Table of contents
- Dr. Cicero Galli Coimbra (Brazil) is not mentioned as an author, contributor, nor as a reference
- Supplementation and therapeutic use of vitamin D in patients with multiple sclerosis:
- VITAMIN D, MS, AND EAE
- RANDOMIZED AND CONTROLLED CLINICAL TRIALS WITH VITAMIN D IN THE TREATMENT OF MS
- VITAMIN D AND OTHER ISSUES
- SAFETY PROFILE
- VITAMIN D – SIDE EFFECTS
- FINAL CONSIDERATIONS
- See also VitaminDWiki
Dr. Cicero Galli Coimbra (Brazil) is not mentioned as an author, contributor, nor as a reference
Suspect it is because Dr. Coimbra:
- Is not running a clinical trial - he apparently gives vitamin D to ALL of his MS patients
- Is not not giving a uniform dose to all of the patients - the dose ranges from 20,000 to 140,000 IU daily - whatever is needed to achieve a 150 ng level
- Is not giving the same amount co-factors to each patient
- Is using dietary restrictions to prevent patients from getting excess Calcium (Most doctors deal with pills and knives, not diet)
Supplementation and therapeutic use of vitamin D in patients with multiple sclerosis:
Consensus of the Scientific Department of Neuroimmunology of the Brazilian Academy of Neurology
Arq. Neuro-Psiquiatr. vol.72 no.2 São Paulo Feb. 2014; http://dx.doi.org/10.1590/0004-282X20130252
Doralina Guimarães Brum 1 , Elizabeth Regina Comini-Frota 2 , Claúdia Cristina F. Vasconcelos 3 , Elza Dias-Tosta 4
1 Departamento de Neurologia, Psicologia e Psiquiatria, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Botucatu SP, Brazil;
2 Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte MG, Brazil;
3 Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ, Brazil;
4 Hospital de Base do Distrito Federal, Brasília DF, Brazil.
Multiple sclerosis (MS) is an inflammatory, autoimmune, demyelinating, and degenerative central nervous system disease. Even though the etiology of MS has not yet been fully elucidated, there is evidence that genetic and environmental factors interact to cause the disease. Among the main environmental factors studied, those more likely associated with MS include certain viruses, smoking, and hypovitaminosis D. This review aimed to determine whether there is evidence to recommend the use of vitamin D as monotherapy or as adjunct therapy in patients with MS. We searched PUBMED, EMBASE, COCHRANNE, and LILACS databases for studies published until September 9 th , 2013, using the keywords “multiple sclerosis”, “vitamin D”, and “clinical trial”. There is no scientific evidence up to the production of this consensus for the use of vitamin D as monotherapy for MS in clinical practice.
The therapeutic use of vitamin D for treating multiple sclerosis (MS) is a controversial issue that is of interest to physicians, researchers, and patients. The Scientific Department of Neuroimmunology (DCNI) of the Brazilian Academy of Neurology (ABN) organized a meeting on September 12, 2013, to discuss the basic aspects of vitamin D metabolism, results of in vitro and experimental studies on experimental autoimmune encephalomyelitis (EAE), and controlled clinical trials of vitamin D in MS. Neurologists and researchers participating in the meeting approved a guideline consensus to guide Brazilian neurologists in the care of patients with MS.
VITAMIN D, MS, AND EAE
Vitamin D is an important hormone for calcium homeostasis and bone metabolism 1 . Besides its action in bone tissue, vitamin D has a role in cell differentiation, cell growth inhibition, and immune system modulation 2 . The main source of vitamin D is ultraviolet-B radiation (95%). However, no consensus has been reached on optimal serum vitamin D levels for human metabolic needs 3 , 4 . The association between vitamin D and autoimmune diseases and neoplasms has been established in recent years 5 , but this relationship has not yet been fully elucidated.
Multiple sclerosis is an inflammatory, autoimmune, demyelinating, and degenerative central nervous system (CNS) disease, whose geographic and ethnic distribution is characterized by a higher prevalence in northern hemisphere countries, particularly in populations of Caucasian origin 6 .
The predominantly temperate climate in the northern hemisphere with long periods of low solar radiation and the relatively high prevalence of hypovitaminosis D observed in population studies 7 have led to the hypothesis that this deficiency may explain the geographical distribution of MS. Moreover, it has been suggested that adequate serum levels of vitamin D could help reduce the risk of developing MS 8 , 9 .
