Lab Lessons – Page 2 – Prof G's MS Blog Archive

Mortality: what risk would you be prepared to take?

Barts-MS rose-tinted-odometer: ZERO-★’S (Black Tuesday – a tear for my beloved country #000000)

As you are aware by now I am a proponent of flipping the pyramid and using high-efficacy DMTs first-line including immune-reconstitution therapies (IRTs) such as alemtuzumab and AHSCT. I justify the latter two options based on the fact that given sufficient time the vast majority of pwMS will become disabled and the real cost of MS to people with MS cannot be underestimated; loss of employment, poor relationships, cognitive impairment, fatigue, depression, anxiety, etc. I think you get the gist; MS is a bad disease.

Alemtuzumab and HSCT are the two standout treatment options that offer pwMS the best chances of long-term remission and in some pwMS it may offer a cure. What impresses me about these two options is their impact on the end-organ, i.e. brain volume loss. After rebaselining at 12 months, pwMS treated with these two options lose brain volume on average at a rate that is within the normal range for age. The other DMTs don’t do this. The downside is that these two treatment options come with more risks. These two real-world studies below report 2 deaths out of 121 (2.5%) alemtuzumab-treated patients in Finland and 3 out of 120 HSCT-treated patients in London. Would you be willing to take these chances of dying to treat your MS with the potential for long term remission, possibly a cure and to protect your most precious end-organ the brain?

Rauma et al. Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients. J Neurol. 2021 Jul 13. doi: 10.1007/s00415-021-10664-w.

Background: Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice.

Objectives: To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients.

Methods: In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files.

Results: Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented.

Conclusions: SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.

Nicholas et al. Autologous Haematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: a Real-world Case Series. Neurology. 2021 Jul 12;10.1212/WNL.0000000000012449.

Objective: to examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting.

Methods: retrospective cohort study on PwMS treated with AHSCT at two centers in London, UK, consecutively between 2012 and 2019 who had ≥ 6 months of follow-up or died at any time. Primary outcomes were survival free of MS relapses, MRI new lesions and worsening of expanded disability status scale (EDSS). Adverse events rates were also examined.

Results: the cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS (RRMS). At baseline, the median expanded disability status scale (EDSS) was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of subjects at 2 years and 85% at 4 years. EDSS progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. EBV reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplant-related deaths within 100 days (2.5%), all following fluid overload and cardiac or respiratory failure.

Conclusions: efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher.

Classification of evidence: this study is rated Class IV because of the uncontrolled, open-label design.

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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 and are not meant to be interpreted as personal clinical advice.

Clash of the Titans: the HILO study

Barts-MS rose-tinted-odometer: ★★★ (I am seeing blue and Spanish yellow today)
Roche blue (#0066CC) & Novartis Spanish Yellow (#F7B516)

Yes, I really do think that intrathecal (within the meninges that cover the brain and spinal cord) or CNS resident B-cells and plasma cells are pathogenic in MS. In other words, the cytokine or chemicals B-cells and plasma cells produce, in particular their antibodies, are what is driving some of the pathologies of smouldering MS. The evidence to support this hypothesis is well rehearsed on this blog and is the reason why we are testing high-dose ocrelizumab (more CNS penetrant) vs. standard-dose ocrelizumab (less CNS penetrant) against each other in two head-2-head studies. It is also the reason we are testing cladribine’s (CLADRIPLAS and CLAD-B) and ixazomib’s (SIZOMUS) effects in intrathecal B and plasma cell markers. Yes, I really do think we need to scrub the CNS clean of B-cells, plasma cells and their products, in particular the oligoclonal IgG bands.

I am therefore proposing a new study; the HIgh-dose versus LOw-dose anti-CD20 study or HILO Study.

In this study, I propose testing high-dose or double-dose ocrelizumab vs. standard or intermediate-dose ocrelizumab vs. low-dose ofatumumab against each other over two years and measure their impact on end-organ damage markers (slowly expanding lesions and brain volume loss) and on CSF markers of B-cell, plasma cell and microglial activity. The latter will include free kappa and lambda immunoglobulin light chains, OCBs, soluble CD14, etc. This will answer at least from a biomarker question whether or not we need CNS penetration of anti-CD20 monoclonal antibodies to target this component of smouldering MS. The following would also answer the question of whether or not you as a person with MS would want to be treated with high-dose or low-dose anti-CD20 therapy?

Would you want to be randomised into this study?

This study would be a clash of the titans; Roche vs. Novartis. Who would win? It really is not that important as Novartis is a major shareholder in Roche and hence when Roche makes a profit so does Novartis. The real winners will be people with MS, the data will allow them to make an informed decision about whether or not they want to go beyond NEIDA (no evident inflammatory disease activity) and be on a treatment that tackles the smouldering B-cell and plasma-cell driven processes within their brains and spinal cords.

