EID – Prof G's MS Blog Archive

#ECTRIMS2021: no loss of effectiveness with 6-weekly natalizumab

Barts-MS rose-tinted-odometer: ★★★★★
Lime green and purple Thursday, #32cd32 & #6a0dad

If you are on natalizumab and are JC virus seropositive, you are at increased risk of developing PML (progressive multifocal leukoencephalopathy). If you transfer from 4-weekly infusions or standard interval dosing (SID) to 6-weekly or extended interval dosing (EID) you reduce the risk of getting PML by close to 90%.

Does shifting from SID to EID affect the efficacy of natalizumab? In short NO.

The following data was presented at ECTRIMS 2021 and should reassure both patients and HCPs

The NOVA trial was designed to estimate the difference in efficacy between EID and

SID dosing in a population that was clinically stable on SID dosing.

Although a small difference in efficacy between EID and SID dosing was estimated for the primary endpoint (number of new or newly enlarging T2 lesions at week 72) this was driven by two subjects in the EID arm with very high lesion values. The one subject had 30 lesions that occurred 3 months after natalizumab discontinuation, which represents rebound disease activity. The other subject had 25 lesions at week 72 and was subsequently diagnosed with asymptomatic progressive multifocal leukoencephalopathy (PML). The latter could have been PML lesions and not MS lesions.

When you exclude these 2 patients or outliers there is no difference in the primary endpoint between EID and SID. This study shows that patients who are stable on natalizumab SID dosing can switch to EID dosing without a meaningful loss of efficacy.

I hope you now feel confident enough to switch from SID to EID without worrying about rebound or loss of efficacy.

Foley_NOVA_ECTRIMS2021_P970_Final

Foley et al. Primary results of NOVA: a randomized controlled study of the efficacy of 6‑week dosing of natalizumab versus continued 4-week treatment for multiple sclerosis. ECTRIMS 2021, P970.

Background: Natalizumab 4-week dosing (Q4W) with 300 mg is approved for treatment of relapsingremitting multiple sclerosis. Dosing frequency of approximately 6 weeks (Q6W) is associated with lower progressive multifocal leukoencephalopathy (PML) risk in retrospective analyses. Real-world data suggest similar effectiveness, but NOVA is the first randomized trial to assess Q6W efficacy.

Objective: Evaluate the efficacy of natalizumab Q6W in patients previously treated with natalizumab Q4W for ≥12 months compared with continuation of Q4W over 72 weeks.

Methods: NOVA is a randomized, contro led, open-label, rater-blinded phase 3b trial. Included patients were treated with natalizumab Q4W without relapse for ≥12 months and had no enhancing lesions at screening. Patients were randomized 1:1 to Q6W or Q4W arms. The primary endpoint was number of new/newly enlarging T2 (N/NET2) hyperintense lesions analysed by negative binomial regression with baseline (BL) weight, prior natalizumab exposure, and region as covariates. Secondary endpoints included relapses and 24week confirmed disability worsening (CDW). Primary estimand used a l observed data; secondary estimand treated post-intercurrent event data as missing. Missing data were imputed by worst value on treatment or multiple imputation depending on discontinuation reason.

Results: 195/248 (79%) Q4W patients and 207/251 (82%) Q6W patients completed NOVA. BL characteristics were wel balanced. Proportions of patients with N/NET2 lesions among observed data were low in both arms (Q4W:4.1%; Q6W:4.3%). Mean N/NET2 lesions in the Q4W and Q6W arms with the primary estimand were 0.05 and 0.20 (P=0.0755) and 0.06 and 0.31 (P=0.0437) with the secondary estimand. The difference was mainly due to 2 Q6W patients with high values: (1) 30 lesions that occurred 3 months after natalizumab discontinuation and (2) 25 lesions that occurred with asymptomatic PML observed at week 72. The sum of a lother N/NET2 lesions in NOVA was 18 with no other patient having >2. Relapse occurred in 2.1% and 2.8% (P=0.64) and CDW occurred in 8% and 10% (P=0.40) of patients in the Q4W and Q6W arms, respectively. Safety data were consistent with the known drug profile and similar between groups.

Conclusions: Despite a sma l difference in efficacy between arms, NOVA data suggest the vast majority of patients stable on Q4W dosing can switch to Q6W dosing with no clinica ly meaningful loss of efficacy. No conclusions on PML risk can be drawn from NOVA.

