Do you have progressive MS; is your MS salvageable?

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Another Jazzy Blues Saturday #163780 (VW’s code)

As you are aware Professor Alan Thompson was awarded the Charcot prize from ECTRIMS this year. The award recognised his long and illustrious career in the field of MS and in particular his contribution to the study of progressive MS.  However, Professor Thompson’s final message in his Charcot Lecture  – Progressive multiple sclerosis – a personal perspective – ‘that once you have clinically manifest progressive MS with disability the therapeutic window has probably shut’ has had some blowback on social media. 

His final message may dampen the spirits of many of you living with progressive MS and challenges some of the research we are involved in.

I was personally disappointed that he did not mention Kurtzke’s length-dependent axonopathy hypothesis and the rationale for multiple therapeutic windows in MS, which we recently resurrected as a concept. It is because MS is a central length-dependent axonopathy that we have therapeutic lag and why we highlighted arm and hand function in pwMS in our #ThinkHand campaign and why we are doing the CHARIOT-MSORATORIO-HAND and UNDER&OVER trials. In short, we have hypothesised that it is never too late to modify the course of MS.

A few years ago during the #ThinkHand campaign one of my colleagues presented a patient who was had advanced MS (EDSS 7.5 = wheelchair-bound) who was still on interferon-beta. In keeping with NHS England guidelines, she had to stop treating this patient with interferon-beta. Three months later this patient presented with double-vision due to a brain-stem relapse. An MRI with contrast showed multiple Gd-enhancing lesions indicative of reactivation of MS disease activity, or rebound, post-interferon-beta. As this patient was not eligible to be restarted on a licensed DMT, we at the MDT recommended that the patient be offered off-label treatment with generic subcutaneous cladribine. Our position was that although the patient may be wheelchair-bound with advanced MS, she still had upper limb (arm & hand) and bulbar (swallowing and speech) function to preserve. Were we wrong to treat this patient and assume that the therapeutic window to modify her disease course has shut? This patient is not unique and almost every MS expert will have similar cases. 

As a result of these and other insights we are challenging the NHS England DMT stopping criteria, are proposing a randomised controlled trial to evaluate whether or not MS is modifiable in the population of patients who have to stop their licensed DMT.  Are these ‘unsalvageables’ salvageable? 

In short, we propose randomising pwMS who are forced to stop their existing DMT to treatment with possible generic cladribine or placebo with the primary outcome being NEDA or disease progression as defined using upper limb function, i.e. the 9-hole peg test. The plan is to make this an event-driven trial and if someone reaches the study end-point they can be unblinded and offered a course of cladribine if they were previously treated with placebo. If they had broken through on cladribine they could be offered a further course of treatment or another off-label salvage therapy, for example, rituximab biosimilar. 

Instead of assuming MS is not modifiable beyond a certain stage should we not at least try and salvage upper limb function in people with more advanced MS?

The real question is do we have the equipoise to do this study? Please note that in a small French study, stopping DMTs in pwSPMS, 35% of the cohort had relapses, or MRI activity, in the follow-up period (~5 years). Similarly, in the MS-BASE study below, of 485 DMT-stoppers vs. 854 DMT-stayers followed for at least 3-years, time to confirm disability progression was significantly shorter among DMT stoppers than stayers. The data from these two studies would indicate that we should ignore NHS England because their stopping criteria are not evidence-based and give the patient the option of stopping their DMT or continuing with it. What do you think? 

Length-dependent axonopathy

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

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

French Study

Bonenfant et al. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis? Eur J Neurol. 2016. doi: 10.1111/ene.13181

BACKGROUND AND PURPOSE: The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS.

METHODS: We included 100 consecutive patients with SPMS who regularly attended our multiple sclerosis clinic. Inclusion criteria were (i) secondary progressive phenotype for at least 2 years, (ii) immunomodulatory treatment for at least 6 months and (iii) treatment stopped with no plans to switch to another. Clinical and magnetic resonance imaging (MRI) data before and after treatment discontinuation were assessed. Factors associated with relapses and/or MRI activity were identified.

