In a moderately sized study from Finland, investigators wanted to know whether the addition of vitamin D to interferon-beta-1b (a first line disease modifying treatment) had a favourable outcome on disease activity. In order to assess this they measured serum (blood) neurofilament levels a protein found in neurones as a marker of MS disease activity.
What they found was that the addition of vitamin D had no effect on neurofilament levels compared to those not supplementing. It would be easy then to conclude that vitamin D has no impact on disease activity in MS over and above that of the disease modifying treatment.
Am I correct?
Let’s just say, I wouldn’t rush to flush all your vitamin D tablets down the toilet because of these findings.
My reservations of this study are two fold. Not being disparaging to the investigators, but their test measure (serum neurofilament) is reading at the bottom range of assay detection and the chances of random performance characteristics influencing the final outcome increase as a result (see Figure below – note that the majority of readings are below 20pg/ml). This means that you would probably have to inflate the sample size by a x100-fold to demonstrate a group difference. Secondly, they found no correlation with EDSS (disability measure for MS) or timed-25 foot walk, and only 5 out of the 32 participants at the start of the study had enhancing lesions on their scans suggesting that the study population were not diverse enough in disease activity or highly active entering into the study, respectively. Again, you would have to inflate the sample size to compensate.
The crux of this study therefore is not the intervention in question i.e. vitamin D, but the test, i.e. serum (blood) neurofilament levels. In subjects who are already on a disease modifying treatment that reduces neurofilament levels you need to have a population that are active despite being on treatment to assess the added benefit of add-on strategies or use a much larger population.
Abstract
Vitamin D supplementation and serum neurofilament light chain in interferon‐beta‐1b‐treated MS patients
Objectives
Serum neurofilament light chain (sNfL) is a promising biomarker of MS activity, progression, and treatment response. The aim of the present study was to address whether sNfL concentrations are affected by supplementation of vitamin D and correlate with disease activity in interferon‐beta‐1b (IFNb‐1b)‐treated Finnish MS.
Materials and Methods
Serum samples were available of 32 participants of the Finnish vitamin D randomized controlled trial (17 vitamin D/15 placebo). Serum 25 hydroxyvitamin D was measured using radioimmunoassay and sNfL using single‐molecule array (Simoa). Correlation of sNfL with brain magnetic resonance imaging (MRI) activity, burden of disease (BOD, mm3), and disability was assessed at the study baseline and at 52 weeks.
Results
Serum NfL concentrations were similar in the patients randomized to high‐dose vitamin D and placebo at the study baseline and at month 12 follow‐up (p‐value). Concentrations of sNfL were higher in patients with Gadolinium‐enhancing lesions in brain MRI: median (95% CI) sNfL was 14.84 (9.9–42.5) pg/ml and 11.39 (8.9–13.2) pg/ml in patients without Gd+ lesions (p = .0144) and correlated with enhancing lesion volume (Pearson r = .36, p = .037) at the study baseline but not at week 52. Serum NfL did not correlate with the MRI BOD or disability measured by expanded disability status scale and 25‐foot walk test.
Conclusion
In this small cohort of clinically stable IFN‐treated Finnish MS patients, sNfL levels were similarly low in patients supplemented with high‐dose vitamin D or placebo. Subclinical disease activity in MRI was associated with higher sNfL levels.
Back in 2008 I insisted on getting a vitD test, although my GP was most reluctant, because I’d been reading about possible deficiency caused by MS. I had been taking NSAIDs plus Zapain for a few years following a fall which had resulted in back injury. I’d had the injections, the physio but even after (minimal) back surgery, the back never healed properly. I couldn’t do breast stroke, I couldn’t turn over in bed or sit for more than half an hour without real pain. The GP rang me at home – prescription waiting at the surgery. I was deficient, bordering on very deficient. A few weeks later as I was due to collect my repeat painkillers/anti-inflammatories I noticed I had a lot left in the cupboard. A bit more reading and I wondered if the vitD could be helping the back issue. Cutting a long story short I asked the neuro and he kindly wrote to the GP recommending I be prescribed 5,000iu daily. Around six weeks after that I threw away the rest of the pills and my back was completely back to normal. So whether or not it affects the course of MS is irrelevant to me!