SHOULD WE DO THE HILO STUDY?

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Smouldering MS – not all bad news

Barts-MS rose-tinted-odometer: ★★★★★ (today’s colour is Delta Red Iron Oxide #9b2f1c)

One of the smouldering MS dogmas that have entered the MS lexicon is that the iron-rimmed slowly expanding MS lesions (SELs) go on enlarging and destroying or shredding the brain tissue around it forever. Another dogma states these SELs don’t respond to current DMTs. The good news is that both of these statements are probably incorrect.

In the recently published longitudinal MRI study below iron rims around lesions gradually diminished with time. However, having these iron rim lesions is not good news in that they are significantly more destructive than non-iron rimmed MS lesions. The question I have is what drives these lesions to form? Knowing the answer to this question will tell us what is causing MS.

The second study below demonstrates that ocrelizumab significantly reduces the expansion of slowly expanding/evolving lesions. This suggests that these lesions may be driven by intrathecal or CNS-derived immunoglobulins. This is why we are doing the high-dose ocrelizumab, SIZOMUS (ixazomib) and CHARIOT-MS (cladribine) studies to see if reducing intrathecal B and plasma cell activity has an impact on smouldering MS.

If the former studies are positive, who would want to go onto a lower-dose anti-CD20 therapy (standard-dose ocrelizumab, ofatumumab, rituximab, ublituximab)? Please note that although these lower dose anti-CD20 therapies are very effective at stopping relapses and focal MRI activity this is not MS. The real MS is smouldering MS and what we see with end-organ damage markers. This is why if I had MS I would choose a DMT that offered the best chance of normalising my brain volume loss and I would volunteer for the SIZOMUS trial.

The good news is that these two studies below show that the so-called chronic active lesions or SELs evolve over many years after their initial formation and that they may be modifiable with DMTs. Let’s celebrate these facts.

Iron-rimmed lesion of SEL expanding over 7 years; image from BRAIN.

Dal-Bianco et al. Long-term evolution of multiple sclerosis iron rim lesions in 7 T MRI. Brain. 2021 Apr 12;144(3):833-847.

Recent data suggest that multiple sclerosis white matter lesions surrounded by a rim of iron containing microglia, termed iron rim lesions, signify patients with more severe disease course and a propensity to develop progressive multiple sclerosis. So far, however, little is known regarding the dynamics of iron rim lesions over long-time follow-up. In a prospective longitudinal cohort study in 33 patients (17 females; 30 relapsing-remitting, three secondary progressive multiple sclerosis; median age 36.6 years (18.6-62.6), we characterized the evolution of iron rim lesions by MRI at 7 T with annual scanning. The longest follow-up was 7 years in a subgroup of eight patients. Median and mean observation periods were 1 (0-7) and 2.9 (±2.6) years, respectively. Images were acquired using a fluid-attenuated inversion recovery sequence fused with iron-sensitive MRI phase data, termed FLAIR-SWI, as well as a magnetization prepared two rapid acquisition gradient echoes, termed MP2RAGE. Volumes and T1 relaxation times of lesions with and without iron rims were assessed by manual segmentation. The pathological substrates of periplaque signal changes outside the iron rims were corroborated by targeted histological analysis on 17 post-mortem cases (10 females; two relapsing-remitting, 13 secondary progressive and two primary progressive multiple sclerosis; median age 66 years (34-88), four of them with available post-mortem 7 T MRI data. We observed 16 nascent iron rim lesions, which mainly formed in relapsing-remitting multiple sclerosis. Iron rim lesion fraction was significantly higher in relapsing-remitting than progressive disease (17.8 versus 7.2%; P < 0.001). In secondary progressive multiple sclerosis only, iron rim lesions showed significantly different volume dynamics (P < 0.034) compared with non-rim lesions, which significantly shrank with time in both relapsing-remitting (P < 0.001) and secondary progressive multiple sclerosis (P < 0.004). The iron rims themselves gradually diminished with time (P < 0.008). Compared with relapsing-remitting multiple sclerosis, iron rim lesions in secondary progressive multiple sclerosis were significantly more destructive than non-iron rim lesions (P < 0.001), reflected by prolonged lesional T1 relaxation times and by progressively increasing changes ascribed to secondary axonal degeneration in the periplaque white matter. Our study for the first time shows that chronic active lesions in multiple sclerosis patients evolve over many years after their initial formation. The dynamics of iron rim lesions thus provide one explanation for progressive brain damage and disability accrual in patients. Their systematic recording might become useful as a tool for predicting disease progression and monitoring treatment in progressive multiple sclerosis.

Ocrelizumab reduces the increase in the volume of SELs compared to placebo; image from BRAIN.

