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Saddled with an inappropriate, poorly predictive animal model and relatively sparse basic research on human MS (multiple sclerosis) lesions, antigenic targets of anti-human MS T and B cell responses remain poorly identified. Such a landscape is barren soil for prospects of more specific, targeted and presumably more effective MS therapies in the near future.

Estriol and Vitamin D entered the picture because of robust epidemiological data showing a connection between pregnancy and sun exposure, respectively.

Prospects For Estriol and Vitamin D as Rx for MS: Open-ended And Currently Unclear

MS relapse rates reduce by >70% in the last trimester of pregnancy (1). That’s when estrogen and progesterone concentrations are highest, and when estriol, a pregnancy-specific estrogen made by placental cells, also reaches its highest concentration. A recent randomized, placebo-controlled phase II trial of 164 patients showed that estriol plus glatiramer acetate could reduce relapse rates and was well-tolerated for 24 months (2). Whether such results would lead to its inclusion as acceptable MS Rx in the next 5 to 10 years is anybody’s guess since there isn’t much more clinical data with estriol yet. Home – ClinicalTrials.gov currently lists only 2 active studies (3).

Since 2000 several large epidemiological studies consistently found association between higher levels of sun exposure, higher vitamin D levels or intake with lower MS risk (4, 5, 6). Do vitamin D supplements reduce/reverse MS symptoms? A 2010 Cochrane review concluded data were too conflicting (7). Either the trials were too small, i.e., not enough power, or used insufficient vitamin D doses or weren’t randomized. Since then, one small pilot study (n=30) showed high dose vitamin D (weekly 50,000 IU of vitamin D3 for 12 months) could decrease optic neuritis progression to MS (8), and numerous other trials are in various stages of completion, total of 30 to be precise according to Home – ClinicalTrials.gov (9). So after garnering increasing promise over the past 15 years, vitamin D’s fate as an MS Rx is very much up in the air.

Main Problem With Basic MS Research: Inappropriate Animal Model Dominates At Expense Of Better Human Research.

Were I a funder/funding agency, I would stop funding basic MS research that uses the utterly superfluous and irrelevant mouse/rat animal model, Experimental autoimmune encephalomyelitis. Induced by injection of mish-mash of nerve-derived proteins plus Adjuvant, characteristic pathology of rodent EAE (inflammatory panencephalitis and relatively sparse demyelination of peripheral nerves) doesn’t even recapitulate basic MS pathology, which is primarily a central nervous system (CNS) disease (10), where CNS demyelination is a cardinal feature. As for the way scientists score degree of mobility impairment/paralysis in these models, less said the better. Not only is the scoring system subjective, not objective, same lab has the propensity to ‘interpret’ the same scoring system differently in different studies. Result? Thousands of papers with utterly dubious results. Unfortunately, over the past few decades EAE has become the mainstay of basic MS research. More relevant Rx possibilities will only emerge if we change the status quo away from this terribly inappropriate animal model.

To top such a parlous state of affairs, it’s galling that after so much research and so much research expenditure, we still don’t even categorically know which antigens are the target of pathogenic immune responses in human MS. There’s a crying need to fund more basic research into the human disease itself, particularly on a comprehensive MS biorepository for identifying antigenic targets of human MS-specific T and B cells. A biorepository of lesional tissues from MS patients would be a necessary first step.

Oral Immunotherapies and Phototherapy May Offer Cheaper, More Effective Rx Options

If we knew the antigens targeted by anti-human MS immune responses, it would open the door for more targeted immunotherapy à la cancer and allergy immunotherapy. Talking of allergy immunotherapy, one of the most ‘innovative’ and yet cheapest therapies to try would be to simply feed patients purified versions of the antigens targeted by the pathogenic anti-MS immune response, an effort to switch the immune response class away from pathogenic towards non-pathogenic, a process called oral tolerance. In the past decade and a half, a variation of this approach has emerged as a low-cost yet extremely effective therapy for many kinds of allergies (Allergen immunotherapy). Immunologically, a strong case can be made that this approach might work in MS and other autoimmune diseases as well.

Currently, 1st line therapy for MS include interferon-beta, glatiramer acetate, azathioprine, fingolimod, dimtethyl fumarate while 2nd line includes monoclonal antibodies (mAbs) natalizumab, rituximab. Alemtuzumab, ocrelizumab, laquinimod, statins are waiting in the wings. All are relatively non-specific and only partially effective against relapses and cumulative disability.

