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