Elliott et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. Brain. 2019 Sep 1;142(9):2787-2799.

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.

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Hey doc what’s my NFL level?

Barts-MS rose-tinted-odometer: ★★★★★ (it’s a Red & White Wednesday, as in the flag of St George, #cf2e2e)

The reason why rheumatologists are so way ahead of us in treating rheumatoid arthritis (RA) and protecting joints (the RA end-organ) is that they have an inflammatory biomarker that is closely linked to outcome, it is called the C-reactive protein (CRP), which they include as part of their treatment target. They also include a PROM (patient-related outcome measure) as part of the DAS (disease activity score); this not only involves RA patients in their treatment but gives patients with RA a deep understanding of what DMARDs (disease-modifying anti-rheumatic drugs) does to their disease.

In MS we need both a CRP and a PROM to be part of our treatment target. Do you agree?

The CRP allows rheumatologists to rapidly assess if inflammation is under control. The area under the CRP curve correlates with joint damage in the future, therefore, rheumatologists like to flatten the CRP curve. The good news is that MSologists may have the equivalent of the CRP in the form of neurofilament light chain (NFL) levels. It is quite clear that NFL is a biomarker of neuroaxonal damage in patients with active MS. Therefore it is only a matter of time before MSologsists and pwMS will want to flatten NFL curves; i.e. peripheral blood NFL levels (pbNFL) will be part of the treatment target. MS centres with the best average NFL levels in their patients will have the best outcomes.

We know that raised NFL levels are a poor prognostic sign and correlate with future MS disability and brain volume loss (end-organ damage). However, we still have several hurdles to get over before pbNFL enters routine clinical practice, but we are getting there. The other issue is setting normal levels. The great tragedy, or not, of life is that life is an age-dependent neurodegenerative disease and hence pbNFL increases with age. Therefore we are going to have to have age-dependent normative data. The paper below shows just how age-dependent pbNLF levels are.

What about a universal MS PROM? There is a big debate going on at the moment about which PROMs to collect in routine clinical practice and which ones are sensitive and reactive enough to include in an MS-DAS score. The problem for the field is when you put all the MS PROM experts in a room each has their own favourite PROM and it is virtually impossible to get a consensus on which is the best and most practical to use in routine clinical practice. Another problem is that most of the most widely used PROMs in MS are not well-liked by patients; patients feel that these PROMs don’t really capture the impact that MS is having on their lives. So I don’t think the PROM issue will be sorted anytime soon. Therefore, my money is on pbNFL levels and I have little doubt that you will be asking for and tracking your own NFL levels in the near future.

Valentino et al. Serum neurofilament light chain levels in healthy individuals: A proposal of cut-off values for use in multiple sclerosis clinical practice. Mult Scler Relat Disord. 2021 Jun 17;54:103090.

Background: Serum Neurofilament Light (sNFL) is the most promising marker for patient’s monitoring in Multiple Sclerosis (MS). However, operating reference values for use in clinical practice are still lacking. Here, we defined sNFL reference cut-off values in a cohort of healthy controls (HC) and assessed their performance in Multiple Sclerosis (MS) patients, as well as the intra-individual sNFL variability.

Methods: We measured sNFL by single molecule array (Simoa) assay in 79 HC assessing their correlation with age. Changes of sNFL levels were evaluated during a short-term follow-up (median 67 days between consecutive samples) in a subgroup of 27 participants. sNFL were tested in 23 untreated MS patients, at both diagnostic time and start of therapy (median 80 days after), considering disease activity.

Results: Findings confirmed a correlation between sNFL levels and age in HC, thus cut-off values specific for age decades were calculated. sNFL did not vary significantly with time during short-term follow-up (median CV 13%). sNFL levels in MS patients were higher and demonstrated a higher variability between diagnostic time and treatment start (median CV 39%). According to cut-off values, “pathologic” sNFL levels were found in 57% of MS patients at diagnostic time, and in 30% of samples at treatment start. In particular, “pathologic” sNFL levels were found in 80% of samples (16/20) obtained during a phase of disease activity, while a total of 85% of samples (22/26) associated with inactive disease showed sNFL in the normal range.

Conclusion: This study demonstrates an overall intra-individual stability of sNFL values in the short-term in HC and suggests age-dependent reference cut-off values that could be beneficial for sNFL implementation in clinical practice.

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Dysbiosis

Barts-MS rose-tinted-odometer: ★★★ (a lilac rose-tinted Sunday; and why not! #C8A2C8)

Dysbiosis refers to abnormalities in the human microbiome that affect disease and life outcomes. In the context of MS, it is claimed that changes in the gut microbiome may not only increase your risk of getting MS but act as a proinflammatory signal to drive MS disease activity and reduce remyelination and recovery. The corollary is that manipulation of your microbiome with antibiotics, faecal transplantation, probiotics and diet can be used to treat MS. Do you agree?