When I was diagnosed with MS, I searched the literature to discover the answer to the question: does Vitamin D help with MS? I felt saddened to find out that such a simple question had not been answered and so, like so many others, take 5000iu daily because it makes biological sense. So much so that I would personally not be prepared to take part a RCT of treatment vs placebo.
This seems to be another poorly designed study which follows on so many others which seem to generate more fog than clarity.
I have found that a lot of studies suffer from under recruitment compromising the original question which is legitimate. This is from lack of participation and lack of funding to extend the study when this occurs. And then there are reviewers who don’t understand the tests and this also proves to be a problem. But, by presenting my thoughts here I wanted our readers to review the findings critically.
The lack of knowledge of what vitamin d does and how receptors regulate up and down is so great it makes designing any trial very difficult. It is not even know if 25(OH)D level is the blood is a good measure of vitamin d level. There are 2 reasons you could have high 25(OH)D, one you have a good supply, the other is you cannot make use of it. Some of the uses could be turned down or off in some individuals and so they have higher levels in the blood, others may not turn off and they would have lower blood levels, but the person with low levels may be healthier because they are still using the vitamin d.
You would think the most important part of any trial like this would be the dose, how often it was given, the original level of vitamin d (25(OH), the change in level of 25(OH)D in the blood and probably the parathyroid hormone levels (as a measure of repleteness). Numbers are carefully calculated for the sNfL but all we get about the vitamin d is ‘high dose’. Is there an International Standard definition of High Dose? Unless you get to greater than 40,000IU a day all the body is going to do is use the vitamin d in a controlled manner. You will only see an effect of vitamin d if the person has too little, if they already have enough there will be no effect. It is not a drug at these levels. It is the lack of vitamin d that is bad for you, not taking vitamin d that is good. If a person has enough then adding a little more will have no effect. Stop considering it as a drug consider it as nutrition. Starving patients tend to do badly.
This was the patient selection: baseline 25(OH)D levels below 85 nmol/L, were randomized to either 20,000 IU of cholecalciferol (Swiss‐Caps), or identical placebo capsules, for 52 weeks. Serum NfL didn’t vary much based on the category of vitamin D measured:
25 (OH)D (nmol/L) NfL (pg/ml)
0‐<25 (N = 5) 11.46 (6.18–12.03)
25‐<50 (N = 14) 10.31 (7.10–12.91)
50‐<75 (N = 27) 13.91 (11.17–17.40)
75‐<100 (N = 23) 12.50 (11.03–19.97)
≥ 100 (N = 10) 11.08 (8.85–13.62)
I am confused by this “Of the 66 patients in the Finnish Vitamin D study, serum samples were available from 32 patients (17 vitamin D/15 placebo) at the study baseline, N = 20 patients (12 vitamin D and eight placebo) at 6 months and of N = 25 patients (13 vitamin D/12 placebo) at both the baseline and 52‐week follow‐up visit. MRI data and 25(OH)D results from the study baseline and week 52 visit were available of all these patients. ” I think they are saying they have 2 readings (at baseline and 52 weeks) for 25 people and they have bits of data for the rest. Doesn’t inspire confidence. I think they have not looked at the effect of supplementation they have plotted 25(OH)D vs NfL for all the data they have and tried to draw conclusions from that. It is as clear as mud.
Also 20,000IU/day is a high dose not 20,000 IU/week.
Talking of vit D my CCG have decided that they will no longer be prescribing it after the initial boosting dose.
Prime example of current state of MS research, underpowered, inconclusive and pointless. For every 10 researh papers that show efficacy, there are 10 other that contradict. The strange coincidence is the only player to benefit is pharma. But just a coincidence right!
