Prof G's MS Blog Archive

Knowing about damage or not

Barts-MS rose-tinted-odometer: ★ (seeing orange; halfway between red and yellow)

Do you want to know how badly damaged your MS brain is or would you prefer to put your head in the sand and ignore it? This is a dilemma facing a large number of you. Do you ask your neurologist if you have exaggerated or accelerated brain atrophy? Do you ask to have cognitive screening to see how good or bad your cognition is?

Another metric that is likely to enter clinical practice in the future is a metric to assess how well your brain’s functional network is working. The brain is like multiple computers working together in parallel. The brains’ computers or functional domains work together in harmony as a functional network. If you acquire enough lesions and damage the functional network the brain stops working as well and efficiently as it should. This manifests as cognitive fatigue and cognitive problems. It takes so much more mental effort to get the brain’s damaged functional network to perform well, which is why it causes fatigue.

The study below shows that in pwMS with damage to the brain measured using both structure (loss of volume) and function (loss of connectivity) do poorly; i.e. they were more likely to become secondary progressive over the next 6 years. Are you surprised by these results? It is amazing how accurate these MRI metrics were in being able to predict who would become progressive or not.

The message from this and other studies is simple, MS damage begets MS damage. This is why we have to diagnose and treat MS as early as possible and if necessary as effectively as possible. Once damage accumulates it is irreversible and when it is detected it represents a sick brain, which then continues to be shredded by the processes that drive smouldering MS.

Rocca et al. Network Damage Predicts Clinical Worsening in Multiple Sclerosis: A 6.4-Year Study. Neurol Neuroimmunol Neuroinflamm. 2021 May 21;8(4):e1006.

Objective: In multiple sclerosis (MS), clinical impairment is likely due to both structural damage and abnormal brain function. We assessed the added value of integrating structural and functional network MRI measures to predict 6.4-year MS clinical disability deterioration.

Methods: Baseline 3D T1-weighted and resting-state functional MRI scans were obtained from 233 patients with MS and 77 healthy controls. Patients underwent a neurologic evaluation at baseline and at 6.4-year median follow-up (interquartile range = 5.06-7.51 years). At follow-up, patients were classified as clinically stable/worsened according to disability changes. In relapsing-remitting (RR) MS, secondary progressive (SP) MS conversion was evaluated. Global brain volumetry was obtained. Furthermore, independent component analysis identified the main functional connectivity (FC) and gray matter (GM) network patterns.

Results: At follow-up, 105/233 (45%) patients were clinically worsened; 26/157 (16%) patients with RRMS evolved to SPMS. The treatment-adjusted random forest model identified normalized GM and brain volumes, decreased FC between default-mode networks, increased FC of the left precentral gyrus in the sensorimotor network (SMN), and GM atrophy in the fronto-parietal network (false discovery rate [FDR]-corrected p = range 0.01-0.09) as predictors of clinical worsening (out-of-bag [OOB] accuracy = 0.74). An expected contribution of baseline disability was also present (FDR-p = 0.01). Baseline disability, normalized GM volume, and GM atrophy in the SMN (FDR-p = range 0.01-0.09) were independently associated with SPMS conversion (OOB accuracy = 0.84). At receiver operating characteristic analysis, including network MRI variables improved disability worsening (p = 0.05) and SPMS conversion (p = 0.02) prediction.

Conclusions: Integration of MRI network measures helped determining the relative contributions of global/local GM damage and functional reorganization to clinical deterioration in MS.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

Am I cured?

Barts-MS rose-tinted-odometer: ★★★★★ (seeing purple; a Sunday morning purple)

Could you imagine if we made the treatment target in MS a cure? This is a very contentious issue; however, based on the current dogma that MS is an autoimmune disease driven by rogue autoreactive cells we should have the ability to either purge these cells from the body or imprison them via tolerance mechanisms indefinitely. Do you agree?