My problem with the field of dysbiosis is how to interpret the data. Many of the hypotheses and claims being explored are plausible, but the lack of vigour and the application of causation theory in regard to some of the claims being made is worrying. More worrying is that some quacks have already jumped on the bandwagon and have started offering faecal transplants and probiotics to treat MS.

There is little doubt that the metagenome, i.e. our genomes and the genomes of the microorganisms that inhabit our bodies, is what life is. For example, without certain bacteria in our gut, we wouldn’t be able to eat certain foodstuffs. The most quoted example is the bacteria Bacteroides plebeius that allows humans to eat and breakdown seaweed; this bacteria is found more commonly in the gut of seaweed eating populations such as the Japanese.

Trying to find the gut bacterium that causes MS or increase the chances of getting MS will be like seeking a needle in ten thousand haystacks. I have been thinking about how we tackle this problem. One way may be to look at populations that had low incidence of MS and then to follow the changes in the gut microbiota longitudinally and see if something shows up in those who develop MS. The problem with this approach is the resources, the time required and the sheer size of the study required.

What is clear is that your microbiome is very plastic and can be changed relatively easily by manipulating your diet; going from a high fibre diet to a low fibre diet or from a high carbohydrate diet to a ketogenic diet changes your microbiome within days. This is very relevant to managing some diseases, for example, ketogenic diets and their presumed effect on the microbiome increases the response rate of some cancers to certain chemotherapy regimens. The question is the metabolic hacking of ketosis or the effect of the diet on the microbiome that is responsible for the treatment effect? I suspect it is both. There is also very compelling data emerging that ketogenic diets are anti-inflammatory, which in addition to their neuroprotective effects, explains why they are being studied in MS and widely adopted by segments of the MS community. Are their other diets with as a compelling scientific rationale? Not to the best of my current knowledge.

In the context of the above, you may be interested in the animal (EAE) study below which shows a small therapeutic effect of the administration of Clostridia, a bacterium that may be beneficial in MS, as a treatment in mice induced to have experimental allergic encephalomyelitis or EAE. The treatment effect is quite modest; I doubt MD would be impressed with the size of the effect. However, the authors conclude “… gut dysbiosis in MS patients could be partially rebalanced by these commensal bacteria and their immunoregulatory properties could have a beneficial effect on MS clinical course”. Really?

The question I have for you is how many of you are using probiotic supplements, diet, etc. to specifically change your microbiomes? How have you heard about these treatments and have you noticed any impact on your MS or MS-related symptoms?

Calvo-Barreiro et al. Selected Clostridia Strains from The Human Microbiota and their Metabolite, Butyrate, Improve Experimental Autoimmune Encephalomyelitis. Neurotherapeutics (2021); Published: 07 April 2021.

Gut microbiome studies in multiple sclerosis (MS) patients are unravelling some consistent but modest patterns of gut dysbiosis. Among these, a significant decrease of Clostridia cluster IV and XIVa has been reported. In the present study, we investigated the therapeutic effect of a previously selected mixture of human gut-derived 17 Clostridia strains, which belong to Clostridia clusters IV, XIVa, and XVIII, on the clinical outcome of experimental autoimmune encephalomyelitis (EAE). The observed clinical improvement was related to lower demyelination and astrocyte reactivity as well as a tendency to lower microglia reactivity/infiltrating macrophages and axonal damage in the central nervous system (CNS), and to an enhanced immunoregulatory response of regulatory T cells in the periphery. Transcriptome studies also highlighted increased antiinflammatory responses related to interferon beta in the periphery and lower immune responses in the CNS. Since Clostridia-treated mice were found to present higher levels of the immunomodulatory short-chain fatty acid (SCFA) butyrate in the serum, we studied if this clinical effect could be reproduced by butyrate administration alone. Further EAE experiments proved its preventive but slight therapeutic impact on CNS autoimmunity. Thus, this smaller therapeutic effect highlighted that the Clostridia-induced clinical effect was not exclusively related to the SCFA and could not be reproduced by butyrate administration alone. Although it is still unknown if these Clostridia strains will have the same effect on MS patients, gut dysbiosis in MS patients could be partially rebalanced by these commensal bacteria and their immunoregulatory properties could have a beneficial effect on MS clinical course.

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Early cladribine treatment prevents MS

Barts-MS rose-tinted-odometer: ★★★★★★ (6-star bull’s blood red #8a0303)

Yesterday’s post on using cladribine to prevent CIS from converting to MS and whether this is MS prevention or an MS cure generated a robust debate. Good, this was the purpose of the post; i.e. to get you thinking.