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.

Laura’s story

Barts-MS rose-tinted-odometer: ★ (a very Black & Red Monday)

I received an email from Laura, a young woman with very active MS, who had been on natalizumab (Tysabri) for 7 years and had recently seroconverted to being high-index JCV seropositive. She was put onto natalizumab extended interval dosing (EID), i.e an infusion every 8 weeks, to derisk PML and to reduced the number of infusions she required during the COVID-19 pandemic. Before starting her switch therapy she was told she needed to be vaccinated with the COVID-19 vaccine. Her natalizumab was stopped and whilst she was waiting for vaccine immunity to develop she developed natalizumab-rebound. This is her story.

“I’m Laura, a pwMS in the UK and I also work in the MS field. Currently, I’m not able to work due to recent rebound disease of MS, following discontinuation of Tysabri, to switch to another DMT. I believe the decision to delay the new treatment, to try to ensure I made antibodies to the second COVID-19 vaccination, was perhaps the wrong decision to be made on my behalf (I did not have any contribution to the decision, I was informed of the decision).

To risk rebound disease is not a small matter and I would urge conversations around this prior to the switch from Natalizumab (Tysabri) or Fingolimod (Gilenya) and potentially other S1P modulators (siponimod, ozanimod and ponesimod). I was in hospital for several weeks and much more disabled than I usually am; even during a typical relapse. It was a frightening and traumatic experience, and one I thought I would never endure. My mental health has also suffered as a direct result from the rebound relapse. I’m now trying to recover at home, to increase my strength and stamina sufficiently to be able to go back to driving again, working and being a Mum to two autistic boys. Independence.

I do not know of course if I will ever go back to my previous baseline. It saddens me that this was potentially avoidable; that we need to be mindful that rebound disease, by its very definition, is more severe than what has previously been experienced, and although COVID-19 vaccination is of course very important, I would have preferred to reduce my risk of rebound disease as the priority. It is my brain and spine after all. And as we know the more lesions we acquire the less reserve we have for the future. Perhaps rebound disease should be a never event, as when managed carefully it can be avoided.”

Laura’s story is tragic and should never have happened. We know enough about natalizumab rebound to prevent it from happening. It is more likely to occur in patients who have high disease activity and a high level of disability prior to starting natalizumab (see paper below). It also occurs around month 3-4 after the last infusion of natalizumab and probably slightly earlier in patients like Laura on 8-weekly EID when the steady-state levels of natalizumab are likely to lower.

There is also no scientific evidence to suggest pwMS on natalizumab will make lower antibody responses to the COVID-19 vaccine whilst on natalizumab. In our centre, this patient will have been on 6-weekly and not 8-weekly EID. She would have had all her vaccine doses whilst on natalizumab. On the day of her last natalizumab infusion, she would have had an MRI and lumbar puncture to exclude subclinical or asymptomatic PML. Provided these were negative she would have been switched to her next DMT approximately 3-4 weeks later. If for some unforeseen reason a delay was going to occur we would have given her another infusion of natalizumab. In short, we have seen too many catastrophic rebound associated relapses and would want to prevent this from happening; we know how to prevent rebound relapses so why not?

Laura, if you are reading this blog post, thank you for agreeing to allow us to publish your story and I sincerely hope you make a good recovery from your relapse. If anything can be learnt from Laura is that please don’t let vaccine-readiness delay starting a natalizumab-switch therapy.

Laura’s case illustrates my biggest fear during COVID-19 that untreated or undertreated MS is more of a concern than COVID-19. The good news is that we should be getting a definitive answer on whether or not EID is as effective as standard interval dosing (SID) in the near future from the NOVA study (ClinicalTrials.gov Identifier: NCT03689972)

Mustonen et al. Risk factors for reactivation of clinical disease activity in multiple sclerosis after natalizumab cessation. Mult Scler Relat Disord. 2020 Feb;38:101498.

Background: Natalizumab (NTZ) is widely used for highly active relapsing-remitting multiple sclerosis (MS). Inflammatory disease activity often returns after NTZ treatment discontinuation. We aimed to identify predictive factors for such reactivation in a real-life setting.