After being taken to task on using the C-word (see blog post 19-May-21) I am relieved that you readers condone the use of the word. This means we can now hopefully refine the definition of an MS cure, look to see if any pwMS treated with immune reconstitution therapies (IRTs) fulfil the definition of an MS cure. Please be aware that an MS cure doesn’t mean the restoration of lost neurological function; you can be cured of further autoimmune attacks on the nervous system, but the damage that is already done won’t necessarily be repaired as part of the cure. This is why we need to at least offer IRTs as early as possible in the course of the disease, which is why we need to have the option of using IRTs first-line. I hope this makes sense.

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Survey Disclaimer: No personal identifiers will be collected as part of these surveys unless otherwise stated. By completing these surveys you are consenting to the data you provide being analysed by Professor Giovannoni and his collaborators. Results of these surveys will be presented on this blog and maybe submitted for publication.

The Big-C

Barts-MS rose-tinted-odometer: ★★★★★ (seeing grey – it’s a very grey Saturday)

Whenever you bring up the topic of using more effective DMTs or flipping the pyramid you get pushed back because of the potential risks associated with these treatments. One risk is the big-C or secondary cancers. It is therefore very reassuring that an analysis of the FDA adverse event reporting system database revealed no safety signal for increased cancer risk among the approved MS DMTs.

The only potential safety signal that was detected in a so-called sensitivity analysis concerned interferon-beta-1a (Rebif/Avonex/Plegridy) and alemtuzumab.

The message is that the cancer risk associated with MS DMTs is probably quite low and not nearly as high as the risk associated with more potent immunosuppressive therapies and the so-called mutagenic therapies. Please note none of our licensed DMTs is mutagenic. Please note this analysis does not include AHSCT, which typically uses cyclophosphamide to mobilise stem cells and to ablate the immune system. There is clear evidence that people who have had AHSCT are at increased risk of developing a secondary malignancy, which is almost certainly a consequence of exposure to cyclophosphamide and other chemotherapy agents given as part of the procedure.

This analysis also puts the FDA cladribine black box warning into perspective, i.e. the real-life data suggests there is no increased cancer risk with cladribine and supports my interpretation of the data that cladribine is not associated with secondary cancer risk. The apparent cladribine cancer risk in the phase 3 or CLARITY trial was driven by the fact that there were zero cases in the placebo arm, which was the outlier. Let’s hope this data will allow pwMS to put the ‘potential cancer risk’ of DMTs into perspective and give them the confidence to access more effective therapies earlier on in the course of their MS.

It has now become abundantly clear that the earlier the average person with MS is treated with a high efficacy DMT the better their outcome. The message is treat-early and treat-effectively.

Stamatellos et al. Disease-modifying agents for multiple sclerosis and the risk for reporting cancer: a disproportionality analysis using US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Br J Clin Pharmacol. 2021 May 16.

Aim: While the efficacy of Disease-Modifying Therapies (DMTs) for patients with Multiple Sclerosis (MS) is established, little is known about their long-term safety. Cancer-risk after DMTs use remains unclear. This study aims to investigate whether the prescription of DMTs for patients with MS increases the risk of reporting cancer.

Methods: Data from the FDA adverse-event reporting system were extracted from 2004 until 2020. After data cleaning, the crude and adjusted Reported Odds Ratios (cROR, aROR) for cancer were calculated for DMTs with Interferon-beta1a as the reference drug. Sensitivity analyses investigated the group of reports with multiple registered DMTs, the effect of indication restriction, and the results when using the rest of the DMTs as reference.

Results: For malignant tumors, aROR (CI 95%) were: Cladribine 0.46 (0.18-0.95) Dimethyl fumarate 0.30(0.27-0.34), Fingolimod 0.61(0.53-0.70), Glatiramer 0.50(0.43-0.58), Alemtuzumab 0.84(0.64-1.08), Interferonbeta-1b 0.49(0.42-0.56), Natalizumab 0.36(0.34-0.39), Ocrelizumab 0.48(0.29-0.74), pegInterferonbeta-1a 0.35(0.26-0.48), Siponimod 0.89(0.47-1.54), Teriflunomide 0.25(0.21-0.30) adjusted to age, gender and concomitant medications. In the sensitivity analysis, when the rest of the drugs were used as a reference, Interferon-beta1a and pegInterferon-beta1a had aROR (CI 95%): 2.60 (2.47-2.74, p<0.001), and Alemtuzumab 1.47 (1.13-1.88, p=0.003).