As you are aware that as the diagnostic criteria for MS evolve many people diagnosed with CIS in the past actually have MS when the new diagnostic criteria are applied retrospectively. This then allows you to see how well cladribine works in preventing conversion to MS in the small subgroup of subjects who have ‘CIS’ and not MS when they were treated with cladribine.

The subjects who were still CIS after applying the newer McDonald diagnostic criteria showed that cladribine’s treatment effect improved with a reduction in risk of conversion to clinically definite MS by 63% on low-dose cladribine and by 75% on high-dose cladribine compared to placebo. I am not sure the MS community has clocked how effective cladribine really is when used early.

This post-hoc analysis also suggests that people with CIS treated with lower doses of cladribine actually do better than those on higher doses. The dose-effect is pretty clear when you look at the time to next attack or three-month confirmed disability worsening. Have we optimised the dose of cladribine? When you are trying to prevent/cure MS maybe not!

Any predictions? I predict that a proportion of patients with CIS treated early with cladribine may never go on to have a second attack or disability progression and hence are prevented from developing MS or cured of their MS, depending on how you define MS. Anyone taking bets?

Freedman et al. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study. Mult Scler J Exp Transl Clin. 2017 Oct 9;3(4):2055217317732802.

Background: Multiple sclerosis (MS) diagnostic criteria have changed since the ORACLE-MS study was conducted; 223 of 616 patients (36.2%) would have met the diagnosis of MS vs clinically isolated syndrome (CIS) using the newer criteria.

Objective: The objective of this paper is to assess the effect of cladribine tablets in patients with a first clinical demyelinating attack fulfilling newer criteria (McDonald 2010) for MS vs CIS.

Methods: A post hoc analysis for subgroups of patients retrospectively classified as fulfilling or not fulfilling newer criteria at the first clinical demyelinating attack was conducted.

Results: Cladribine tablets 3.5 mg/kg (n = 68) reduced the risk of next attack or three-month confirmed Expanded Disability Status Scale (EDSS) worsening by 74% vs placebo (n = 72); p = 0.0009 in patients meeting newer criteria for MS at baseline. Cladribine tablets 5.25 mg/kg (n = 83) reduced the risk of next attack or three-month confirmed EDSS worsening by 37%, but nominal significance was not reached (p = 0.14). In patients who were still CIS after applying newer criteria, cladribine tablets 3.5 mg/kg (n = 138) reduced the risk of conversion to clinically definite multiple sclerosis (CDMS) by 63% vs placebo (n = 134); p = 0.0003. Cladribine tablets 5.25 mg/kg (n = 121) reduced the risk of conversion by 75% vs placebo (n = 134); p < 0.0001.

Conclusions: Regardless of the criteria used to define CIS or MS, 3.5 mg/kg cladribine tablets are effective in patients with a first clinical demyelinating attack. ClinicalTrials.gov registration: The ORACLE-MS study (NCT00725985).

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Prevention vs. cure

Barts-MS rose-tinted-odometer: ★★★★★ (a bright blue buzz – #0096FF)

I was at a mid-summer party last night when someone suggested that I should not waste my time trying to answer peripheral or trivial questions in relation to MS and focus on the really big questions.

This got me thinking about which are the biggest MS questions in MS that I can try to tackle and answer. Apart from (1) MS prevention, i.e. does preventing primary EBV infection with a sterilizing EBV vaccine prevent MS, the next major question must relate to (2) curing MS.

The BIG-C issue is one I have been exploring on this blog for several years but is hampered by defining what an MS cure looks like and then looking for it. The problem with the latter is the issue of smouldering MS, which clouds the definition of a cure. Even if you cure someone from the biological drivers of MS, if they have relatively advanced MS they may still get worse from downstream smouldering processes that become independent of the initial MS attack(s). So the only solution is to test the hypothesis of an MS cure is very early in the disease, i.e. at the RIS (radiologically-isolated syndrome) or CIS (clinically-isolated syndrome) stage.

To cure MS what treatment strategy do you need to use? I have made the point that we can only cure MS with an IRT (immune reconstitution therapy) and at present we only have three IRTs that are used routinely in MS., i.e. cladribine, alemtuzumab and AHSCT. It is clear that cladribine is the safest IRT and has the added advantage as being the most CNS penetrant, which I think is important. Cladribine levels in the spinal fluid of treated patients are high enough to have an effect on CNS resident T and B-cells. Cladribine is also the safest and easiest IRT to use and therefore the most likely to get widely adopted. I am convinced that a proportion of pwMS treated early, within 12 to 24 months of MS diagnosis, with either alemtuzumab and AHSCT are cured. Despite the stunning results of this treatment approach the adoption of both alemtuzumab and AHSCT as a mainstream treatment for MS has been abysmal. I suspect cladribine as an early effective treatment would have a greater chance of being adopted. My conclusion then is that the IRT has to be cladribine and it has to be done evry early at the CIS or RIS stage.