Methods: We conducted a retrospective survey in four Finnish hospitals. A computer-based search was used to identify all patients who had received NTZ for multiple sclerosis. Patients were included if they had received at least six NTZ infusions, had discontinued treatment for at least three months, and follow-up data was available for at least 12 months after discontinuation. Altogether 89 patients were analyzed with Cox regression model to identify risk factors for reactivation, defined as having a corticosteroid-treated relapse.

Results: At 6 and 12 months after discontinuation of NTZ, a relapse was documented in 27.0% and 35.6% of patients, whereas corticosteroid-treated relapses were documented in 20.2% and 30.3% of patients, respectively. A higher number of relapses during the year prior to the introduction of NTZ was associated with a significantly higher risk for reactivation at 6 months (Hazard Ratio [HR] 1.65, p < 0.001) and at 12 months (HR 1.53, p < 0.001). Expanded Disability Status Scale (EDSS) of 5.5 or higher before NTZ initiation was associated with a higher reactivation risk at 6 months (HR 3.70, p = 0.020). Subsequent disease-modifying drugs (DMDs) failed to prevent reactivation of MS in this cohort. However, when subsequent DMDs were used, a washout time longer than 3 months was associated with a higher reactivation risk at 6 months regardless of whether patients were switched to first-line (HR 7.69, p = 0.019) or second-line therapies (HR 3.94, p = 0.035). Gender, age, time since diagnosis, and the number of NTZ infusions were not associated with an increased risk for reactivation.

Conclusion: High disease activity and a high level of disability prior to NTZ treatment seem to predict disease reactivation after treatment cessation. When switching to subsequent DMDs, the washout time should not exceed 3 months. However, subsequent DMDs failed to prevent the reactivation of MS in this cohort.

Riancho et al. Does Extended Interval Dosing Natalizumab Preserve Effectiveness in Multiple Sclerosis? A 7 Year-Retrospective Observational Study. Front Immunol. 2021 Mar 25;12:614715.

The extended interval dosing (EID) of natalizumab has been suggested to be associated with a reduced risk of progressive multifocal leukoencephalopathy (PML) and short-term preservation of efficacy but its long-term effectiveness remain unknown. We aimed to determine the long-term effectiveness and safety of natalizumab in an EID setting in a cohort of patients with multiple sclerosis (MS) treated for more than 7 years. We conducted an observational retrospective cohort study, including 39 (34 female, 5 male) patients with clinically definite relapsing-MS, initially treated with standard interval dosing (SID) of natalizumab (mean time 54 months [SD29]) who were then switched to EID, every 8 weeks (mean time 76 months [SD13]). The main outcome measures included the following: i) annualized relapse rate (ARR), ii) radiological activity, iii) disability progression, and iv) NEDA-3 no evidence of disease activity index. EID preserved ARR, radiological activity, and prevented disability worsening during follow-up. The proportion of patients maintaining their NEDA-3 status after 24, 48, and 72 months of natalizumab administration in EID was 94%, 73%, and 70%, respectively. Stratified analysis according to history of drug therapy showed that the EID of natalizumab was slightly more effective in naïve patients than in those previously treated with other immunosuppressive drugs. No cases of PML or other severe adverse reactions were reported. In conclusion, long-term therapy with natalizumab in an EID setting following an SID regimen maintained its disease-modifying activity, and was safe and well tolerated for over 7 years. These encouraging observational results need to be confirmed in controlled clinical trials.

Conflicts of Interest

Preventive Neurology

Twitter

Medium

#MSCOVID19 – natalizumab extended interval dosing

More questions around managing MS during the COVID-19 pandemic; this time in relation to natalizumab (Tysabri) dosing.

The COVID-19 NHS crisis is a double-whammy for pwMS. First, it is redeploying staff away from MS services to work on the frontline. Secondly, the message has gone out to stop pwMS coming to NHS hospitals, or even connecting with other healthcare facilities such as GP practices, in an attempt to prevent them from being exposed to SARS-CoV-2. Most MS centres, including ours, have converted all of our clinics to telemedicine. Saying that I saw a very anxious patient with recently diagnosed highly-active MS in our urgent face-2-face neurology clinic yesterday. She needed to be seen as she was in the middle of an attack and in my opinion, should start on a high-efficacy DMT as soon as possible (possibly natalizumab). I am not prepared to make her wait 3, 6, 9, 12 or 18 months to access a high-efficacy therapy and bridging her on a low efficacy DMT would not be in her best interests. If time is brain why should we be compromising on her treatment because of COVID-19? Do you agree?