Okay, just speed read that study and I am no expert. I really like that they have been very thorough with the limitations and I think it is well written. There are a lot of sources of confounding through and, as it has been said, we need to acknowledge that it is underpowered. The change in NFL on those not on immunolodulatory tx with Vit D is interesting to me. I don’t know why but my attention keeps being drawn to all those noisy outliers – those co-efficients of variation aren’t that bad to me. They could have done quite a bit more with that data as well.
I probably should get out more! You’re referring to the average CV? The authors put the full range as such: interquartile range 1.7%–6.3%, min–max range 0.02%–23%. For an analyte based assay CV>20% would not be acceptable. Nonetheless, the sensitivity is listed as 4pg/ml, it would have been nice if we had the lower limit of detection. From my experience it is not unusual to see this clump of readings at below the 20nmol/l without the spread the statistical analysis become very swayed by the outliers. This clumping has more to do with the substrate (serum is full of other proteins) and less so to do with the machine.
With regard to the outliers, NfL is very sensitive to disease activity. As IFN is very good at lowering NfL levels (a consistent finding in more than one study) what you’re seeing are those with disease activity i.e. non-responders to IFN-beta-1b – really these individuals should change treatment!!!
70 ng/ml 25 OH D for life and regular midday sun for the rest of your life.
What the F does a mainstream doctor know about anything other than supporting the pharmacology lie?
Other than Viagra what’s new in the last 50 years?
Well, that’s one way of looking at it, I suppose.
“Other than Viagra what’s new in the last 50 years?”
Cialis.
If you keep your vit d levels at a good level your less likely to get MS, cancer, and other auto immune diseases.
I doubt it’s a coincidence that vitamin D has been implicated almost as often as EBV over the years.
Yes, the results of these many studies vary and are not conclusive, but the mere fact that EBNA-3 blocks vitamin D receptors should definitely attract more attention.
I have no particular opinion of high-dose vitamin D therapy. But if you take a closer look at various international social media groups about the subject, the number of positive feedback from patients and treating physicians, sometimes over decades, is surprisingly high.
I don’t often give public opinions on stuff we have an interest in but, we have had hundreds of vitamin D studies in virtually every single immune-disease and without reading a lot I bet they have shown very little and have had no major impact. Does this say vitamin D is not important…absolutely not. But we have to think a little before we commit to mega-costly studies. Sadly when academics do autoimmune trials they are typically grossly underfunded and typically poorly powered and have an estimated treatment effect that far outways the ability of agent.
I hate to say it, but we are like lemmings and all follow the same trendy idea in a monoculture of thought and just as we have had many vitamin D studies, we are now doing countless microbiome studies, in every disease under the sun. We say vitamin D is important in the generation of autoimmunity and then do a trial not to stop autoimmunity from occuring but to try and reverse the effect of autoimmunity. We do this because it is easy to do.
However, the biology suppports the idea that it may protect you from autoimmunity. So we should supplement our mothers and perhaps children and wait 10-20years to see if it has an affect. But why do this in MS, why not do it in diabetes which has the same vitamin D story but people get diabetes in childhood so you could do a trial and get an answer in less than 5 years. We have done the said with COVID-19 we have all had the same idea and rather than trial lots of different things properly we have done lots of the same drugs over and over again in many different countries. We have done the easy option trial and not what should have been done. e.g. you give anti-viral when you are first infected, not 2-3 weeks later and then wonder why it doesn’t work so we have has hundreds of thousands of people infected, thousands of deaths and no real set of drugs to fight the infection.
Anyway back to vitamin D and control of autoimmunity. Potent disease modifying drugs can do it but they come with side effects. If the immune response is blocked to stop autoimmunity, the same agent is going to stop the same cells fighting infection. The more potent you are at fighting autoimmunityt the more likely you are to to get infections. You don’t get one without the other. So the MS DMT without the serious side-effects are simply not that effective in my mind. You can’t have one without the other.