Meantime, a more effective approach to garner the ‘vitamin D’ effect would be to use UVB phototherapy instead. Years of epidemiology clearly implicates a role for sun exposure or UV-B exposure. Genetic factors support a biologically plausible role for vitamin-D-related genes in MS (11, 12, 13, 14, 15, 16). However, direct vitamin D supplementation proved to be a mixed bag, not yielding results expected from a magic bullet (17). Maybe zooming in from sun exposure to vitamin D left out other factors that play important roles? If so, they would be amply covered by UVB phototherapy instead. Indeed, recent studies show UVB phototherapy at 5X per week for 6 weeks could induce higher levels of vitamin D and improve well-being (18). Unfortunately, not an effect on MS relapse rate or disability score. Home – ClinicalTrials.gov currently lists 30 active trials for vitamin D in MS (9) but only 13 for phototherapy (19). In fact, many of these trials do not even primarily focus on phototherapy. Rather, it’s an afterthought. That’s a shame because this therapy merits closer scrutiny. It’s low-cost and broader than vitamin D. If it could improve, even reverse, some MS symptoms, research effort would be well worth it.

Unfortunately, efforts such as oral tolerance and phototherapy require breaking free of the stranglehold of current dogma that dominates both MS researchers and their funders, dogma consisting of an extraneous animal model and therapies that are expensive, non-specific and largely palliative. This will remain the state of affairs until effort is focused more usefully on identifying target antigens in human MS, more careful delineation of disease, specifically disease subsets and their genetic underpinnings.

Bibliography

1. Confavreux, Christian, et al. “Rate of pregnancy-related relapse in multiple sclerosis.” New England Journal of Medicine 339.5 (1998): 285-291. https://www.researchgate.net/pro…

2. Voskuhl, Rhonda R., et al. “Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial.” The Lancet Neurology 15.1 (2016): 35-46.

3. multiple sclerosis – List Results – ClinicalTrials.gov

4. Duan, Shurong, et al. “Vitamin D status and the risk of multiple sclerosis: a systematic review and meta-analysis.” Neuroscience letters 570 (2014): 108-113.

5. Theodoratou, Evropi, et al. “Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials.” Bmj 348 (2014): g2035. http://www.bmj.com/content/bmj/3…

6. Simpson, Steve, Bruce V. Taylor, and Ingrid Van der Mei. “The role of epidemiology in MS research: Past successes, current challenges and future potential.” Multiple Sclerosis Journal 21.8 (2015): 969-977.

7. Jagannath, Vanitha A., et al. “Vitamin D for the management of multiple sclerosis.” Cochrane Database Syst Rev 12 (2010). https://www.researchgate.net/pro…

8. Derakhshandi, Hajar, et al. “Preventive effect of vitamin D3 supplementation on conversion of optic neuritis to clinically definite multiple sclerosis: a double blind, randomized, placebo-controlled pilot clinical trial.” Acta neurologica Belgica 113.3 (2013): 257-263

9. Search of: vitamin D

10. Hauser, Stephen L. “The Charcot Lecture| Beating MS: A story of B cells, with twists and turns.” Multiple Sclerosis Journal (2014): 1352458514561911. http://www.ncbi.nlm.nih.gov/pmc/…

11. Simon, K. Claire, et al. “Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis.” Multiple Sclerosis 16.2 (2010): 133-138. http://www.ncbi.nlm.nih.gov/pmc/…

12. Bahlo, Melanie, et al. “Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20.” Nature genetics 41.7 (2009): 824-828.

13. Smolders, Joost, et al. “The relevance of vitamin D receptor gene polymorphisms for vitamin D research in multiple sclerosis.” Autoimmunity reviews 8.7 (2009): 621-626.

14. Ramasamy, Adaikalavan, et al. “Genetic evidence for a pathogenic role for the vitamin D3 metabolizing enzyme CYP24A1 in multiple sclerosis.” Multiple sclerosis and related disorders 3.2 (2014): 211-219. http://ac.els-cdn.com/S221103481…

15. Ramagopalan, Sreeram V., et al. “Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1* 1501 is regulated by vitamin D.” PLoS Genet 5.2 (2009): e1000369. http://journals.plos.org/plosgen…

16. Oksenberg, Jorge R., and Sergio E. Baranzini. “Multiple sclerosis genetics—is the glass half full, or half empty?.” Nature Reviews Neurology 6.8 (2010): 429-437. http://zider.free.fr/papers/Pape…

17. Lucas, Robyn M., et al. “Ultraviolet radiation, vitamin D and multiple sclerosis.” Neurodegenerative disease management 5.5 (2015): 413-424. http://www.futuremedicine.com/do…

18. Breuer, Johanna, et al. “Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity.” Annals of neurology 75.5 (2014): 739-758. https://www.researchgate.net/pro…

19. multiple sclerosis – List Results – ClinicalTrials.gov

https://www.quora.com/Estriol-and-Vitamin-D-are-being-tested-on-MS-patients-Do-you-foresee-significant-changes-to-the-treatment-of-MS-within-the-next-five-to-10-years/answer/Tirumalai-Kamala

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