Seeing this patient face-2-face yesterday helped. She was very anxious and being face-2-face allowed me to counsel her properly. The consultation felt right and is a possible example of why you can’t necessarily do everything using a telemedicine portal.

One of the consequences of COVID-19 is that some pwMS are finding it difficult getting hold of NHS staff and getting their questions answered, which is one the reasons I started the MS-Selfie COVID-19 & MS microsite. Some centres such as ours have converted all our patients on natalizumab onto 6-weekly infusions, others have pushed this out to 8 weeks and some patients from other centres are reporting that their natalizumab infusions have been suspended indefinitely. The mixed messages around dosing and/or suspending dosing is causing a lot of anxiety (see my daily Q&A sessions on MS-Selfie).

Is it safe to suspend natalizumab infusions?

No, it is not safe. I am particularly concerned that some patients are having their natalizumab infusions stopped without a definite date for recommencing their infusions or at least transitioning them onto another DMT to prevent rebound disease activity, which can on rare occasions be life-threatening.

How does extended interval dosing work?

Yes, EID looks safe. Real-life data suggest from a clinical perspective it is not associated with an obvious increase in disease activity (relapses). However, the data on this is preliminary and Biogen is currently doing a study to address whether or not EID is associated with any loss of disease activity. This is called the NOVA trial and will include MRI monitoring as part of the outcome. One thing that is clear is that EID reduces the risk of PML in JCV positive patients substantially.

The theory behind EID is that some cells are less sensitive to the effects of natalizumab and that if you delay the next natalizumab infusion by 1 or 2 weeks the saturation of their surface receptors drops below a threshold and allows these cells to traffic into the central nervous system. If these less natalizumab-sensitive cells are the antiviral CD8+ T-cells and/or the natural-killer cells that fight viruses then this could allow immune surveillance of the CNS to occur that will prevent PML from occurring. If you get the EID right the desaturation of the immune cells causing MS, possibly the memory B cells, is insufficient not to allow these cells to traffic and to reactivate MS. It is clear that not all cells are made equal when it comes to the effect of natalizumab. Importantly, there are several other adhesion molecules on cells that impact on their adhesion (stickiness) to the blood vessels in the CNS. It could also be a delicate balance between the availability of different accessory adhesion molecules that makes the difference.

How safe is extended interval dosing and does it matter if it is every 6 or 8 weeks?

Everyone gets a standard natalizumab dose of 300mg every 4 weeks. This means a 50kg person gets double the relative dose compared to a 100kg person. The half-life of antibody therapies, such as natalizumab, is linked to how much drug or antibody is given. Therefore for the 50kg smaller person, 8 weeks may be fine, but for the larger 100kg person 8 weeks is too long a gap. Based on the real-life data 6 weeks seems to be a good compromise. Therefore I personally would not be comfortable recommending an 8-week interval for all patients. Slide 38 in the deck below demonstrates that as the dosing interval increases so does the impact of body weight on natalizumab’s efficacy.

In reality every person with MS on natalizumab should probably have personalised dosing based on actual saturation of the VLA-4 molecule or equivalent biomarker (e.g. sVCAM-1). This would get us away from guessing and optimising the effectiveness of natalizumab at the same time as decreasing the risk of PML or other CNS complication linked to reduced immunosurveillance.

Zhovtis Ryerson et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Aug;87(8):885-9.

BACKGROUND: Natalizumab (NTZ), a monoclonal antibody to human α4β1/β7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days.

METHODS: A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks.

RESULTS: 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort.

CONCLUSIONS: Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

CoI: multiple

The Time-to-Think DMT

At an MS Masters Forum in Rome yesterday I was teaching MSologists and MS clinical nurse specialists using a recently created board game, which I like to think of as being MS Monopoly. MS monopoly is based on a game of chance that lets you discuss case scenarios and make treatment choices. Then you roll a dice, which determines the outcome of your choice.

Two things emerge from playing the game. Firstly, how choosing an immune reconstitution (IRT) addresses so many of the treatment aims and longterm issues of safety. The question I ask is why aren’t the IRTs dominating the treatment landscape?

