Changes in the Risk of Reaching Multiple Sclerosis Disability Milestones In Recent Decades: A Nationwide Population-Based Cohort Study in Sweden.Beiki O, Frumento P, Bottai M, Manouchehrinia A, Hillert J. JAMA Neurol. 2019 Mar 18. doi: 10.1001/jamaneurol.2019.0330. [Epub ahead of print
IMPORTANCE:Clinicians’ experience and findings from recent natural history studies suggest that multiple sclerosis (MS) may now be running a more slowly progressing course than before.
OBJECTIVE: To investigate whether the risk of reaching MS disability milestones has changed over the last decade in Sweden.
DESIGN, SETTING, AND PARTICIPANTS:A nationwide population-based retrospective cohort study. By April 2017, 12 512 patients with available information on demographics, MS phenotype, and date of MS onset and diagnosis were registered in the Swedish MS Registry of which 7331 patients with at least 2 recorded Expanded Disability Status Scale scores (EDSS) and diagnosed between January 1995 and December 2010 were included. No further exclusion criteria were applied. Patients were followed up until December 2016 with a median duration follow-up of 8.5 (interquartile range, 4.7-13.8) years. Statistical analysis began in April 2017.
MAIN OUTCOMES AND MEASURES: Patients were followed up from MS onset date to the date of sustained EDSS 3.0, 4.0, and 6.0. To handle interval-censored observations, a Weibull model was fit, and the change in the risk of EDSS 3.0, 4.0, and 6.0 over calendar years was estimated and hazard ratios (HRs) with corresponding CIs were calculated.
RESULTS:Of 7331 patients, 5196 (70.9%) were women, and the mean (SD) age at diagnosis was 38.3 (11.7) years. Adjusting for sex, number of clinic visits, diagnostic delay, and onset age, a 3% decrease per calendar year of diagnosis for the risk of sustained EDSS 3.0 (HR, 0.97; 95% CI, 0.96-0.97), a 6% decrease for the risk of EDSS 4.0 (HR, 0.94; 95% CI, 0.93-0.95), and a 7% decrease for the risk of EDSS 6.0 (HR, 0.93; 95% CI, 0.91-0.94) among patients with relapsing-onset MS was found. The trends were not significant for patients with progressive-onset MS (EDSS 3.0: HR, 1.01; 95% CI, 0.98-1.03; EDSS 4.0: HR, 1.00; 95% CI, 0.98-1.02; EDSS 6.0: HR, 1.00; 95% CI, 0.98-1.02).
CONCLUSIONS AND RELEVANCE: Risk of reaching major disability milestones has significantly decreased over the last decade in patients with relapsing-onset MS in Sweden. Several factors could potentially be responsible for this observation. However, given that no change was seen in disability accrual of patients with progressive-onset MS and the absence of efficacious treatment option in this group, increased use of more efficacious disease-modifying treatments could be a possible driver of this change.
More evidence for treatment value for early effective treatment also more evidence we need something else actually I mean extra for progressive MS.
Given Sweden uses off label Rituximab. Does this reinforce b treatment as viable effective treatment?
” Does this reinforce b treatment as viable effective treatment?”
Absolutely..it’s a viable treatment…it gets rid of relapses..problem is relapses aren’t the disease..so no cure.
Dr. Langer has 1500 patients on Rituximab at Kaiser in L.A. and has not moved to Ocrevus.
Thanks Adam. Unfortunately Bart’s can’t make up their minds if B or T cells is the driver in MS.
One may have perineal splinters but the majority are definitely of one mind.
OK. Simple answer. B or T? Which one drives ms? If B why is Alemtuzumab and HSCT most effective?
All revealed here (Open access).
That is certainly one way to look at the results. Can you also comment on the followings two points made in this publication?
1. In the full publication, the authors state that “It should be noted that since DMT variables were only intended for model adjustment, the coefficient obtained from these variables cannot be used to interpret the drug effectiveness. Owing to the complexity of analyses for treatment effect, such a study requires a different design and a control group.” They also indicate tht there was no difference bin the results between moderately efficacious and highly efficacious disease-modifying treatments.