Even though the etiology of MS has not yet been fully elucidated, there is evidence that genetic 10 , 11 and environmental 12 factors interact to cause the disease. Among the main environmental factors studied, those more likely associated with MS include certain viruses 13 , smoking 14 , and hypovitaminosis D 15 , 16 . The latter is particularly important in the northern hemisphere, where the seasonal variation and subsequent reduction in ultraviolet-B radiation in winter may lead to a higher prevalence of hypovitaminosis D. Some conditions represent risk of hypovitaminosis D in the general population such as long stay indoors, use of sunscreen, and skin pigmentation 17 , 18 . Motor limitations associated with later stages of MS may contribute to the occurrence of hypovitaminosis D in this group of patients 19 .
Unlike northern hemisphere countries, solar radiation in Brazil is believed to be plentiful in all seasons and regions to prevent hypovitaminosis D. Thus, the amount of sunlight one is exposed in Brazil should be enough to avoid hypovitaminosis D in healthy individuals when exposed to sunlight even for short periods. Nevertheless, no studies have compared serum vitamin D levels among Brazilian regions, whereas few studies have analyzed serum vitamin D levels in a selected risk group 20 .
Preliminary experimental studies have demonstrated an immunomodulatory role of vitamin D on human immune cells in vitro 21 , 22 and in an experimental animal model (EAE) 23 , 24 . An in vitro study with peripheral blood cells of patients on vitamin D therapy showed that serum levels above 40 ng/ml may exert modulatory action on immune cells 20 . Additional studies are underway to better understand this immunomodulatory effect on autoimmune diseases.
This review aimed to determine whether there is evidence to recommend the use of vitamin D as monotherapy or as adjunct therapy in patients with MS. We searched PUBMED, EMBASE, COCHRANNE, and LILACS databases for studies published until September 9 th , 2013, using the keywords “multiple sclerosis”, “vitamin D”, and “clinical trial”. Randomized controlled clinical trials with vitamin D in patients with MS were included in the analysis.
RANDOMIZED AND CONTROLLED CLINICAL TRIALS WITH VITAMIN D IN THE TREATMENT OF MS
To evaluate the therapeutic response of vitamin D in MS patients, we selected double-blind, randomized, controlled clinical trials from the literature 25 , 26 - 28 . These studies are still scarce and most were not designed to evaluate therapeutic response to vitamin D. Next, we discuss the most relevant studies.
A clinical study conducted in Finland 25 in 66 patients with relapsing-remitting multiple sclerosis (RRMS) compared a group with 34 patients using 20,000 IU/week of vitamin D and interferon beta-1b (IFNβ-1b) to another group with 32 patients using IFNβ-1b only. In that study, primary outcomes included tolerability and safety aspects, and number of new lesions and gadolinium enhancing lesions on MRI scans. Secondary outcomes included clinical parameters such as annual relapse rate and changes in the Expanded Disability Scale Score (EDSS), in addition to other imaging parameters. The authors observed that the treated group showed fewer new T2 lesions, but there were no significant differences in clinical parameters between the two groups after 12 months. However, there was a significant reduction in the number of gadolinium enhancing lesions in the vitamin D group.
Another study, conducted in Norway 26 , compared bone mineral density, relapse frequency, disease progression, and motor function measures between 35 patients with MS using 20,000 IU of cholecalciferol per week associated with 500 mg/day of calcium and a control group of 33 patients with MS using 500 mg/day of calcium only for two years 26 . Patients in both groups had been previously using immunomodulatory drugs (interferon beta or glatiramer acetate) for a similar period of time. No differences in annual relapse rate and changes in functional capacity measured by EDSS were observed between the two groups, even though vitamin D levels ranged from 24.72 ng/ml in the placebo group to 49.26 ng/ml in the vitamin D group. The study was not powered to address clinical outcomes 12 .
A phase II study developed in Iran 27 compared 25 patients with RRMS receiving the active form of vitamin D (calcitriol) at a dose of 0.25 µg/day with patients receiving placebo 27 . Both groups used conventional immunomodulators. There was no difference in the EDSS between the calcitriol and placebo groups after 12 months followup 13 . It should be noted in that study the small sample size and inclusion criterion of serum 25-hydroxyvitamin D level >40 ng/ml.