Secondly, it became clear how many times natalizumab was considered as a treatment option and discarded because of its PML risk. From yesterday’s discussions it clear to me that natalizumab is the ‘time-to-think’ DMT, i.e. you start someone on natalizumab for 6-12 months whilst you make the necessary long-term decisions. This may be necessary to wait for lymphopaenia to recover, to complete a vaccination programme (e.g. the three-dose HPV polyvalent vaccine), to wait to get the all-clear on a previously-treated malignancy, to prevent rebound on stopping fingolimod so that the woman with MS can fall pregnant, or to complete a diagnostic work-up. The latter indication underpins our #AttackMS trial design.

Another indication for natalizumab is to prevent CNS adverse events associated with cancer immunotherapy. I recently recommended that a patient with MS who had disseminated bowel cancer and was about to start an immune checkpoint inhibitor go onto natalizumab despite being JCV positive to prevent exacerbation of her MS. The rationale being that the polyclonal activation of her T-cells in the periphery, including her autoimmune cells responsible for her MS, would not traffic to the brain and spinal cord and cause an MS relapse. The downside of this strategy is that if she had occult secondaries in her CNS then natalizumab will prevent her T-cells finding and clearing these cells. As bowel cancer rarely metastasizes to the CNS we thought this was a risk worth taking. Last I heard she was doing well from the MS perspective, but not that well in relation to her bowel cancer.

I am sure natalizumab will prevent the CNS complications associated with CAR-T cell therapies. Could this be a repurposing opportunity for natalizumab?

What makes natalizumab so uniquely special as a DMT are the observations that it has the most rapid onset of action of all the DMTs, it has very high efficacy, its mode of action can be reversed with plasma exchange and natalizumab does not cause systemic immunosuppression. The only downside of natalizumab therapy is the long-term PML and other CNS infection risk and the emerging CNS lymphoma risk. These are all due to reduced CNS immune surveillance. The fact that extended interval dosing (EID) reduces the PML risk by over 80% suggests natalizumab may make a resurgence and all these CNS side effects may be preventable. However, for this to happen we need to be able to prescribe natalizumab more liberally as a first-line treatment for active MS. If anyone from Biogen is reading this blog post can you please ask the powers that be in Biogen to consider asking the EMA to reconsider natalizumab’s label? By not doing this you are denying many pwMS access to natalizumab, albeit for a short period of time as highlighted above.

The good news is that the EMA has accepted the EID data and it is now in natalizumab’s summary of product characteristics.

New text in the EMA’s SmPC: In a pre-specified, retrospective analysis of US anti-JCV antibody-positive natalizumab patients (TOUCH registry), the risk of PML was compared between patients treated with the approved dosing interval and patients treated with extended interval dosing as identified in the last 18 months of exposure (EID, average dosing intervals of approximately 6 weeks). The majority (85%) of patients dosed with EID had received the approved dosing for ≥1 year prior to switching to EID. The interim analysis showed a lower risk of PML in patients treated with EID (hazard ratio = 0.06 95% CI of hazard ratio = 0.01- 0.22). The efficacy of natalizumab, when administered with EID, has not been established, and therefore the benefit/risk balance of EID is unknown (see section 4.4).

For those interested, I have included the latest PML figures from Biogen.

CoI: multiple

Japan epicentre of an Asian MS epidemic

I am about to return from a short MS meeting in Tokyo. This was my first exposure to Japan and Japanese culture. It is everything and more than I expected.

I am beginning to get a sense of what ikigai means. Ikigai translates ‘to a reason for being, encompassing joy, a sense of purpose and meaning and a feeling of well-being’. Ikigai derives from iki, meaning life and kai, meaning the realisation of hopes and expectations.

I first learnt about ikigai from the ‘Blue Zones’, a book by Dan Buettner, on the secrets of the world’s ‘happiest places’, where people are super-agers. One of the blue zones is Okinawa, a subtropical Japanese island to the South of Japan. Some of the philosophy underpinning happiness and super-ageing is cultural and is specific to the Japanese culture.

The lessons of the blue zones are applicable to our Brain Health initiative and I would urge you to read the book. Who knows it may change the way you want to live your life regardless of whether or not you have MS.