2. While this was labled as a “nation-wide study”, the authors did mention that 5.181, or over 40% of the 12.512 patients observed were discarded because, over the course of this study, they never reached EDSS 3.0 ad that probably 20% of MS patients weren’t in the Swedish register at all? Could one then infer that the results published here only apply to roughly 50% of those with the diagnosis in Sweden whereas for the other half, the pathology is sufficiently stable that they actually wouldn’t need treatment?
“They also indicate there was no difference bin the results between moderately efficacious and highly efficacious disease-modifying treatments”
Exactly..all treatments are similar they work best early in disease.
In later progressive disease they don’t work at all.
In the old blog there was a man who went 50 years untreated
before progression set in.
Nobody on Ocrevus will be so lucky.
So I advise quiting job and doing what you want to do..now.
If climbing mountains is it. Do that now cause guaranteed
one day you will not be able to.
No Neuro will tell you that but I just did.
Neuros have no treatment for ALS..Alzheimers..
or a host of other more rare diseases like the one
that took Dudley Moore Progressive supranuclear palsy (PSP).
So they think that w/ MS they finally have one.
Problem is they don’t.
It’s one disease..so if they don’t work on progressive disease
they won’t work on RRMS progression. It’s just a matter of time
before they don’t work.
“In the old blog there was a man who went 50 years untreated
before progression set in.
Nobody on Ocrevus will be so lucky.”
Geeky obligatory XKCD reference for extrapolating from one data point https://xkcd.com/605/
This is the old blog; all posts were transferred across.
Yes, this blog is very good at spin. They’re very New Labour in that way.
The current political shambles makes me for one pine for New Labour.
“whereas for the other half, the pathology is sufficiently stable that they actually wouldn’t need treatment?”
Oh..dear..you must be new to the MS field.
So when is the evidence of the value of earlier diagnosis coming. It should be a straight forward and quite “easy” step while waiting for neuroprotective and demyelinating agent testing which has proven to be hard.
I suggest to follow stroke, now we have good treatments “like thrombolysis and thrombectomy”, so diagnose patients as soon as possible, inform society and family doctors about MS symptoms and when they need to do an MRI, start a campaign.
I would love to hear Prof. G thoughts on this.
Early treatment yes but perhaps equally important early diagnosis.
I think this Italian study supports the Swedish experience and shows that part of the results are driven by (1) earlier diagnosis, (2) earlier treatment and most importantly higher efficacy DMTs. Nothing more to say, but how do we get GPs or family doctors to be more alert and refer patients more quickly? Education?
Capra et al. Assessing long-term prognosis improvement as a consequence of treatment pattern changes in MS. Mult Scler. 2017 Nov;23(13):1757-1761.
OBJECTIVE: To assess whether the age at which multiple sclerosis (MS) patients reach Expanded Disability Status Scale (EDSS) milestones changed as long as new drugs for the treatment of MS became available.
METHODS: We evaluated the long-term impact of therapies on disability progression assessing whether there is a detectable delay in the age at which patients reached EDSS milestones in more recent years. We used data collected over more than 30 years in the Center of Brescia, Italy. We compared the age at EDSS = 6 among patients diagnosed with relapsing-remitting MS in different time periods, adjusting for age at diagnosis and median interval among EDSS visits, by a multivariate Cox model.
RESULTS: A total of 1324 MS patients were included. Patients diagnosed in more recent periods reached EDSS = 6 at an older age: the rate at which patients reached EDSS = 6 in those diagnosed in 1991-1995 was similar to those diagnosed in 1980-1990 (hazard ratio ( HR) = 1.09, p = 0.68) and to those diagnosed in 1996-2000 ( HR = 0.85, p = 0.44), it was reduced by 37% in patients diagnosed in 2001-2005 ( HR = 0.63, p = 0.05), by 46% in patients diagnosed in 2006-2010 ( HR = 0.54, p < 0.02). CONCLUSION: A clear modification of MS course is observed after 2000; among other causes, this can be associated to the changes in the treatment patterns experienced in those years.
Great, yes I think education is one thing, a campaign is another, go out to the news and say that now we have good treatments, we need you to refer patients more quickly.