Conclusions: No safety signal for increased cancer-risk was detected among the approved DMTs, although more robust evidence is needed. A potential safety signal detected in the sensitivity analysis concerning Interferon-beta1a, Alemtuzumab, requires further evaluation with more robust evidence.

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Tickled pink

Barts-MS rose-tinted-odometer: ★★★ (seeing pink; tickled pink)

Thank you for completing yesterday’s poll. It is quite clear that you, our blog readers, want us to prioritise the following changes to the way we prescribe DMTs in the NHS. The most important priority is for pwMS to access immune reconstitution therapies (alemtuzumab, cladribine and HSCT) early as 1st-line therapies for active MS. Please note if you have rapidly evolving severe MS (RES) you can be treated with alemtuzumab and cladribine first-line, but outside of this very small group of patients, we can’t prescribe IRTs first-line. For more information on RES vs. active MS classification system and its implications for some pwMS, I would recommend you read ‘Watchful Waiting 2‘.

The next priority is access to natalizumab, a very high efficacy therapy, as 1st-line therapy for active MS. At the moment the only agent that covers this broad bracket is ocrelizumab. My reading into this is that if you don’t have RES but just active MS, you would like more choice and not simply have one high-efficacy option first-line.

The third priority relates to treating advanced or progressive MS, i.e. getting rid of the stopping criteria when people with MS reach EDSS 7.0 (wheelchair) and liberalise the prescribing of ocrelizumab and siponimod for primary progressive and secondary progressive MS, respectively. My interpretation of the latter is that you want to challenge the active vs. inactive progressive MS dichotomy.

Finally, treating asymptomatic MS and liberalising the use of platform therapies and fingolimod is not a priority. This worries me because as we move into an area of testing and exploring the induction-maintenance paradigm we need to be able to use platform therapies 2nd- and 3rd-line. I have made the point before that pwMS are not going to be able to remain on anti-CD20 therapies indefinitely because of the potential risks; for example, as your immunoglobulin levels drop and serious infections increase the benefit-risk balance changes. Therefore, we are going to need to test de-escalation approaches to derisk anti-CD20 and other chronic immunosuppressive treatments. This is the rationale of the iTeri study that I have proposed doing; i.e. induction with ocrelizumab or rituximab followed by maintenance with teriflunomide.

I would be interested to know if you are surprised by the poll’s findings?

I wonder if the Australian neurologists chuckle when they read this sort of blog post? They have no restrictions on how they treat MS and can use any DMT, including AHSCT, as they and their patients see fit. If only the NHS would allow us to practice in this way 🙁

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DMT wishlist

Barts-MS rose-tinted-odometer: ★★★★★ (seeing green; the green shoots of spring)

I was asked yesterday if I could have a wish and change three things in relation to the prescribing of MS DMTs in the NHS, which ones would I prioritise? Can you help? The idea is to make changes based on how we would want to manage MS proactively as possible and to give pwMS choice. The idea of this exercise is to get an idea of what is most important to the MS community given our current restrictions. Please note you can add your own priority at the bottom of the survey if you don’t feel satisfied with the limited selection provided.

The poll will take 3 seconds to complete and you are welcome to complete it if you live outside of the UK and/or are not someone with MS.

Thanks

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The C-word

Barts-MS rose-tinted-odometer: zero-★s (seeing red)

After my blog post on potentially curing MS, I have been criticised by several people in the MS community for using the C-word. Do you agree? Have I raised false hopes?

I am of the opinion that unless we define what an MS cure looks like and then look for it we will never find it; i.e. the holy grail will always elude us. Another factor is that if we are really curing some people with MS with IRTs (immune reconstitution therapies) shouldn’t the MS community know about it? Wouldn’t that shift the risk:benefit ratio in favour of the benefits? Just maybe more people will choose to be treated with AHSCT, alemtuzumab or cladribine if there was a small chance of a cure. One commentator has suggested I use the term long-term remission rather than cure. The problem with long-term remission is that it doesn’t quite have the same emotional impact as a cure.