RESULTS: Mean treatment duration was 60.4 ± 39.3 months, and mean follow-up duration after treatment withdrawal was 62.4 ± 38.4 months. The annualized relapse rate remained stable at 1 and 3 years after treatment withdrawal [0.09, 95% confidence interval (CI), 0.05-0.17 and 0.07, 95% CI, 0.05-0.11, respectively], relative to the 3 years prior to treatment withdrawal (0.12, 95% CI, 0.09-0.16). Sixteen patients experienced a relapse and 19 had a gadolinium-positive MRI scan without relapse during follow-up. A gadolinium-positive MRI scan within the previous 3 years before treatment withdrawal and Expanded Disability Status Scale score of <6 were positively associated with relapse and/or MRI activity after discontinuation (P = 0.0004 and P = 0.03, respectively).

CONCLUSION: In this retrospective study, including a limited number of patients with SPMS, the annualized relapse rate remained stable after treatment withdrawal, relative to before treatment withdrawal. Further prospective studies are needed to confirm this result and provide evidence-based guidelines for daily practice.


Kister et al. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016 Oct;87(10):1133-7.

BACKGROUND:  Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking.

OBJECTIVES: (1) To compare time to first relapse and disability progression among ‘DMT stoppers’ and propensity-score matched ‘DMT stayers’ in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers.

METHODS: Inclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model.

RESULTS: Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period.

CONCLUSIONS: Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.

Conflicts of Interest

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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. 

#ECTRIMS2021: Cladribine and COVID-19

Barts-MS rose-tinted-odometer: ★★★★
Monday morning lime green & purple haze, #800080 #32CD32

How safe is cladribine during COVID-19?

I have been saying that based on its mode of action cladribine works as a semi-selective B-cell depleting agent similar to an anti-CD20 or anti-CD19 therapy. However, cladribine has an advantage as it is used as an IRT (immune reconstitution therapy) so is not associated with continuous immunosuppression. Cladribine is also CNS penetrant and hence targets CNS resident B-cells.

Another advantage of cladribine is that as it kills B-cells in the periphery new migrant naive cells are emerging from the bone marrow. Hence peripheral B-cell counts don’t drop to zero, which explains why pwMS treated with cladribine are vaccine ready and make good antibody and T-cell responses to the COVID-19 vaccines. Importantly, the latter seems to be independent of where in the cladribine treatment cycle vaccinations occur and appears to be independent of peripheral lymphocyte counts. 

The following is the safety data I presented and ECTRIMS in relation to pwMS treated with cladribine who had COVID-19. Importantly, out of 503 cladribine-treated pwMS, there were only 3 fatalities (0.6%). This is an order of magnitude lower than that recently reported with ocrelizumab (Hughes et al. Mult Scler Relat Disord. 2021 Apr;49:102725.).

The list of other adverse events is self-explanatory. 

Overall of the high-efficacy B-cell depleting DMTs, cladribine is emerging as the one DMT that seems to be the best tolerated with a low risk of severe COVID-19 and at the same time allowing to receive COVID-19 vaccinations with confidence. The fundamental difference is that cladribine is an IRT and many HCPs and pwMS don’t feel comfortable with the fact that after an IRT you have to play a wait-and-see game, i.e. no treatment until MS disease activity returns. If you are one of these people you need to ask yourself if you are not prepared to have an IRT could you please ask yourself how are we the MS community going to ever find a cure for MS? 


Please note that I am the principal investigator on the oral cladribine phase 3 programme and have been involved with its development since 2002. I am therefore heavily conflicted so you may want to interpret anything I say that is positive about cladribine with caution. 

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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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. 

#ECTRIMS2021: ocrelizumab the game-changer

Barts-MS rose-tinted-odometer: ★★★★★★★
The first  7-star ‘Teal Blue Monday’ #367588

The next in the series of #ECTRIMS2021 long-term follow-up posts. This is the 7.5 year follow-up of the ocrelizumab OPERA 1&2 (relapsing MS) cohort. The efficacy data looks very impressive. 

  1. Annualised relapse rates well below one in 10 years or 0.1 p.a.

2. 82% of ocrelizumab treated subjects had no confirmed disability progression.

3. Less than 7% of ocrelizumab treated subjects needed a walking stick compared to 10% of subjects randomised to interferon for 2-years before switching to ocrelizumab. Sadly, the 2 years on interferon have come at a price; time really is brain and spinal cord. This data like most contemporary data sets make a strong case for flipping the pyramid. 

