Au revoir

Dear the-MS-Blog (formerly Barts-MS Blog) Reader

Today is the first anniversary of my near-death experience. What a year? It is good to be alive and appreciative of things I always took for granted; these are mostly simple things. 

I am still having to adjust to my new normal and realise I am unable to do many of the things I used to be able to do. I need to prioritise and focus on fewer things with the aim of hopefully doing them well and seeing them to completion. I have decided to pack away my soapbox and I will therefore not be contributing to The MS-Blog going forward.

I have moved all my prior blog posts to this ghost site as an archive.

Thank you for your support over the last 12 months and the last 12 years. 

Prof G 

P.S. Please note that I have no responsibility for the-MS-Blog (formerly Barts-MS Blog) or any of its future content. Please don’t refer to the MS-Blog as Prof G’s blog or Prof G’s old blog. My old blog posts are archived here.

NHS letter to patients regarding COVID-19 antivirals

If you have MS and live in England you should be on the Government’s shielding/vulnerable list that allows you to be given a 3rd dose of a COVID-19 vaccine as part of your primary course of vaccinations and hence you are eligible for a 4th dose as a booster three months after your 3rd dose. In addition to this, in the event of developing COVID-19 you are also eligible for receiving antivirals, in both the community and hospital.

If you have received the following letter in the last few days you are on the list. If you are not on the list you may want to contact your GP to let them know.

Conflicts of Interest

MS-Selfie Newsletter 

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. 


Please note this is not an active blog. I am just using an old WordPress site I set-up a 2 years ago as an archive for my old blog posts. MS-Selfie is now a newsletter on substack and uses email as its main tool of dissemination.

Please note that MS-Selfie Newsletter’s primary aim is to help people with MS and their families self-manage their MS. It is not about interpreting MS research and other news unless it has a direct impact on the management of MS.

Lest we forget

Barts-MS rose-tinted-odometer: ★
Black Friday #000000

The COVID-19 pandemic has had an extraordinary impact on ethnic minorities in the UK. Most of us had ascribed this excess mortality to the social determinants of health. However, the study below suggests some of the excess mortality may be related to genetic factors. 

A gene that acts as a switch to turn on a defence mechanism that prevents the SARS-CoV-2 from entering epithelial cells in the lung may be an important factor. With the high-risk version of the gene, these defence mechanisms are blunted, allowing the virus to enter, infect and damage cells in the lung for a longer time period after exposure and infection. 

Having the high-risk version of this gene doubles your risk of respiratory failure and death from COVID-19 and could explain why people of South Asian origin are more vulnerable to the disease. The high-risk gene is carried by ~60% of people with south Asian backgrounds, compared to only 15% of those from a white European background. 

I wonder if my friend and colleague Dr Peter Tun, who died last April from COVID-19, carried this gene variant?

Downes et al. Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus. Nature Genetics. 4-Nov-2021.

The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Genome-wide association studies identified the 3p21.31 region as conferring a twofold increased risk of respiratory failure. Here, using a combined multiomics and machine learning approach, we identify the gain-of-function risk A allele of an SNP, rs17713054G>A, as a probable causative variant. We show with chromosome conformation capture and gene-expression analysis that the rs17713054-affected enhancer upregulates the interacting gene, leucine zipper transcription factor like 1 (LZTFL1). Selective spatial transcriptomic analysis of lung biopsies from patients with COVID-19 shows the presence of signals associated with epithelial–mesenchymal transition (EMT), a viral response pathway that is regulated by LZTFL1. We conclude that pulmonary epithelial cells undergoing EMT, rather than immune cells, are likely responsible for the 3p21.31-associated risk. Since the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may represent a therapeutic target.

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. 

HPV vaccination reduces cervical cancer by up to 90%

Barts-MS rose-tinted-odometer: ★★★★★
(Cancer Pink Thursday #ffbfc3)

News, news, news! 

In fact, great news (see Lancet paper below)! HPV vaccine cuts cervical cancer rates by close to 90%, using the new polyvalent HPV vaccine (Gardasil-9), which clovers 9 HPV strains. This stunning bit of innovation doesn’t address the other benefits of preventing HPV infection, which include preventing penile, anal, nasopharyngeal and oesophageal cancers not to mention the simple wart. 

So what to advise pwMS about the HPV vaccine?

The HPV vaccine prevents infection with the sexually transmitted human papillomavirus (HPV) which is known to cause cervical cancer and several other cancers.

Cervical Cancer: Screening, Recognition, and Treatment
Cervical cancer: image Medscape.

If you decide to go onto an immunosuppressive therapy, in particular, potent immunosuppressive therapies. The suppression of your immune system allows viruses to escape and to start replicating. This is a particular problem with alemtuzumab and potentially HSCT. So there is a strong augment to get yourself vaccinated, or to upgrade your immunity from the quadrivalent to the polyvalent vaccine, before starting a potent IRT and other immunosuppressive therapy.  

HPV is not only a problem for women. HPV is a well-established cause of penile and anal cancer and causes a small proportion of throat and oesophageal cancers. Therefore it makes sense for males to be vaccinated against HPV as well.