It is clear that MS is a problem in Japan and the incidence and prevalence is rising. Why? Japan is now one of the epicentres of the global MS epidemic; i.e. an area of the world where MS has gone from a low to a medium incidence area, similar to Iran, and will quite soon become a high incidence area. The clue to this is the rapidly increasing sex ratio of females to males that is now over 3:1.

As an MS community, we need to study these epicentres to see if we can pin down the cause of MS and put in place robust prevention trials. Japan has rapidly westernised and the Japanese neurologists I spoke to think this is the reason why the incidence of MS is increasing in Japan. Not sure I buy this at face value. What is it about the Western lifestyle that is causing MS? Could it be childhood obesity? Processed carbohydrate/sugar consumption? Smoking? Change in the epidemiology of EBV infection; a different strain, later infection, more infectious mononucleosis? Less sunshine and lower vitamin D levels?

It is interesting that Japanese neurologists think MS is more benign in Japan than elsewhere. I am not sure why they think this. All the evidence I saw this weekend points to Japanese MS being identical to Western European MS. Unfortunately for Japanese MSers, they have access to fewer DMTs and there are only two highly effective DMTs licensed in Japan, i.e. fingolimod and natalizumab. There is also a much higher JCV seroprevalence rate in Japan of close to 80% with a higher proportion of people with a high anti-JCV index. This makes the risk of PML potentially much higher in Japan. For example, there have been 4 cases of non-carryover PML on fingolimod, which equates to a PML rate of about 1 in 1,000 to 1,500 per fingolimod-treated MSer. This is an order of magnitude higher than the non-carryover PML rate on fingolimod outside of Japan and clearly needs further study.

Another factor is the reluctance of Japanese neurologists to use off-label treatments, for example, subcutaneous cladribine and rituximab. The reasons for this are multiple but mainly relate to lack of reimbursement and cultural factors. It was also clear that the Japanese neurologist, similar to British neurologists, are quite conservative and prefer a step-care approach. The Japanese are particularly concerned that because of their ancestry they may respond differently to DMTs, which have been tried and tested in other populations. In other words, they need data on the safety and efficacy of specific DMTs in their own Japanese MS population. To get a drug licensed in Japan Pharma has to trials in Japan.

As a result of the JCV problem extended interval dosing of natalizumab, also referred to as EID, and PML surveillance (3-monthly MRI monitoring) is very important for natalizumab-treated Japanese MSers. In fact, Japan is the one country that the derisking of PML for natalizumab is critical. Until other high-efficacy DMT arrive the Japanese are going to have to make do with fingolimod and natalizumab. In comparison, we are spoilt for choice in the UK and other high-income countries; we have forgotten what it was like to manage MS before the avalanche of new DMTs.

I have uploaded my slides from Japan on my slideshare site; you are welcome to download them and repurpose the slides for your own uses. I presented our #AttackMS study as a way to illustrate how important time matters in MS. I am not sure the Japanese neurologists agreed with such an active approach to treating MS. Do you?

Houzen et al. Consistent increase in the prevalence and female ratio of multiple sclerosis over 15 years in northern Japan. Eur J Neurol. 2018 Feb;25(2):334-339.

BACKGROUND AND PURPOSE: The prevalence of multiple sclerosis (MS) is considered to be lower in East Asia than in Western countries. An increasing trend has been reported globally for the prevalence of MS. We investigated the changes in the prevalence and clinical characteristics of MS in the Tokachi province of Hokkaido, northern Japan from 2001 to 2016.

METHODS: Prevalence was determined on 31 March 2016. Data-processing sheets were collected from all MS-related institutions in Tokachi province. We applied Poser’s diagnostic criteria for MS as used in our previous three studies. Cases of neuromyelitis optica spectrum disorders were excluded.

RESULTS: In 2016, the crude MS prevalence was 18.6/100 000 (95% confidence interval, 14.3-23.8) in northern Japan. Over the last 15 years, the prevalence of MS in the same area was 8.1, 12.6 and 16.2 in 2001, 2006 and 2011, respectively. The female:male ratio was 3.57, which increased from 2.63 in 2001. The ratios of primary progressive, relapsing-remitting and secondary progressive MS types were 2%, 84% and 14%, respectively.

CONCLUSION: Our results demonstrated a consistent increase in MS prevalence among the northern Japanese population, particularly in females, and relatively lower rates of progressive MS in northern Japan than in Western countries.

CoI: multiple