A randomized study in Australia 28 compared 11 patients with RRMS treated with vitamin D2 in a dose of 6,000 IU twice daily in addition to a daily low-dose (1,000 IU) with 12 patients receiving the 1,000 IU/day dose only 28 . The neuraxial index of inflammatory activity on MRI was compared between the high-dose and low-dose groups. No significant differences between the groups were detected.
A meta-analysis of the studies cited above detected no difference in the number of relapses between the groups 29 . The number of new lesions and gadolinium enhancing lesions were compared to serum vitamin D levels in other two studies and the findings were conflicting 26 , 30 . Limitations of the studies include different dosages and forms of vitamin D administered.
In contrast to epidemiological and experimental studies, randomized trials on the use of vitamin D in MS showed no significant differences in the parameters of disease activity – relapse rate, EDSS progression, and new or gadolinium enhancing lesions on MRI – between the group receiving vitamin D and groups receiving placebo or a smaller dose of vitamin D. These differences and other contradictions indicate the need to conduct double-blind, randomized, controlled trials in large groups of patients, considering the differences between clinical, neuroimaging, biological, and immunological variables, and powered to accurately estimate the therapeutic efficacy and possible side effects of vitamin D in MS.
VITAMIN D AND OTHER ISSUES
The Institute of Medicine (IOM) and the American Society for Endocrinology advocate different levels of vitamin D to maintain bone health: ≥20 ng/ml and ≥30ng/ml, respectively 3 , 4 . There is no consensus on whether bone cells and immune cells require different levels of vitamin D. In addition to the lack of consensus on the normal range values for vitamin D, the toxic serum concentration and the concentration leading up to this condition are also controversial. In adults, doses greater than or equal to 10,000 IU/day are associated with hypercalcemia 31 , 32 .
High performance liquid chromatography (HPLC) followed by mass spectrometry is considered the gold standard for analysis of serum 25-OH vitamin D levels. However, the technique is laborious, expensive, and is not available in most Brazilian laboratories. Other methods such as chemiluminescence, enzyme immunoassay, and radioimmunoassay are also used. Thus, variability in results can occur depending on the assay used 33 . In Brazil, there is no efficient inter-laboratory validation system, which can also result in great variability in results. Moreover, certain medications such as anticonvulsants and corticosteroids may have a role in reducing serum levels of vitamin D.
The safety profile of different serum vitamin D levels has been evaluated in an open, randomized study conducted in Canada 31 . In that study, a group of 25 patients with MS used escalating cholecalciferol (vitamin D3) doses up to 40,000 IU/day, whereas a second group of 24 patients used 4,000 IU/day. Patients in both groups used immunomodulators (interferon beta and glatiramer acetate) in combination with cholecalciferol. The maximum 40,000 IU/day dose was used for up to six months, followed by 10,000 IU/day for three months and gradual suspension over three months. Both groups received calcium (1,200 mg/day) throughout the trial, and serum calcium was determined. Serum 25-hydroxivitamin D (25-OH-vitamin D) reached a maximum mean above 250 nmol/l (100ng/ml) during the 40,000 IU/day dosing period. No hypercalcemia was detected during the 10,000 IU/day dosing period, even with serum levels ≥ 100 ng/ml, suggesting that that dose is safe (Class level II evidence). In addition, neither serum calcium nor parathormone urinary levels were altered, even when serum concentrations were higher. Further studies are needed to confirm these findings.
VITAMIN D – SIDE EFFECTS
Clinical picture of vitamin D intoxication may include signs and symptoms originating in different systems: nausea and vomiting, anorexia, abdominal pain, constipation; polydipsia, polyuria, dehydration, nephrolithiasis, nephrocalcinosis, nephrogenic diabetes insipidus, chronic interstitial nephritis, acute and chronic renal failure; hypotonia, paresthesia, confusion, seizures, apathy, coma; arrhythmia, bradycardia, hypertension, cardiomyopathy; muscle weakness, calcification, osteoporosis; and conjunctival calcification 34 - 36 . Hypercalcemia is the most important side effect, and when observed in the laboratory is suggestive of intoxication 37 .
During use of vitamin D, in addition to serum calcium, urinary calcium should be assayed periodically. Serum concentration of parathyroid hormone (PTH) should also be determined and must not exceed the lower reference values of normality indicative of suppression, which is a non-recommended condition 35 .
Considering the body of information presented here, the DCNI/ABN defines the consensus that:
- It is recommended to dose vitamin D in patients with clinically isolated syndrome and MS, regardless of the stage of disease, particularly those making frequent use of corticosteroids or anticonvulsivants.
