration impairment

What other conditions can mimic a relapse?

Pseudo-relapse: A pseudo-relapse is a period of clinical worsening that could mimic a relapse but that is not related to disease activity. Pseudorelapses are caused by some intercurrent process such as a fever or an infection. Once this process is reversed you should get better. The most common causes are:

Heat: hot weather, hot shower, fever.
Infections: especially virus (flu) or urinary infections.

Paroxysmal symptoms: They are neurological signs or symptoms that occur with a sudden onset and a sudden end. They last a short period of time (often seconds), they are usually repetitive and stereotyped (same symptoms repeating themselves with each episode). Some examples of paroxysmal symptoms are Lhermitte’s sign (electric-shocklike sensation down back when bending your neck), trigeminal neuralgia (paroxysms of facial pain), tonic spasms (spasms of the arm and/or legs), dystonia (writing movements of a part of the body), myoclonus (sudden jerking movements), dysarthria (slurred speech).

Progression: It is a slow and progressive worsening of symptoms, over weeks, months or even years. In this case, you could not be able to identify a significative worsening from one week to another. This is indicative of the gradual loss of nerve fibres and function that characterises more advanced or progressive MS.

I hope this post has helped better understand your disease and clarify some doubts that can come up quite often.

CoI: I have received honoraria from Sanofi-Genzyme and UCB Pharma for preparing and grant for an online subscription from Sanofi-Genzyme.

Treating carry-over PML after immunodepletion

Treating PML in the presence of immunodepletion is not necessarily a death sentence. There are some solutions on the horizon.

At present we don’t have an anti-viral agent that works against the JC virus that causes PML (progressive multifocal leukoencephalopathy). Therefore we have to rely on your own immune system to fight and clear the virus if you develop PML. This is why we wash out natalizumab with plasma exchange or stop the immunosuppressive when somebody develops PML. A problem arises when we can’t reconstitute CNS immunosurveillance or your immune system. The latter can happen with IRTs (immune reconstitution treatments) and potentially with anti-CD20 therapies (they do reduce CD8+ T-cells as well) or in people with persistent lymphopenia post fingolimod or dimethyl fumarate or other DMTs for that matter. This is where immunotherapies are needed.

One strategy is to give unfortunate people with PML in this situation donor anti-JCV lymphocytes that are matched to their HLA (human leukocyte antigens) to fight the infection. In short, this is an immune transplant, i.e. giving them donor-matched T-lymphocytes to fight JCV. The study below uses T-cells that were designed to attack the BK virus a virus that is very similar to JCV.

The logistics of immunotherapy for PML are not insignificant and ideally need to be established before hand so as not to delay treatment. One option is to rely on Pharma to create a bank of HLA-specific cytotoxic T-lymphocytes that are frozen and cane be mobilised within 24-48 hours as a licensed treatment for PML.

When I was at the NIH earlier this year I heard about such a trial and would urge you to contact them if and when the need arises.

Muftuoglu et al. Allogeneic BK Virus-Specific T Cells for Progressive Multifocal Leukoencephalopathy. N Engl J Med. 2018 Oct 11;379(15):1443-1451. doi: 10.1056/NEJMoa1801540.

JC virus, the cause of progressive multifocal leukoencephalopathy (PML), and the BK virus are genetically similar and share sequence homology in immunogenic proteins. We treated three immunosuppressed patients with PML with ex vivo-expanded, partially HLA-matched, third-party-produced, cryopreserved BK virus-specific T cells. The immunosuppression in these patients was due to the conditioning regimen for cord-blood transplantation in one patient, a myeloproliferative neoplasm treated with ruxolitinib in another, and acquired immunodeficiency syndrome in the third. After T-cell infusion in two of the patients, alleviation of the clinical signs and imaging features of PML was seen and JC virus in the cerebrospinal fluid (CSF) cleared. The other patient had a reduction in JC viral load and stabilization of symptoms that persisted until her death 8 months after the first infusion. Two of the patients had immune reconstitution syndrome. Donor-derived T cells were detected in the CSF after infusion. (Funded by the M.D. Anderson Cancer Center Moon Shots Program and the National Institutes of Health; ClinicalTrials.gov number, NCT02479698 .).