One of my patients with both MS and breast cancer was bowled over by her breast cancer consultant who said to her, “we have an 80% chance of curing you of your breast cancer”. Saying “we have an 80% chance of putting your breast cancer into long-term remission”, just doesn’t quite cut the mustard.

If you have the time can you please respond to this three-question survey, which will take you literally 15 seconds to complete? Thank you.

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Anti-CD20 vs. Teriflunomide

Barts-MS rose-tinted-odometer: ★★ (seeing blue)

When I state that the real MS is smouldering MS and that relapses and focal MRI activity are not the disease I really mean it.

PwMS who are NEDA-2, without relapses and with no new MRI lesions, but getting worse must have something going on in their brains and spinal cords. This is why we need to go beyond NEIDA (no evidence of inflammatory disease activity) as a treatment target in MS and focus on protecting the end-organ so that pwMS can have enough reserve to cope with normal ageing when they get older.

One example or ugly fact to illustrate the disconnect between inflammation (relapses and focal MRI activity) and the end-organ (brain volume loss) is the recent ofatumumab vs. teriflunomide trials.

Gd-enhancing lesions (↓~95%): Ofatumumab >>>> teriflunomide

New T-2 lesions (↓~83%): Ofatumumab >>> teriflunomide

Relapses (↓~55%): Ofatumumab >> teriflunomide

Disability progression (↓~33%): Ofatumumab > teriflunomide

Brain volume loss (↓~0%): Ofatumumab = teriflunomide

If ofatumumab is so much more effective as an anti-inflammatory than teriflunomide why doesn’t it protect the end-organ more than teriflunomide? I don’t know but is clear, at least to me, that there is something else going on that is driving the end-organ damage in MS that is not linked to focal inflammation. Could something about teriflunomide’s mode of action that is downstream of focal inflammation be telling us something fundamental about the cause of MS?

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Which side of the fence are you on?

Barts-MS rose-tinted-odometer: zero-★s (still seeing red)

Apologies some more definitions:

Side of the fence: used to refer to either of the opposing positions or interests involved in a particular situation.

Status quo: the current situation; the way things are now. The MS community, i.e. patients and HCPs are content with the status quo and aren’t looking for a change.

NEDA: no evident MS disease activity

The question you need to ask yourself is which side of the fence are you on? MS is a focal inflammatory disease of the central nervous system vs. MS is a smouldering disease process and focal inflammatory events are in response to what is causing the disease. If you favour the former you will be happy with being NEDA-2, i.e. having no relapses or new focal inflammatory lesions. If you are in the latter camp you will want to focus on end-organ damage and preserving your brain and spinal cord volume for old age.

The wider MS community seems to prefer the current dogma and status quo; i.e. that MS is a focal inflammatory disease and that everything we see can be explained by relapses and focal MRI activity. I think this is wrong and have argued this from not only a scientific point of view but also from a philosophical one.

Deciding which side of the fence you are on may make an enormous difference to your outcome. It is clear that not all DMTs are made equal when it comes to preserving brain volume and hence brain reserve.

Did you know that pwMS lose brain volume at a 2-7x faster rate than age-matched controls from the general population? Accelerated brain volume loss predicts and is strongly associated with cognitive impairment and long term disability. The following picture shows you just how much brain someone with MS can lose over an 18 month period.

If we moved our treatment target to go beyond NEDA to focus on protecting the end-organ so that pwMS may have a brain that is in good enough condition to withstand the ageing process in later life I suspect the treatment landscape would change dramatically. To achieve this we need to diagnose MS and treat it early and effectively and in many cases, we need to flip the pyramid and use high efficacy therapies at the beginning, in particular agent such as alemtuzumab and AHSCT, which have been shown to protect the end-organ better than other DMTs.