4. The safety of ocrelizumab looks similar to what it was 2-years ago. The risk of serious infections is 1.73 per 100 patient-years of follow-up; i.e. in 1,000 patients on ocrelizumab, 17 will have a serious infection per year. This needs to be balanced against the COVID-19 data showing a doubling of risk of severe COVID-19 in ocrelizumab-treated subjects and an ~80% chance of not seroconverting when being vaccinated with one of the COVID-19 vaccines.

Unfortunately, no end-organ damage data (brain volume loss) to present, but this will come in time.

It is clear that anti-CD20 therapies are a real game-changer when it comes to the management of MS; i.e. very high efficacy therapies, in terms of switching off MRI activity and relapses, with a relatively good short and long term safety profile. 


Giovannoni et al. Long-term  reduction  of  relapse  rate  and  confirmed  disability  progression  after  7.5  years  of ocrelizumab  treatment  in  patients  with  relapsing  multiple  sclerosis  in  the  OPERA  OLE. ECTRIMS 2021, P723. 

Introduction:  The  efficacy  and  safety  of  ocrelizumab  (OCR)  in  relapsing  multiple  sclerosis  (RMS)  were demonstrated  in  the  96-week  contro led  double-blind  period  (DBP)  of  the  Phase  I  OPERA  I  (NCT01247324) and  OPERA  I (NCT01412333)  trials.

Aims:  To  assess  the  efficacy  of  switching  from  interferon  (IFN)  β-1a  or  maintaining  OCR  therapy  on  disease activity  and  confirmed  disability  progression  (CDP)  after  5.5  years  of  fo low-up  in  the  open-label  extension (OLE)  of  OPERA  I  and  OPERA  I.

Methods:  In  the  DBP  of  OPERA  I  and OPERA  I, patients  were  randomised  to  receive  OCR  or  IFN  β-1a. Patients  completing  the  DBP  either  continued  OCR  (OCR-OCR)  or  switched  from  IFN  β-1a  to  OCR  (IFN-OCR) when  entering  the  OLE.  Adjusted  annualised  relapse  rate  (ARR),  time  to  onset  of  48-week  CDP  (CDP48)  and time  to  48-week  confirmed  Expanded  Disability  Status  Scale  score  ≥6.0  (time  to  require  a  walking  aid)  were analysed  up  to  Week  384.

Results:  Overa l,  76.3%  of  patients  who  entered  the  OLE  period  completed  OLE  Year  5.5.  Adjusted  ARR decreased  year-on-year  from  the  pre-switch  year  to  OLE  Year  5.5  in  IFN-OCR  switchers  (pre-switch,  0.20;  OLE Year  1,  0.10;  OLE  Year  5.5,  0.03)  and  was  maintained  at  low  levels  in  OCR-OCR  continuers  (pre-switch,  0.12; OLE  Year  1,  0.10;  OLE  Year  5.5,  0.03).  Rates  of  CDP48  were  lower  in  OCR-OCR  continuers  vs  IFN-OCR switchers  at  the  end  of  the  DBP  (4.1%  vs  8.5%  [Δ=4.4%;  p<0.001])  and  numerica ly  lower  at  OLE  Year  5.5 (17.9%  vs  21.5%  [Δ=3.5%;  p=0.118]).  Rates  of  patients  requiring  a  walking  aid  were  lower  in  OCR-OCR continuers  vs  IFN-OCR  switchers  at  the  end  of  the  DBP  (0.8%  vs  3.1%  [Δ=2.4%;  p=0.001])  and  numerica ly lower  at  OLE  Year  5.5  (6.6%  vs  9.5%  [Δ=2.9%;  p=0.060]).  Over  the  DBP  and  OLE  periods,  the  risk  of  CDP48 was  23%  lower  (overa l  percent  of  patients  with  CDP48  in  OCR-OCR  vs  IFN-OCR:  14.5%  vs  16.4%;  HR [95%CI]:  0.77  [0.60–0.98];  p=0.034)  and  the  risk  of  requiring  a  walking  aid  was  35%  lower  (overa l  percent  of patients  requiring  a  walking  aid  in  OCR-OCR  vs  IFN-OCR:  5.2%  vs  7.0%;  HR  [95%CI]:  0.65  [0.44–0.97]; p=0.034)  in  OCR-OCR  continuers  vs  IFN-OCR  switchers.