- Peripheral blood levels of vitamin D lower than 30ng/ml should be corrected in patients with MS, at any stage, or in patients with demyelinating isolated syndrome (grade D recommendation).
- Peripheral blood levels of vitamin D higher than 100 ng/ml should be avoided until new guidelines are established (grade D recommendation).
- There is no scientific evidence up to the production of this consensus for the use of vitamin D as monotherapy for MS in clinical practice . Therefore, currently, vitamin D monotherapy for MS is considered experimental. For its use in clinical trials, these must be approved by the Human Research Ethics Committee, regulated by the National Commission for Ethics in Research (CONEP), approved by the Regional Medical Board, and informed consent should be provided by patients.
- According to data from in vitro studies with peripheral blood cells of patients using vitamin D, serum levels above 40 ng/ml are likely to cause modulating action on immune cells 17 . Based on that evidence, vitamin D supplementation at doses that maintain serum levels of patients between 40 ng/ml and 100 ng/ml may be recommended, as these are safe levels (grade D recommendation).
- Considering the individual differences in replacement needs and serum levels of vitamin D, that a study in healthy subjects showed that 5,000 IU/day of vitamin D for 15 weeks increased serum levels up to 60ng/ml, and that doses up to 10,000 IU/day were considered safe, we recommend individualized doses until reaching serum levels between 40 ng/ml and 100 ng/ml (grade D recommendation).
- Considering that low vitamin D serum levels in patients with isolated demyelinating syndrome could affect the relative risk of conversion to MS 16 , we recommend the analysis of serum vitamin D levels in those patients and that a correction is made whenever necessary (grade D recommendation).
- Because vitamin D3 is a secosteroid hormone, its use should be escalated. Moreover, monitoring serum 25-hydroxivitamin D would be extremely important before increasing dosage to determine whether supplementation is actually effective (grade D recommendation).
We thank the contributors who performed critical review of the manuscript: Amilton Antunes Barreira, Danilo Lima Varela, Denis B. Bichuetti, Felipe von Glehn, Eduardo Antônio Donadi, Gutemberg Augusto Cruz dos Santos, Marcos Papais-Alvarenga, Maria Fernanda Mendes, Maria Cecilia Vecino, Maria Lúcia Vellutini, Paulo Pereira Christo, Thiago Faria Junqueira, Soniza Vieira Alvez Leon, and Yara Dadalti Fragoso (Fragoso, YD). We also thank the invaluable expert assistance of Paulo S. Moraes Júnior in using Microsoft Lync for support in the online meeting.
This manuscript was reviewed by a professional science editor and by a native English-speaking copy editor to improve readability.
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Received: January10, 2014; Accepted: January20, 2014
Correspondence : Doralina G. Brum. Departamento de Neurologia, Psicologia e Psiquiatria da Faculdade de Medicina de Botucatu, Universidade Estadual Paulista - UNESP. Distrito de Rubião Júnior, s/n; 18618-970 Botucatu SP, Brasil. E-mail: dbrum at fmb.unesp.br
Support: This guideline was developed with financial support from the Brazilian Academy of Neurology. None of the authors received honoraria for their participation.
Conflict of interest: The Brazilian Academy of Neurology (ABN) is committed to produce clinical guidelines critically and independently. This guideline is part of ABN’s continuing education activity. It is based on review of scientific and clinical knowledge. Its purpose is not to address the subject in its entirety. Treatment decision is shared between patient and physician and according to each situation.
The conflict of interest form for the issue specifically addressed in this article was signed by all authors.
List of contributors: Amilton Antunes Barreira, Antônio Pereira Gomes Neto, Cláudio Roberto Carneiro, Carlos Augusto de Albuquerque Damasceno, Daniel Lima Varela, Damácio Rámon Kaimen-Maciel, Denis Bernardi Bichuetti, Denise Sisterolli Diniz, Eber Castro Correa, Elizabeth Batista da Silva, Fabio Siquineli, Fernando Coronetti Gomes da Rocha, Felipe von Glehn Silva, Fernando Faria Andrade Figueira, Gutemberg Augusto Cruz dos Santos, Heloise Helena de Figueiredo Siqueira, Jefferson Becker, Leandro Cortoni Calia, José Mauricio Godoy Barreiros, Luiz Domingos Mendes Melges, Marcos Aurélio Moreira, Marcos Papais-Alvarenga, Maria Cecília Aragon de Vecino, Maria Cristina Brandão de Giacomo, Maria Fernanda Mendes, Maria Lúcia Brito Ferreira, Maria Lúcia Vellutini Pimentel, Monica Koncke Fiuza Parolin, Nívea de Macedo Oliveira Morales, Osvaldo J.M. do Nascimento, Paulo Pereira Christo, Regina Maria Papais Alvarenga, Renata Brandt de Souza, Renato Puppi Munhoz, Rogério de Rizo Morales, Sidney Gomes, Solange Maria das G. G. Camargo, Soniza Vieira Alvez-Leon, Suzana Costa Nunes Machado, Tarso Adoni, Thereza Cristina D`Avila Winckler, Thiago de Faria Junqueira, Yara Dadalti Fragoso, and Yuna de Ribeiro Araújo.