The epidemiology of HPV infection is also changing. People are becoming infected later in life and are spreading the virus. Social media and dating apps have revolutionised the dating world and many older people are becoming promiscuous and are having unsafe sex later in life. As a result of this, there has been a large increase in the incidence of sexually transmitted diseases in older people, including HPV infections. This has prompted some commentators to suggest that public health officials extend the HPV vaccine to all women and possibly all men. Why wouldn’t you want to reduce your risk of getting cervical cancer? Isn’t prevention better than having to treat HPV infection and its downstream effects, i.e. premalignant cervical lesions or cervical cancer?

Warts and all – The MS-Blog
Cutaneous warts

Question 1: If I have been vaccinated with the older quadrivalent vaccine could I receive the new vaccine to cover the other strains of the virus?

Yes, there is data that shows that the previous vaccination against HPV doesn’t stop your immune system from responding to the components that cover the new strains.

Question 2: As I am on a DMT can I have the HPV vaccine?

This all depends on the DMT you are on. For the non-immunosuppressive immunomodulators such as interferon-beta, glatiramer acetate and teriflunomide vaccination is unlikely to be a problem. Similarly for the fumarates, natalizumab, cladribine and alemtuzumab the level of immunosuppression and the window of vaccination are unlikely to affect vaccine responses. However, based on the COVID-19 vaccine studies if you are on an S1P modulator (fingolimod, siponimod, ozanimod or ponesimod) or an anti-CD20 (ocrelizumab, ofatumumab, rituximab) the response to the HPV vaccine is likely to be blunted. 

Question 3: I need to start a DMT, but I want to have the HPV vaccine or extend my cover with the new polyvalent vaccine, how long will I need to wait before I can start treatment?

The polyvalent vaccine at the moment requires 2 or 3 doses with the last dose given at 5 or 6 months. Ideally, to give your immune system a chance to respond to the vaccine you will need to wait until 4 weeks after the final booster, i.e. 6 or 7 months.

Question 4: Should I delay starting DMTs to have the vaccine?

There is no simple answer to this question. You have to balance the risks and benefits of having the vaccine against the risks of untreated MS. In relation to the IRTs, I would suggest going ahead and starting the IRT and delaying the vaccine until you have reconstituted your immune system. Delaying starting an IRT to have the vaccine does not make immunological sense in that the memory responses you have just made to the vaccine could potentially get depleted and depending on the intensity of the immunodepletion may not recover. For maintenance DMTs, in particular, the S1P modulators and anti-CD20 therapies you should probably delay starting treatment to have the vaccine.

Question 5: If I want the new polyvalent vaccine will the NHS cover it?

At present, the answer is no. The UK is in the process of switching from the quadrivalent (Gardasil-4) to the polyvalent vaccine (Gardasil-9) under the national vaccine programme. At present, if you want to be vaccinated against HPV you will have to cover the costs of the vaccine yourself. This is not too dissimilar to what happens with travel vaccines.

I predict that HPV vaccination is going to be one of those factors that have to be put in the mix when deciding which is the correct DMT for you. It is not a major factor but is an important factor nevertheless. I have only just started to routinely discuss this topic with my patients. It clearly has future health implications. 

What is your view on this? Do you think MS healthcare professionals should be obliged to discuss issues around HPV vaccination before pwMS start a DMT?

Falcaro et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. The Lancet 2021:November 03.

Background: Human papillomavirus (HPV) immunisation with a bivalent vaccine (Cervarix) was introduced in England, UK, in Sept 1, 2008: routine vaccination was offered to girls aged 12–13 years with a catch-up programme for females aged 14–18 years in 2008–10. We quantified the early effect of this immunisation programme on cervical cancer and cervical carcinoma in situ, namely grade 3 cervical intraepithelial neoplasia (CIN3), registrations.

Methods: In this observational study, we used an extension of the age-period-cohort Poisson model to estimate the relative risk of cervical cancer in three vaccinated cohorts compared with earlier cohorts that were not eligible for HPV vaccination. Data from a population-based cancer registry were extracted on Jan 26, 2021, and were assessed for diagnoses of cervical cancer and CIN3 from Jan 1, 2006 to June 30, 2019 in women aged 20–64 years and who were a resident in England. We used three vaccinated cohorts to account for differences in the school year in which the vaccine was offered and its national coverage. Adjustment for confounding was made using information on changes in cervical screening policy and historical events that affected cervical cancer incidence. Results were compared across models with different adjustments for confounders.

Findings: We used data from a total of 13·7 million-years of follow-up of women aged 20 years to younger than 30 years. The estimated relative reduction in cervical cancer rates by age at vaccine offer were 34% (95% CI 25–41) for age 16–18 years (school year 12–13), 62% (52–71) for age 14–16 years (school year 10–11), and 87% (72–94) for age 12–13 years (school year 8), compared with the reference unvaccinated cohort. The corresponding risk reductions for CIN3 were 39% (95% CI 36–41) for those offered at age 16–18 years, 75% (72–77) for age 14–16 years, and 97% (96–98) for age 12–13 years. These results remained similar across models. We estimated that by June 30, 2019 there had been 448 (339–556) fewer than expected cervical cancers and 17 235 (15 919–18 552) fewer than expected cases of CIN3 in vaccinated cohorts in England.