CoI: multiple

triMS-online: helping female academics

Another development at ECTRIMS 2018, which I heard about via the ECTRIMS grapevine, is that female academics are mobilising and have formed a group to demand gender equality at the top table of MS academia. Good!

Apparently, our posts on this blog (MS Establishment) and our recent letter to the Annals of Neurology (MSexism) has triggered a response from female neurologists and female academics working in the field of MS. The women involved have penned a letter that they are, or have, submitted to the Annals. I haven’t seen it, but I and sure it will address the issues at the heart of this debate.

From my perspective, three things happened at ECTRIMS that are relevant to this debate. Firstly, we held our first face-to-face ORATORIO-HAND (ocrelizumab in PPMS trial extending into wheelchair users) steering committee. The first, steering committee with close to 50% female representation; we wanted 50%, but due to family and other commitments some women who were approached were unable to participate; the female headcount is over 40%.

Secondly, the Burning Debate at ECTRIMS this year was an all female affair. This was deliberate and was designed to counter the all-male debate we hosted last year.

Thirdly, we have now launched triMS-online, the first virtual online conference for MS. The aims of triMS-online are multiple. You may remember that the original idea of triMS-online came from this blog. The objective is to do punchy, short, themed MS-related conferences online that can be viewed live or asynchronously in your own time. triMS-online is also environmentally friendly; imagine how many air miles we are avoiding by not having to fly people to conferences?

The other advantage of triMS-online is that it takes high-quality MS research and education to resource-poor environments across the globe. We want a new generation of MS researchers and HCPs to have access to the latest MS research and teaching.

As founding chair of the scientific committee of triMS-online, I wanted to use the opportunity to shake things up a bit. When you go to ECTRIMS it is generally the same-old faces and KOLs on the platforms. We, therefore, invited a diverse group of ‘young’ MS academics from across the globe to run triMS-online and we made a strategic decision of having at least an equal number of women on the steering committee; in fact, 6 out of 10 members are women.

The following is the first triMS-online programme. We plan to run about 2-3 a year and have many ambitious plans for the triMS-online platform going forward. I, therefore, urge you to register. We will be inviting feedback, including suggestions for future meetings.

We would encourage young academics, in particular, those who are disadvantaged and from under-represented groups to submit ideas and posters for the next meeting.

CoI: multiple

Early reflections on ECTRIMS 2018

I am writing this post on the flight back to London from Berlin. Being trapped in a tin tube at over 10,000m above sea level is always a good time to think.

under&over – ProfG’s #1 non-scientific highlight at #ECTRIMS2018

Guess what my #1_scientific_highlight was at #ECTRIMS2018?

Raju Kapoor with ProfG’s #1 scientific highlight at #ECTRIMS2018

The avalanche of neurofilament data, in particular, the serum neurofilament results from the natalizumab SPMS, or ASCEND, trial. This was presented by Dr Raj Kapoor as a late-breaking poster. In summary, it showed that peripheral blood neurofilament levels were responsive to natalizumab therapy regardless of whether or not SPMSers had baseline Gd-enhancing lesions (aka baseline activity).

Why is this so important?

Please remember that the population of SPMSers in the ASCEND trial were very advanced with more than 60% needing a walking stick or sticks, i.e. they were almost off their feet and had markedly reduced reserve in the neuronal system supplying their legs. This study was negative on lower limb function (EDSS and timed-25 foot walk), but positive on upper limb function (9-hole peg test) at 2-years becoming positive at 3 years in the extension study. These results are consistent with MS being a length-dependent central axonopathy. The good news is that these results are now backed-up with data from the hottest biomarker in town.