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Watchful waiting 2

Barts-MS rose-tinted-odometer: zero-★s (still seeing red)

Did you know that MS disease activity defines if you are eligible for therapy and which therapy?

The following is a list of definitions that are generally applied to MS in England.

Inactive: Patients with MS with no relapses or imaging features of disease activity in the last 2 years.

Active: Patients with active disease are defined as having one or more relapses in the preceding 2 years and/or evidence of one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI in the last two years.

Highly active: Patients with high disease activity despite treatment with a platform DMT. This group is defined as patients who have failed to respond to a full and adequate course of a platform or other DMT. Patients should have had at least one relapse in the previous year while on therapy and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.

Rapidly evolving severe or RES: Patients with rapidly evolving severe relapsing-remitting multiple sclerosis defined by two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.

Disabling relapse: if the relapse is severe enough to affect the social and/or occupational functioning of the patient.

The problem with these definitions is that they entrench the clinico-radiological worldview of MS and are not based on biology or for that matter data. For example, the RES definition was a negotiation between Biogen representatives and the EMA to get natalizumab licensed in Europe. RES MS was not a prespecified population and there were no requirements for study to subjects to have an increasing lesion load on MRI or to have prior relapses classified as disabling or non-disabling to be included in the AFFIRM study (phase 3 natalizumab study). So in reality the RES population is hypothetical. Despite this, the concept of RES MS has stuck and is likely to be entrenched in our MS algorithms for the foreseeable future, unless we challenge these definitions.

So if you are NEDA-2, i.e. have no relapses or focal MRI activity in the last 2 years, you have inactive MS. The latter definition is independent of disability worsening, accelerated brain volume loss, raised neurofilament levels, worsening cognition, accelerated retinal nerve fibre loss, slowly expanding lesions or progressive spinal cord atrophy. In other words, the definitions are based on clinical relapses and focal MRI activity, which is our concept of active inflammation. None of our current definitions for treatment acknowledges smouldering disease; hopefully, this will change in time.

Clearly, these definitions are subject to change or hacking as technology evolves. So if you move from a 3 tesla to a 7 tesla MRI you may find it easier to show a change in lesion load due to the better definition of lesions and the ability to see cortical lesions. Simply increasing the number of MRI scans will increase the sensitivity of the measure of activity, particularly if you are using Gd-enhanced MRI scans.

The definition that worries me the most is RES. The number of people with RES is getting smaller simply because we tend not to let someone diagnosed with MS after one relapse wait to have a second relapse before treating them. Therefore the number of patients with RES is going down and this is why so few pwMS are eligible for cladribine, alemtuzumab and natalizumab as first-line therapies. The only highly effective therapy that is allowed first-line for active MS is ocrelizumab. So if you want to flip the pyramid and start on one of the other top-tier DMTs you have to either start on ocrelizumab or wait and hope you have a disabling attack within 12 months of your first attack to become eligible for natalizumab or one of the licensed IRTs (alemtuzumab or cladribine).

Waiting and hoping to become RES is what I call watchfully waiting 2.

This watchful waiting for the next disabling attack to become eligible is really incompatible with the concept of time-is-brain and hence access to IRTs are not really a first-line option for the majority of people with recently diagnosed MS.

I hope this makes sense? The following is NHS England’s DMT treatment algorithm that explains things using a flow diagram.

MS-Treatment-Algorithm-v2

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To switch or not to switch that is the question

Barts-MS rose-tinted-odometer: ★★★

The one good thing about thinking aloud is that your colleagues’ chip in and provide feedback. Case 2 from my ‘ethical quandary post‘ is generating an important debate about whether to support this patient’s decision to switch therapy or not.

As a reminder, this is the 40-year old woman who started natalizumab as a first-line therapy 11 years ago after presenting with two disabling relapses in a four-month period. She has done exceptionally well on natalizumab, i.e. she is NEDA-3 (no relapses, no MRI activity and no change in her EDSS). In fact, her original disabilities from the two relapses recovered. At present she is fully functional, working full-time and very active physically. For example, she plays competitive tennis in her local sports club and ran the London marathon 2 years ago. Her current EDSS is 1.0.