Guidelines: for example atypical sciatica with negative laseqeu don’t just do a lumbar MRI, information to physiotherapists, leg weakness that improves after three weeks is not always muscle problems. I think there are many ways and might be even more important than to prove that alemtuzumab is 5% better than ocrelizumab. It can have a huge impact on the quality of life of newly diagnosed people. The concept is diagnose as early as possible because now we have good treatments.
“The concept is diagnose as early as possible because now we have good treatments.”
Your concept is flawed because we don’t have “good treatments.”
Early treatment saves you x number of years of legs and
then abit more years of hands. But then people continue to progress..and progress..end stage is loseing sight..ability to talk…etc.
“I suggest to follow stroke, now we have good treatments “like thrombolysis and thrombectomy”, so diagnose patients as soon as possible..”
Your comparing a one time event “stroke” with a progressive disease…that has no treatments to stop progression.
It has no treatment to stop progression because the treatment is late, most people have already more than 20 T2 lesions at diagnosis. Accordingly if you give thrombolysis after 6 hours it will not work…
After a couple years on interferon therapy, I started on Tysabri immediately when it came to market & spent 7 years on the medication. Because of my concern of my increasing risk of developing PML due to my JCV+ status, I switched to Tecfidera when the medication came to market. However, after developing severe lymphopenia, I discontinued Tecfidera after 2 years of treatment. It is worth noting that while I was on the interferon medications, I developed relapses, but that was never the case on either Tysabri or Tecfidera. However, tired of worrying about developing a deadly brain infection (Tysabri), disillusioned after having gone through a hellish 2 years (Tecfidera) and unimpressed with the other medications at the time available, I decided to take a 2.5 year medication break. I must say, I felt better than I had in years, most likely due to the contributing factor of committing to a modified fasting diet, but I wound up developing optic neuritis, new brain & spinal cord lesions and mild brain atrophy along the way. Faced with this reality, I knew I had to refocus and not only make decisions about today but, more importantly, about my future. So, I restarted the Tysabri, now EID, one year ago and haven’t developed any more lesions since. I am now certain that my MS had not progressed early on because I had been so proactive since my diagnosis, and that is almost entirely due to the Tysabri. Unfortunately, I don’t feel as well on medication as I did when I was off of it, which can be quite frustrating at times, but I now understand how important it is to remain on medication. While I anticipate some sort of worsened disability in the future, I know I am doing everything possible to slow down the disease process so that what had always been assumed about the progression of MS is no longer a foregone conclusion. JSV
It reminds me of the response ProfG got at his presentation in Sweden “I presented data, mainly from ocrelizumab, that shows MS continues to smoulder away on ocrelizumab despite patients being NEDA. The response to the data was what we are seeing was simply secondary progressive MS. “.
“However, given that no change was seen in disability accrual of patients with progressive-onset MS”
If you see MS as two diseases you can be happy with stoping relapses. Only MS is one disease and it can go on without relapses (PPMS). So, bye bye axonopathy theory. Let’s talk about neurodegeneration.
Nice debate but there is a problem with trying to define the terminology, one disease, 2 diseases or 10 diseases. Let’s agree it is one disease, it has 2 different mechanisms. All data show that it begins outside the CNS ( natalizumab) and then the inflammation activates microglia and neurodegeneration in a way we don’t understand and we don’t have treatment. Stroke also activates microglia but not in the same very detrimental way. About PPMS how do you know that these patients did not have RIS in late childhood and are not actually “secondary progressive” meaning more CNS innate immune activation, not disease terminology and categories.
The tools are there to check, check the ocrelizumab or natalizumab or any other study for which patients progressed: those that have 3 lesions or those that had 50 lesions before starting treatment. A metaanalysis would be needed. If you select patients with 50 lesions for highly effective medicines there is a higher chance that the disease progresses because innate immunity, neurodegeneration, metabolic dysfunction is already activated and we don’t have medications to stop them.
Anyway what is the meaning of treating early when you don’t diagnose early…
The concept is not to not do more research on slowly expanding lesions and neurodegeneration. It is that we already have the tools to diagnose early, it is a pity if we don’t use them. It makes also a difference for the individual patient to live 10 years with an EDSS of 3 and not with EDSS 0 which would be the case if diagnosed already after first relapse. I have seen many such patients but perhaps that’s not the general case.