But this experiment has already been done. The ORACLE study below was of oral cladribine in CIS. So what has happened to these patients? We don’t know, which is why Merck is doing the CLASSIC MS study to try and find out what has happened to these patients with CIS. Wouldn’t it be brilliant if a significant proportion of the cladribine exposed patients have not developed MS compared to those in the placebo group? Would this be sufficient to convince the wider MS community that very early cladribine treatment cures a proportion of people with CIS, i.e. prevents them from developing MS? I suspect not. This is why a new global RIS-CIS study will need to be done.

Please note some people would argue that stopping people with CIS from getting MS is MS prevention, whereas others would argue, including me, that CIS is already MS and hence preventing CIS from becoming MS is an MS cure. This is not just semantics but challenges disease definitions and is an important philosophical debate. This is why I want to study medical philosophy to tackle some of these issues.

Kaplan–Meier estimates of time to conversion to CDMS and McDonald MS in the intention-to-treat population during the double-blind period. Cumulative percentage probability of conversion to (A) CDMS according to the Poser criteria and (B) MS according to the 2005 McDonald criteria. CDMS=clinically definite multiple sclerosis. MS=multiple sclerosis. Figure from Lancet Neurol 2014.

Leist et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014 Mar;13(3):257-67.

Background: Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS.

Methods: Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985.

Findings: Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, p<0.0001; HR for 3.5 mg/kg=0.33, 0.21-0.51, p<0.0001). Adverse events were reported in 165 (81%) patients in the cladribine 5.25 mg/kg group, 168 (82%) patients in the cladribine 3.5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group.

Interpretation: Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS.

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Oh, my thyroid!

Barts-MS rose-tinted-odometer: ★★★ (mid-summer orangey-yellow #f5bd1f)

As you are aware if you choose to be treated with the most effective IRTs (immune reconstitution therapies) you stand a relatively high chance of developing a second autoantibody-mediated autoimmune disease, with thyroid disease being the most common. For example, the cumulative incidence of second autoimmune diseases post-alemtuzumab is ~45%. In other words, if you want a potential cure from MS with these treatments you need to be prepared to get a second autoimmune disease.

At present secondary autoimmunity seems to be more common post-alemtuzumab when compared to AHSCT and we haven’t seen this complication with cladribine, but I suspect there will be isolated cases. The true incidence of these autoantibody-mediated problems post-AHSCT is not known, but is clearly an issue and I am beginning to wonder why we don’t put in place the same monthly blood and urine monitoring post-AHSCT as we do post-alemtuzumab.

By far the commonest is autoimmune thyroid disease with about 20% of males and 40% of females with MS being treated with alemtuzumab developing autoimmune thyroid disease. The type of autoimmune thyroid disease post-IRT is not quite the same as standard Grave’s disease. It tends to be more brittle with frequent fluctuations and even remissions. The reason for this is that post-IRT Grave’s disease tends to have stimulatory antibodies against the thyrotropin receptor, which activates the thyroid gland to produce thyroid hormone. These anti- thyrotropin receptor antibodies don’t seem to damage the thyroid gland in the same way as other anti-thyroid gland antibodies. Despite this many patients end up with hypothyroidism and need to go onto thyroxine or thyroid replacement therapy.

NOTE: “ Levothyroxine is best taken on an empty stomach 30 minutes before food, and not to be taken with caffeine. This is not commonly taught and may be a cause for poor response—so worth sharing”. Simon Hodes. Investigating hypothyroidism: how to take levothyroxine.BMJ 2021;373:n1463

The following figure and review paper is worth reading if you are more interested in the diagnosis and management of thyroid problems post IRTs.

a) Hyperthyroidism/thyrotoxicosis. b) Hypothyroidism. TSH, thyroid-stimulating hormone; TRAb, thyrotropin receptor autoantibodies; FT4, free-thyroxine; FT3, free-triiodothyronine; GD, Graves’ disease; ATD, antithyroid drug; RAI, radioiodine; TPOAb, autoantibodies to thyroid peroxidase; LT4, levothyroxine. Image from Eur Thyroid J.

Muller et al. 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy. Eur Thyroid J. 2019 Jul;8(4):173-185.