An interesting observation that has yet to be published from the ASCEND trial is the data showing that natalizumab-treated SPMSers are more likely to have a confirmed disability improvement compared to placebo-treated subjects in the 2-year period of blinded observation. Could the drop of peripheral blood NFL levels indicate not only a reversal of the neurodegenerative pathology but possibly be a marker of neuroregeneration? Pity we don’t have CSF from this trial it would be fascinating to look at regenerative biomarkers, i.e. is there any evidence of axonal sprouting and synaptogenesis on natalizumab?

What this new blood NFL analysis tells us that so-called non-relapsing advanced MS is inflammatory and this inflammation is modifiable by a highly effective MDT such as natalizumab. Please note that this was not seen in the data presented on the effect of siponimod on peripheral blood NFL levels at the AAN earlier this year.

I am now convinced that natalizumab is an effective treatment for SPMS. It also further validates serum NFL as a surrogate marker of neuroaxonal damage in MS. Is there now enough data for the regulators, i.e. the FDA and EMA, to evaluate NFL as a surrogate end-point for MS? I personally think so, which is why we have been using CSF NFL levels in clinical practice at Barts-MS for about 3-4 years to aid clinical decision making. We use CSF NFL as an inflammatory biomarker and include it in our treatment target for more advanced MSers.

Once the FDA and EMA accept NFL as a surrogate end-point in MS I would urge Biogen to go back to the regulators to discuss natalizumab getting a label for progressive forms of MS. If Biogen don’t think they have a chance of getting a label change via this route I would urge them to do ASCEND-2 or ASCEND-HAND, i.e. trial of natalizumab in advanced MS only this time extending recruitment into MSers in wheelchairs. Another option is to do the randomised withdrawal study that I proposed last year. The latter would have to be done in the UK, where we are being forced to stop DMTs in MSers who become wheelchair bound. The idea is to randomise people to placebo or natalizumab with the primary outcome being time to confirmed relapse or evident disease activity using MRI and serum NFL levels. Some of you may ask, what about PML? Yes, what about PML? This can potentially be derisked using the current tools including extended interval dosing (EID) in the trial. I have also made the point that JCV and PML are biological problems and they will be cracked with time. We need to keep up on the pressure on the scientific community to solve these problems.

I was asked by a colleague at ECTRIMS if I envisage NFL replacing MRI as an assessment of MS disease activity? Potentially, yes. The good thing about NFL monitoring is that it is an integrator of MS disease activity and will assess both brain and spinal cord activity. This is important because most of us don’t include spinal cord imaging in our monitoring protocols. NFL is also potentially cheaper and easier to standardise and as it is a lab-based immunoassay could really help in resource-poor environments with limited access to MRI. It will also be more convenient for patients; having a blood test is quicker and easier than coming in for an MRI scan. At the moment one company have the monopoly on peripheral blood NFL measurements and are charging an extortionist price for their assays, reagents and the maintenance of their platform. The other good news at ECTRIMS is that competition will be arriving soon in the NFL space. Hopefully from at least another two platforms, one of which who has a large footprint in routine laboratories. We need some good old competition to drive down prices.

In support of NFL replacing MRI monitoring was a poster from Tjalf Ziemssen’s group in Dresden showing that when you do monthly blood NFL levels, NFL levels were noted to rise prior to detecting MRI activity or clinical relapse. This is not surprising; I have data from my PhD on daily urinary neopterin levels, an inflammatory marker, showing the same thing. So yes, I envisage a world in the not so distant future when MSers will be having frequent blood neurofilament levels measured, hopefully, using home finger-prick technology to monitor their MS disease activity. Once we get to this stage then we will be able to apply true precision medicine to individual patients and we will be able to optimise treatments based on real-time biomarker measurements.

We have been working on NFL in MS for over 15 years and to see it transforming MS research and translating so fast into clinical practice makes the work we have done seem worthwhile.

CoI: multiple

Is it time to reunify MS as one disease?

I am just about to leave Berlin tired but content that the MS world is finally beginning to acknowledge that #MS_is_1_and_not_2_or_3_diseases. We have covered this topic extensively over the last 4-5 years and I did so again in my talk as part of the Roche satellite symposium.

I have also uploaded all my other ECTRIMS-related slides and posters to my new SlideShare site for download.

