Will the real slim-shady please stand up?

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Vitamin D is one of the biggest confounders in MS clinical trials. It’s like a chess piece, where every move has an effect on the outcome.

This latest piece of research from Romania studying the effect of Copaxone (immune modulator) versus prednisone (steroid) on circulating immune complexes (auto-antibodies) in RRMS, shows exactly this. The investigators found low serum levels of immune complexes in the Copaxone group after three months of treatment, but the vitamin D level was greater in the group on Copaxone versus those on steroids. The treatment effect on immune complexes therefore cannot be solely attributed to Copaxone!

We have been here before. In a previous study Vitamin D supplementation has been shown to reduce relapse rates in MS patients treated with natalizumab. Whilst, supplementing Vitamin D on Rebif (Interferon) treatment when levels were low to start with, resulted in lower relapse rates, less new MRI T1 lesions and lower EDSS (disability) progression.

Vitamin D is therefore probably one of biggest hidden gems in MS treatments

Exp Ther Med. 2021 May;21(5):542. doi: 10.3892/etm.2021.9974. Epub 2021 Mar 23.

Abstract

Assessing the values of circulating immune complexes in multiple sclerosis patients following immunomodulator or corticosteroid treatment

Any Docu Axelerad Alina Zorina Stroe Anca Elena Gogu Daniel Docu Axelerad

Multiple sclerosis is defined as an immune-mediated disease that affects the central nervous system, and also is characterized by the presence of immune cells and mediators which contribute to the subsidiary neuroinflammation associated with multiple sclerosis. Throughout the evolution of multiple sclerosis, it has been observed that circulating immune complexes (CICs) have higher values in these patients, especially in the acute phase of the disease. Thus, the aim of the present study was to observe, if in acute attack, relapsing-remitting multiple sclerosis patients still present high values of CICs after treatment with glatiramer and prednisone. We divided 70 patients with multiple sclerosis with high values of CICs into two treatment groups, one treated with glatiramer (Copaxone) (immunomodulatory treatment) and the other with prednisone (corticosteroid treatment). After three months of treatment, we assessed the levels of CICs of the two multiple sclerosis groups and we observed that the patients that followed the immunomodulatory treatment had lower values of CICs than the group that followed the corticosteroid treatment. In addition, another observation established was that the glatiramer treatment group had higher levels of vitamin D in the serum than the prednisone group of multiple sclerosis patients. To conclude, better outcomes, from the point of view of the results obtained from the comparative analysis of the values of CICs and vitamin D, were demonstrated by following immunomodulatory treatment.

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Neuro Doc Gnanapavan

13 comments

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  • Have not most of vitamin d trials have been inconclusive regarding vitamin d ?

    That the impact of vitamin d is relatively small ?

    I think that is what prof G mentionned.

    • I would keep an open mind on this. The difficulty is that a lot of people take Vitamin D, but when you have studies that use 100+ patients that show an effect based on how much is measured in the blood stream there is a found of truth to this also.

    • Another possible reason that vitamin d research is inconclusive is we may be measuring the wrong thing. Vitamin D levels are measured as blood 25(OH)D levels but it is now being realised that there are two forms of 25(OH)D in the blood one that is bound tightly to a protein and one that is not. It also appears that taking a daily dose is not the same as the same daily dose taken as a single dose every week or further apart in its effect. This may be due to the ratio of bound to unbound 25(OH)D. This may also explain the differences between using vitamin d and using 25(OH)D to treat COVID-19. If you are going to do a vitamin d trial it would be more sensible to use a daily dose of 25(OH)D. If you want to know if vitamin d is important consider the evolutionary pressure driving white skin that burns easily as you move away from the equator. This is trading Spring vitamin d production against skin cancer and in evolutionary terms vitamin d production wins.

    • The complexities of interpretation of trial data is challenging at best of times. If not impossible. Time to apply ML and AI to churn through the data millions of times faster and more accurately then the human mind? If me and my fellow colleagues succeed in making the human researcher irrelevant then there would no such thing as inconclusive trial. Just the data hasn’t been diced or mined correctly. You can now have cubes to n power of number 9f axis. Meaning you get value using all the dimensions to intersect. Bring on the revolution of automation of research without bias and conflicts on interests of the human mind.

  • This is a difficult subject to separate all the confounding variables. Supplementation of oral Vitamin D showed no effect in the SOLAR and CHOLINE studies. An alternative hypothesis is that more effective treatments (glatiramer vs steroids) enable pwMS to return to activities, getting more sun exposure and hence their vitamin D levels rise. Hence, Vitamin D levels are hence just a surrogate marker for clinical improvement.

    • With the Choline study, they did meet the secondary endpoints (they were still powered for this):
      In patients who completed the 2-year follow-up (45 with cholecalciferol and 45 with placebo), all efficacy parameters favored cholecalciferol with an ARR reduction (p = 0.012), less new hypointense T1-weighted lesions (p = 0.025), a lower volume of hypointense T1-weighted lesions (p = 0.031), and a lower progression of EDSS (p = 0.026).

      I agree, environmental factors are difficult to control for.

  • It may decrease relapse rates also looks to lower the severity of MS

    It would be good to see a trial in higher MS / autoimmune risk areas for children with vitamin D supplements as a preventative measure to lower MS rates as well as other autoimmune diseases.
    However this would probably take 20/30 years to complete and to hard to monitor.

    • Hi John, it would be easier to add Vitamin D as an add-on arm to an existing DMT that is undergoing testing. May be one for the societies to fund?

      • Great idea, it would be interesting to see the differences in therapy’s with a recommended vitamin D dose.

        I’d like to see a prevention study, maybe it would save MS and auto immune disease cases and the NHS money and time in the long run.

  • When I lived up North, I was so concerned about skin cancer I used topical sunblock all the time. One spring I fell and broke my arm. A Doctor I worked with said stop using sunscreen unless prolonged intense exposure.. All about the D. Did all that accelerate the Shredder, MS?

  • Doc,
    Vitamin D, I have been part of trial with the assistance of my neurologist and a Endocrinologist involved, to make sure calcium is not built up. The goal is 80-100 on Vitamin D scale to maintain. I am on Copaxone.
    This has required me to take upwards of 180,000 Iu/week of vitamin D. Gene technology became involved, which showed receptors that were not working, or absorbing vitamin D in lower intestines. A adjustment on time of day I take my 10,000 iu pills, and how many lowered me to 120,000 Iu week to maintain 80+. Yes a Difference in my MS. A point that needs alot more research. I started in a range #13 on scale. Everchangingms.blogspot. com seems like I am being my own scientist, but if others can learn, it might be helpful.

    • What may be of interest to you is that the RDA for vitamin d was miscalculated https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541280/ and the correct RDA is about 9000IU a day, which is oddly close to what the skin produces on sun exposure. So the amounts you are taking is not as high as you think. Toxicity seems to set in somewhere above 40,000IU a day if sustained. It is also starting to look like it is important to take vitamin d every day not weekly or monthly, so as to mimic the effects of daily sun exposure.

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