Conclusions:  Switching  from  IFN  β-1a  to  ocrelizumab  at  the  start  of  the  OLE  period  was  associated  with  a rapid  and  robust  reduction  in  ARR  that  was  maintained  through  the  5.5-year  fo low-up  of  the  OLE  period.Compared  with  patients  switching  to  ocrelizumab  at  the  OLE,  patients  initiating  ocrelizumab  2  years  earlier had  a  significantly  reduced  risk  of  requiring  a  walking  aid  and  48-week  CDP.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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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. 

#ECTRIMS2021: a potential cure?

Barts-MS rose-tinted-odometer: ★★★★★★★
A 7-Starred Bright Pink Sunday Special #ff007f

Some asked about the 10-year alemtuzumab follow-up data. Here are the headline results:

  1. 60% of subjects are free of disability worsening.

2. 50% had confirmed improvement in disability.

3. Annualized brain volume loss consistently below 0.2% (essentially normal).

4. Tragically, the trial subjects who were randomised to interferon-beta for the first 2-years never catch up; time really is brain and spinal cord.

As you will see these results are clouded by a 40% drop-out rate and hence may be enriched for responders. However, these results still support hitting MS early and hard with an IRT will result in a significant number of pwMS going into long-term remission. 

I did the TOPAZ exit assessments of a large number of study subjects for both the CARE-MS1 and CARE-MS2 cohorts and I have never seen so many people with MS living normal lives with no disability in long-term remission, but still carrying around the label of having MS.

Wouldn’t it be great to be able to tell some of these pwMS you are cured? 


Knowing what MS can do to people and seeing these results who wouldn’t want to be treated with, or at least offered the option of being treated with, alemtuzumab or another IRT when they are diagnosed? 

Giovannoni et al. Early treatment with alemtuzumab maintains its efficacy on clinical and MRI disease activity outcomes, including slowing of brain volume loss, over 10 years in RRMS patients: CARE-MS II follow-up (TOPAZ Study). ECTRIMS 2021, P722.

Introduction: In CARE-MS II (NCT00548405), alemtuzumab (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved clinical/MRI outcomes versus SC IFNB-1a over 2 years (y) in RRMS patients with inadequate response to prior therapy and further minimised disease in a 4-y extension study (NCT00930553). Further follow-up was available in an additional 5-y extension, TOPAZ (NCT02255656).

Aims: Evaluate the efficacy and safety of alemtuzumab in CARE-MS II patients over 10 y.

Methods: At investigator discretion, patients in TOPAZ can receive additional alemtuzumab as needed for disease activity (≥12 months apart) or other disease-modifying therapy (DMT) at any time.

Results: Proportions of patients remaining on study after 10 y were 62% (271/435) among those treated initially with alemtuzumab in the core study and 73% (107/146) among those treated with SC IFNB-1a for 2 y before switching to alemtuzumab in the extensions. In the extension studies, 39% of the alemtuzumab group did not receive further treatment (alemtuzumab or other DMT). Among the alemtuzumab group over the combined core and extension studies, 71% of patients had stable/improved EDSS scores, the mean change in EDSS score was +0.34, 58% of patients were free of 6-month confirmed disability worsening, and 49% achieved 6-month confirmed disability improvement. In Y10, the annualised relapse rate was 0.11, 71% of patients were free of MRI disease activity, 92% were free of new gadolinium-enhancing lesions, and 72% were free of new/enlarging T2 hyperintense lesions. The median annual brain volume loss was ≤0.19% each year over Y3–10. Alemtuzumab had a consistent safety profile over 10 y, with the incidence of overall adverse events (AEs) and infections declining through Y10. Cumulative incidence of thyroid AEs was 44% and immune thrombocytopaenia was 4%. Efficacy and safety in SC IFNB-1a–treated patients from the core study who switched to alemtuzumab in the extension were consistent with those treated with alemtuzumab in both the core and extension.

Conclusions: Early treatment efficacy with alemtuzumab on clinical, MRI lesion, and brain volume outcomes was maintained over 10 y in CARE-MS II patients, with 62% remaining on study and 39% receiving no additional courses or other DMTs through Y10. Safety remained consistent and manageable over 10 y, with declining AE incidences over time, including a consistent reduction in autoimmune AE occurrence after Y3.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

Twitter   /  LinkedIn  /  Medium

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.

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