CoI: multiple

ECTRIMS 2018: will MS become one again?

I arrived in Berlin yesterday and already I am seeing ECTRIMS 2018 turning into a battle between the lumpers and splitters, i.e. is MS one, two or three diseases.

Making Berlin one again

Roche, who has ocrelizumab licensed for relapsing and primary progressive MS want MS to be one disease. On the other hand, Novartis who have just submitted siponimod to the FDA for SPMS want it to be at least two diseases. This new battle helps nobody. We have been running the #MS-is-1-not-2-or-3-diseases for several years on this blog and I am not going to change my position on this.

Our MS as a length-dependent axonopathy hypothesis makes a strong case of MS being one disease, which is why we are arguing that advanced MS (formerly known as progressive MS) is modifiable. This principle underpins our #Chariot-MS and the #Oratorio-Hand studies and explains the positive low-dose oral methotrexate and ASCEND (natalizumab) trials. If we had interpreted the results of the low-dose oral methotrexate progressive trial from over 20 years ago correctly we would have had licensed therapies for progressive MS decades ago; yes, decades ago.

In reality, the salami slicing-up of MS into relapsing and non-relapsing forms, and of chronic progressive MS into primary and secondary progressive MS, was driven by money. When the interferon trials started it was important to make MS an orphan disease, i.e. to having fewer than 200,000 patients classified as having the disease. Being an orphan disease allowed Pharma (Bayer-Schering) to access the market with one pivotal trial, gave them market exclusivity and allowed them to charge much more for their product. The consequences of this is that we have divided MS into being many diseases, which is to the detriment of people with MS. The consequences of this are not trivial. Being diagnosed as having MS is bad enough, but then being diagnosed as having secondary-progressive disease is like getting another disease. The latter is still interpreted by most people with MS as now having a disease that is not modifiable. For example, in the NHS we are meant to stop DMTs in patients who develop SPMS. There are also many other reasons to avoid a diagnosis of SPMS.

An analogy to the RRMS vs. SPMS dichotomy is being diagnosed with a low-grade tumour, that on average is quite indolent and slow growing, however, after time the tumour mutates to become highly-malignant, life-threatening and often terminal. Just as people fear their tumour mutating, and becoming ‘terminal’, people with relapsing MS live in fear of developing progressive MS.

Recruitment for our PROXIMUS trial, which is now closed and being analysed, has been a victim of MS being two and not one disease. We made the mistake of calling it a secondary progressive trial. Very few of my colleagues referred patients for this trial simply because it meant diagnosing their patients as having early SPMS. Almost every neurologist I know avoids making a diagnosis of SPMS as long as possible because of the repercussions it has for their patients.

I think we need to turn the clock back and get rid of arbitrary, non-science, based definitions of MS. They don’t help us clinically. MS begins long before the first clinical attack. Similarly, progressive MS is present from the start of the disease. There is simply no magic point in time when you become SPMS. Dividing MS into relapsing and progressive phases may have helped Pharma get interferons licensed under the orphan-drug act, made them lots of money, but it is now doing the field of MS a major disservice.

Now that there are marketing reasons to keep MS sliced-up as multiple diseases I can only imagine the Pharma shenanigans that will emerge. ECTRIMS-BERLIN 2018 is witnessing the first shots of this epic battle. Who will win? At least this new battle buries the dogma that advanced, or progressive, MS is not modifiable. We have won one battle only to replace it with another one.

I am determined to remain an optimist and view this change in perspective as being positive for the field; at least both sides believe progressive MS is now modifiable.

CoI: multiple

ProfG’s MS-related Twitter activity: week 1st-7th October 2018

It is a draw interferon-beta 1 vs. glatiramer acetate 1. #ClinicSpeak There is no difference in the comparative effectiveness between the beta-interferons and glatiramer acetate. But what about the other attributes, e.g. pregnancy, NABs, monitoring, etc. ? https://t.co/b6VygWzrQq pic.twitter.com/90qwG5wAtI

— Gavin Giovannoni (@GavinGiovannoni) October 6, 2018