Thyroid dysfunction (TD) frequently occurs as an autoimmune complication of immune reconstitution therapy (IRT), especially in individuals with multiple sclerosis treated with alemtuzumab, a pan-lymphocyte depleting drug with subsequent recovery of immune cell numbers. Less frequently, TD is triggered by highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV), or patients undergoing bone-marrow/hematopoietic-stem-cell transplantation (BMT/HSCT). In both alemtuzumab-induced TD and HIV/HAART patients, the commonest disorder is Graves’ disease (GD), followed by hypothyroidism and thyroiditis; Graves’ orbitopathy is observed in some GD patients. On the contrary, GD is rare post-BMT/HSCT, where hypothyroidism predominates probably as a consequence of the associated radiation damage. In alemtuzumab-induced TD, the autoantibodies against the thyrotropin receptor (TRAb) play a major role, and 2 main aspects distinguish this condition from the spontaneous form: (1) up to 20% of GD cases exhibit a fluctuating course, with alternating phases of hyper- and hypothyroidism, due to the coexistence of TRAb with stimulating and blocking function; (2) TRAb are also positive in about 70% of hypothyroid patients, with blocking TRAb responsible for nearly half of the cases. The present guidelines will provide up-to-date recommendations and suggestions dedicated to all phases of IRT-induced TD: (1) screening before IRT (recommendations 1-3); (2) monitoring during/after IRT (recommendations 4-7); (3) management of TD post-IRT (recommendations 8-17). The clinical management of IRT-induced TD, and in particular GD, can be challenging. In these guidelines, we propose a summary algorithm which has particular utility for nonspecialist physicians and which is tailored toward management of alemtuzumab-induced TD. However, we recommend prompt referral to specialist endocrinology services following diagnosis of any IRT-induced TD diagnosis, and in particular for pregnant women and those considering pregnancy.

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Purple haze

Barts-MS rose-tinted-odometer: ★★ (Purple Haze Friday #7D7098; looking forward to the weekend)

It is quite amazing how large and extensive the focal inflammatory lesion blindspot or scotoma is in the field of MS. I was on a call with a few American neurologists last week and they were saying how anti-CD20 therapy has transformed their MS practice. One neurologist claimed that 4 out of 5 of their patients were now going onto ocrelizumab or ofatumumab. He even said that ofatumumab will become the new Copaxone; i.e. no blood monitoring and very safe. Do you agree? When I reminded this neurologist of the end-organ damage data, i.e. brain volume loss, and the progression independent of relapse data in relation to anti-CD20 therapies he dismissed me saying that these patients were free of relapses and their MRI’s were quiet so he had done his job.

And herein lies the problem, the wider MS community including MS experts are not prepared to look beyond relapses and MRI activity; for them this is MS. In other words, if you render people relapse and MRI activity free then you have treated their MS. However, if you scratch the surface this is clearly not the case. If relapses were MS then they would predict long term outcome, but they don’t except when you are on therapy. According to the Prentice criteria that define a surrogate endpoint for relapses to be MS they need to predict outcome regardless of treatment. This is why relapses cannot be MS; relapses and their MRI equivalent (focal lesions) simply represent the immune system’s response to what is causing the disease or the real MS.

The data set below from the MS-Base register supports this proposition; i.e. off-therapy relapses do not predict long-term outcome, unlike on-therapy relapses. This point is so fundamental to understanding the real MS that most people can’t get their heads around it.

So what does this mean to you if you have MS? It means that if you have no evident inflammatory disease activity (NEIDA), and are relapse-free and MRI-activity free, it doesn’t mean your MS is necessarily under control. In other words, you could still be losing brain volume at double the rate of what is expected for your age and you could still be worsening. This is why we mustn’t be lulled into a sense of false security that we have cracked MS with our current therapies, in particular with the anti-CD20 therapies. We really need to go beyond NEIDA and target smouldering MS with new add-on strategies.

I hope all this makes sense? I have asked you before, would you rather be NEIDA or NEIDA and NEO-EOD (no evident ongoing end-organ damage)? The challenge for the MS community is to shift our focus to the latter target.

Figure from the Ann Neurol. Contribution of on- and off-therapy annualized relapse rate (ARR) to 10-year median Expanded Disability Status Scale (EDSS) changes (95% confidence interval). Here the ARR is normalized to 1. This figure shows the results of 2 adjusted quantile median regression analyses. All analyses were adjusted for gender, age at baseline, disease duration, the proportion of follow-up on first-line disease-modifying therapy (DMT), pregnancies, first DMT identity, baseline EDSS score, and clinic country. Subanalysis 1 (S1) includes all 2,466 patients from the primary analysis. Subanalysis 2 (S2) only models those patients who were able to contribute to both on-treatment and off-treatment epochs (n = 1,475). This figure demonstrates that on-treatment relapses have a profound effect on long-term EDSS increases, whereas off-treatment relapses have a marginal effect on disability outcomes.

Jokubaitis et al. Predictors of long-term disability accrual in relapse-onset multiple sclerosis. Ann Neurol. 2016 Jul;80(1):89-100.

Objective: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis.

Methods: Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.

Results: We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009).

Interpretation: We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100.

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How many ofatumumab doses should I miss?