Interpretation: We observed a substantial reduction in cervical cancer and incidence of CIN3 in young women after the introduction of the HPV immunisation programme in England, especially in individuals who were offered the vaccine at age 12–13 years. The HPV immunisation programme has successfully almost eliminated cervical cancer in women born since Sept 1, 1995.

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. 

How environmentally friendly is your DMT?

Barts-MS rose-tinted-odometer: ★★★★★
COP26 Land Green & Ocean Blue  #37328c #8cdc73

Did you know that the world will use between 8 billion and 10 billion syringes for COVID-19 vaccinations alone? Apart from this, the world uses approximately 16 billion syringes per year. Over half of these are used outside of the health care system each year by individuals with diabetes, migraines, allergies, infertility, arthritis, HIV, hepatitis, multiple sclerosis, osteoporosis, psoriasis, or other conditions. 

With COP26 top of mind do you ever consider the environmental impact of your DMT? I have simply assumed that because they are medicines and prescribed for a serious disease the environmental impact is justified. Could the environmental impact of injectable or intravenous therapies be another reason to embrace oral treatments? Or is the environmental impact related to the manufacturing process of oral treatments greater? 

Is this something that you would consider to be an important factor when making a decision about which DMT to choose? For example, would a lower environmental impact of a 6-monthly ocrelizumab infusion be a factor in choosing it over a monthly subcutaneous injection of ofatumumab?  After all, both of these DMTs are anti-CD20. Would you not want to choose the one with the lowest environmental impact?

Some of you may already be aware of our ClinicSpeak DMT decision aid we run to help pwMS make decisions about which DMT to start. Do you think we should include the environmental impact of the various DMTs on the list of factors to consider when making a decision?

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. 

EBV: is it time to pluck the black swan?

Barts-MS rose-tinted-odometer: ★★★★★
London Gray & Raining #666677 #C4D3DF

SEPSEPIEN a commentator this morning said: “Would have been more rewarding to find a DMT that successfully addresses the causes of MS”. I agree and I really think we have found the cause of MS. It is Epstein Bar Virus (EBV). The epidemiology is pretty convincing that EBV acts in the MS causal pathway and all of our effective i.e. licensed DMTs work on memory B-cell where the latent EBV virus resides. 

The piece on my #1 ECTRIMS-2021 highlight, i.e. the MRI changes in relation to treatment with Atara Bio’s anti-EBNA1 allogeneic CTLs (cytotoxic T-cells), has resulted in at least ten emails from business analysts wanting to speak to me about the product. I think it is my reference to a ‘Black Swan’ that piqued their interest. What they don’t realise is that when you pluck a black swan it looks just like a plucked white swan.

So if Atara Bio gets their product to market they will get pipped by the simple repositioning of the licensed DMTs as anti-EBV agents. What do I mean? 

Rituximab (anti-CD20) is licensed to treat EBV-associated lymphoproliferative disorders. Peripheral EBV viral loads plummet when you administer anti-CD20 therapies. In other words, anti-CD20 therapies are anti-EBV drugs so why would you need to use an expensive cellular therapy? To get into the CNS. Step up the CNS penetrant BTK inhibitors.

Ibrutinib the first licensed BTKi is a potent anti-EBV drug and works very well against EBV-associated lymphomas including CNS lymphomas. EBV in fact uses BTK as a signalling molecule to bypass B-cell receptor-mediated cell cervical signals.  

MD produced a wonderful and very influential review showing all of our DMTs in MS work via memory B-cell reducing their levels in the periphery with the exception of natalizumab that blocks trafficking of memory B-cells into the CNS. 

So all it will take for Big Pharma to pluck Atara Bios black swan is for them to produce data showing how their DMTs impact EBV viral infection in the periphery and potentially in the CNS. The frustrating thing for me is I have been trying to get Pharma to do these studies for decades. Just maybe with a black swan soaring up above they may start to listen. I suspect some of the companies have data on this already.

The good thing that Atara Bio has done is to move EBV centre stage. So maybe now we will get some momentum behind our EBV vaccination study off the ground. 

For those of you who have progressive MS please note how much improvement occurred in the study subject in the Atara Bio phase 1 study. It is almost too good to be true, which is why I referred to it as the Lazarus effect

Plucked Swan | monsieurpolk
A plucked swan; was it a black or white swan?

Baker et al. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017 Feb;16:41-50. 

Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore, it was interestingly to find that current MS-treatments, believed to act via T cell inhibition, including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19+, CD27+ memory B cells. This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity. Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS. This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.

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. 

Do you have progressive MS; is your MS salvageable?

Barts-MS rose-tinted-odometer: ★★★★★
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. 

https://platform.twitter.com/widgets.js https://platform.twitter.com/widgets.js

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

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. 

#TeachMS: new treatment strategies

If you are free this Thursday you may want to listen to Mark Freedman and me discussing different treatment strategies in relation to managing MS in the current environment. All of our discussions will be case-based. Please register as there are limited places available.

CoI: multiple

#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

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.