The problem is that her serial annual MRI studies demonstrate that she has progressive macroscopic (visible by the naked eye) brain volume loss. Being an intelligent woman and a self-taught MS expert she knows this is a poor prognostic sign and she wants to stop natalizumab and have HSCT or alemtuzumab. She is aware from reading The MS-Blog (formerly the Barts-MS blog) that alemtuzumab and HSCT have a greater impact than natalizumab on end-organ damage or brain volume loss. After HSCT and alemtuzumab treatment brain volume loss is on average in the normal range (please see BEYOND NEDA).

What I didn’t say to you is that this lady has already made the decision that she wants to be treated with AHSCT, either on the NHS (not possible at present), abroad at one of the reputable private BMT units or in the private sector within the UK. The problem we have is that we have no idea what will happen to her BVL once she makes the switch. I suspect she will have accelerated BVL in the first year post-AHSCT, which is well described and is likely to be due to the neurotoxicity of the chemotherapy. After year-1 the BVL may or may not normalise. We have no idea what happens to the MS brain after being subjected to smouldering MS pathology on natalizumab for a decade.

Fortunately, we do have data from interferon-beta to alemtuzumab switching and, yes, after 2 years of interferon-beta therapy switching to alemtuzumab does normalise BVL. What is clear from the 8-year alemtuzumab follow-up data (see below) is that the rate of brain volume loss is age-dependent. Being in the 35-45 year age group the BVL was 0.13% per annum ((1.51-0.71)/6) on alemtuzumab. When you compare this to the 0.06% per annum in study subjects 18-25 years of age ((1.24-0.87)/6) you realise how important age is in determining treatment effects.

Is this data sufficient to talk this young woman down from her decision to have AHSCT and to go with alemtuzumab? What do you think? If this patient is reading this blog post will it affect your decision?

Another thing this ‘thinking out loud’ exercise has taught me is that having annual BVL measurements on our patients with MS on DMTs could be very helpful. I also think we should ask around to see if we can get a case series of natalizumab to alemtuzumab switchers to see what happens to the trajectory of BVL before, on natalizumab, and after the switch to alemtuzumab. At least then we will have data to inform such difficult decisions.

Bass et al. Alemtuzumab outcomes by age: Post hoc analysis from the randomized CARE-MS studies over 8 years. Mult Scler Relat Disord. 2021 Apr;49:102717.

Background: Alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with sustained efficacy in 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]).

Methods: Post hoc analysis of 8-year alemtuzumab efficacy and safety in pooled CARE-MS patients (N=811) stratified by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years).

Results: Compared with SC IFNB-1a over 2 years across age cohorts, alemtuzumab lowered annualized relapse rates (ARR; 0.22-0.24 vs. 0.38-0.51), improved or stabilized disability (freedom from 6-month confirmed disability worsening [CDW]: 85%-92% vs. 62%-88%; achievement of 6-month confirmed disability improvement [CDI]: 20%-31% vs. 13%-25%), increased proportions free of MRI disease activity (70%-86% vs. 42%-63% per year), and slowed brain volume loss (BVL; -0.45% to -0.87% vs. -0.50% to -1.39%). Through Year 2, the treatment effect with alemtuzumab did not significantly differ among age groups for ARR (p-interaction=0.6325), 6-month CDW-free (p-interaction=0.4959), 6-month CDI (p-interaction=0.9268), MRI disease activity-free (p-interaction=0.6512), and BVL (p-interaction=0.4970). Alemtuzumab remained effective on outcomes through Year 8 across age groups. Age-related increases in malignancies (≤45 years: 0.9%-2.2% vs. >45 years: 8.1%) and deaths (0%-1.7% vs. 7.0%) were observed. Serious infections also increased from the youngest (5.1%) to oldest (12.8%) age cohorts.

Conclusions: Alemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups. Efficacy on relapse, disability, and MRI outcomes continued through Year 8 across age groups. Age-related increases in serious infections, malignancies, and deaths were observed.

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