Barts-MS rose-tinted-odometer: ★★★ (It feels like a sky blue rainy Friday = #87ceeb)

“Prof G how many of my monthly ofatumumab injections should I miss to guarantee that I will have an adequate antibody response to the COVID-19 vaccine?”

This was the gist of one of the direct messages I received on Twitter from a person with MS living in the US.

I really don’t know. However, I have tried extrapolating data from the repopulation kinetics of ofatumumab given 3-monthly and the modelling data below on ocrelizumab and rituximab. For ocrelizumab and rituximab to have 80% confidence it requires at least 9 months from the last infusion to the first vaccination to have a >50% chance of seroconversion in response to an RNA-based COVID-19 vaccine. This equates to missing close to one dose of ocrelizumab or rituximab as you have to wait 9 months then have two vaccine doses and wait 3-4 weeks after your second or booster dose of vaccine before recommencing your 6-monthly infusions. i.e. ~11 months after your last infusion. Although Mike Famulare has treated rituximab and ocrelizumab as being equipotent in his modelling I suspect he is wrong and the gap for ocrelizumab may in fact have to be substantially longer. I predict that the average person will need to wait about 11-12 months post their last infusion of ocrelizumab to be confident of an antibody response.

As ofatumumab, is a lower dose anti-CD20, with more rapid B-cell repopulation kinetics than ocrelizumab or rituximab (see figure below). I estimate that you will need to wait about 6 months from your last injection before being vaccinated and you would then have two vaccine doses and wait 3-4 weeks after your second or booster dose of vaccine before recommending your monthly injections. i.e. ~8 months later. As this is all based on modelling I suspect in real life you will simply need to wait for peripheral blood B-cell reconstitution to occur before being vaccinated. The problem with the latter is how high do your peripheral B-cells have to be before being vaccinated; more than 3, 5, 10, 20, 50 or 80 CD19+ B-cells per mm3? Clearly, this is something that needs further study and I would urge Pharma or one of the MS groups interested in answering this question to do the study. Let’s call it the ‘Peripheral B-cell Threshold Vaccine Study‘ or the ‘PerBeC Vax Study‘.

I want to reiterate that vaccine immunity is not only about B-cell and antibody immunity, T-cells also have an important role to play. Granted that if you don’t make antibodies it indicates that your follicular T-helper cells memory may not be that great, but this does not tell you about other CD4+ and CD8+ T-cell memory responses. Therefore, please be patient until these data emerge.

My message remains the same; #GetVaccinatedASAP. During this phase of the pandemic, some immunity is better than no immunity. The risk associated with getting COVID-19, particularly if you are on a B-cell depleting agent, far outweighs the risks associated with vaccination.

covid_vax_seroconversion_probability_vs_time_since_BCDT.png — Seroconversion rate following complete COVID-19 vaccination vs. time since most recent b-cell depleting therapy (BCDT). Best fit, 80%, and 95% confidence interval shows logistic regresssion model of seroconversion probability over time.

Mike Famulare. Seroconversion after COVID-19 vaccination in patients using B-cell depleting therapies to manage multiple sclerosis increases with time between treatment and vaccination. Github v0.2 03 June 2021.

B-cell depleting therapies (BCDT) such as ocrelizumab and rituximab used for the management of multiple sclerosis are associated with reduced seroconversion rates following COVID-19 vaccination. In this note, I reanalyze data from the literature to examine how the probability of seroconversion depends on the time interval between the last BCDT dose and the first vaccine dose. While uncertainty is high due to limited data, the results show that the seroconversion probability increases with time. Under a Bayesian interpretation of logistic regression, I estimate with 80% confidence that it requires at least 9 months from last BCDT to first vaccination to have a >50% chance of seroconversion following complete mRNA vaccination, with large uncertainty on when higher confidence of seroconversion can be expected. Among subjects who do seroconvert following vaccination, anti-Spike IgG levels correlate with time since last BCDT. Limited data indicate that levels comparable with immunocompetent response can be achieved with intervals of 12 or more months between BCDT and vaccination. With combined data from multiple sources, I argue that time development of the seroconversion probability and antibody response parallels that of CD19+ and naive B-cell repopulation following BCDT, suggesting that monitoring B-cell repopulation will be useful at the individual level for optimizing vaccine response while maintaining adequate MS control.

Pharmacodynamic response showing dose-response depletion of CD19 B cells and repletion kinetics (safety population). The median time to repletion based on Kaplan-Meier estimates was ≈11 months for the ofatumumab 3 and 30 mg every 12 weeks groups and ≈14 months for the ofatumumab 60 mg every 12 and 4 weeks groups.

Bar-Or et al.Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. Neurology. 2018 Sep 11;91(11):538.

Objective: To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS).

Methods: Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.

Results: The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.

Conclusion: Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.

Classification of evidence: This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.

Trial registration: ClinicalTrials.gov NCT01457924.

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