Vitamin D is innoccuous and does not cause major side-effects, therefore you should never expect it to have a major therapeutic effect. It is not a major disease modifying drug. This is a simple biology. I am happy to be proved wrong but this view has been remarkably supported over decades of research. There have been so many trials saying the same thing. Do I take vitamin D tablets yes, why because I want to ensure that I am replete and you should be willing to walk the talk. The lemmings have said it protects against COVID-19 as could anti-oxidants, etc. etc. so do I take supplements sure, don’t you.
The reason vitamin D at sensible levels has no major side effects is because it is not acting as a drug. It is something that should be there at those levels. However, a lack of it is so damaging that my ancestors developed white skin, thus risking skin cancer in later life and sunburn every spring/summer, and remember they lived outdoors. A lack of vitamin C is bad for you, you get scurvy, but above a certain point there is no effect until you exceed the bodies ability to cope. Vitamin C is not a drug at naturally occurring levels and neither is vitamin D. Vitamin D is, however, important enough to drive natural selection to favour white skin (away from the equator) and that alone shows why people should take a vitamin D supplement.
I agree with you, that vitamin D is/was a very popular trendy topic. But that just means that one has to be especially critical on the topic.
But I don’t agree with your statement about side effects.
The human body is programmed to produce and use vitamin D and can handle various dosages and blood levels to a great degree because of that. Same goes for many other substances and supplements. That doesn’t automatically mean, that its disease modifying capabilities aren’t potentially potent.
It’s like saying water isn’t essential, because I can survive on 1 litre per day and drinking 700% of that won’t do me harm.
Pete made a very good point about skin color. Evolutionary pressure wouldn’t be so high if vitamin D wasn’t absolutely essential for the human body. Vitamin D has a direct influence on fertility and sex hormones.
Double-blind placebo controlled peer reviewed studies are all well and good, but sometimes I have the feeling that many scientists can’t see the forest for the trees and thoughtlessly dismiss essential biological relationships because there is no suitable study.
NDG,
Thanks for your post. There was an article about NFLs on another website:
https://www.ms-uk.org/higher-levels-blood-protein-linked-faster-ms-progression
While I can see the benefit of measuring NfL as a marker of ongoing damage, how do you treat in response to a measure of NFL in a patient? If a patient is on Natalizumab or has had Alemtuzumab and their NfLreadings are still high what other therapy can you offer? Is NfL being used in any current trials eg neuro-protective trials to replace MRI measures or to supplement them?
Thanks
Yes, blood neurofilaments have already entered into clinical trials and not surprisingly the degree of suppression is dependent on the efficacy of the drug. It’s currently being used to supplement MRI, but may replace it as time goes on.
Maybe learn a little bit about Neurofilament light levels before commenting.
You said … “My reservations of this study are two fold. Not being disparaging to the investigators, but their test measure (serum neurofilament) is reading at the bottom range of assay detection and the chances of random performance characteristics influencing the final outcome increase as a result
(see Figure below – note that the majority of readings are below 20pg/ml). REALLY???
“reading at the bottom range of assay detection…” REALLY?
“ Not being disparaging to the investigators…” OH I THINK THEY ARE OK! Considering the majority of non-MS patients levels are below 10 and MS patients levels are somewhere between 10 and 16 on therapies and 15 to 20 untreated.
Look at this –
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831970/figure/fig1-2055217319885987/
Read this –
Blood neurofilament light levels segregate treatment effects in multiple sclerosis
B ́en ́edicte Delcoigne, PhD, Ali Manouchehrinia, PhD, Christian Barro, MD, Pascal Benkert, PhD, Zuzanna Michalak, PhD, Ludwig Kappos, MD, David Leppert, MD, Jon A. Tsai, MD, Tatiana Plavina, PhD, Bernd C. Kieseier, MD, Jan Lycke, MD, Lars Alfredsson, PhD, Ingrid Kockum, PhD, Jens Kuhle, MD,* Tomas Olsson, MD,* and Fredrik Piehl, MD*
Neurology® 2020;94:e1201-e1212. doi:10.1212/WNL.0000000000009097