External collaborators: Alessandro Farias (researcher), Eduardo Antônio Donadi (immunologist), and Marcelo de Paula Corrêa (meteorologist).
PDF is attached at the bottom of this page
See also VitaminDWiki
- Overview MS and vitamin D contains the following summary
Clinical interventions have shown that Vitamin D can prevent, treat, and even cure Multiple Sclerosis, at a tiny fraction of the cost of the drugs now used to treat it, and without side effects.
- Fact: Low Vitamin D results in higher risk of getting MS
Increase latitude leads to decreased Vitamin D, which leads to increased risk of MS
Dark skinned people are far more likely to get MS (dark skin people typically have low vitamin D)
Elderly (who typically have low vitamin D) are more likely to get MS
Is there increased risk in people who already have diseases associated with low vitamin D - TB, for example ? ? ?
Women typically have 3X increased MS risk then men (note: women typically have 20% lower levels of vitamin D than men)
Exception: women in very sunny climates and dark-skinned women have the same MS risk as men
Obese are 60% more likely to get MS
Smokers - smokers have lower level of vitamin D and have higher incidence of MS (also, smokers are difficult to cure of MS in Brazil)
MS recurrence is much higher in spring - the lowest time of the year for vitamin D
increase in clouds/rainfall (which reduces available Vitamin D) is associated with increased risk of MS (Scotland, Western Washington)
MS incidence has increased 70% in a decade while the incidence of vitamin D deficiency doubled
Less MS in those with outdoor occupations PDF file, not a web page
- Fact: MS uses up Vitamin D
- Fact: Lower vitamin D (due to MS using up Vitamin D while fighting the disease) results in many other health problems (such as broken bones), so depleted vitamin D levels must be restored.
- Fact: Vitamin D looks so promising for preventing and treating MS that there were 25 INTERVENTION clinical trials as of Feb 2014
- Fact: Vitamin D reduced the MS relapse rate far better than Fingolimod which is now used for that purpose.
- Note: Fingolimod costs $25,000/year while vitamin D, which works better and has no site effects is 1000 times less expensive.
- Fact: 98% of the genes affected by Interferon are also affected by Vitamin D
- Note: 1 week of Interferon = $4,700, 1 week of vitamin D 10,000X lower cost
- Fact: MS Doctors in Brazil recommending 40-100 ng/mL of Vitamin D
- Fact: Many MS forums are recommending vitamin D to treat MS, with some taking 5,000 to 10,000 IU daily
Observation: Risk of going from pre-MS to MS reduced 68 percent with 7100 IU vitamin D – RCT Dec 2012
- This is an observation instead of a fact - it has not yet been confirmed.
- Fact: VERY LARGE doses of vitamin D have CURED 2,000 people of MS in Brazil
- Controversy: UVB fron sunlight or UVB bulb may be BETTER than Vitamin D for reducing the risk of getting MS
- Hypothesis: In addition to Vitamin D there are many other photoproducts produced by UVB that may promote health.
Summary: lack of consensus on how much to prevent, treat, or cure MS.
- How much Vitamin D to prevent many diseases - such as MS
- How much Vitamin D is needed to treat MS? There is currently no agreement
The recommendations range from 40 to 100 ng - which can result of a dose ranging from 3,000 to 20,000 IU/day
- How Vitamin D is needed to Cure MS?: It appears that 20,000-140,000 IU daily may be needed to CURE the disease
You must be under the supervision of a doctor who knows what to watch for in your individual situation.
High doses of Vitamin D cannot be used as a monotherapy.
You will need to adjust the cofactors: Typically increasing Magnesium and Vitamin K2, and reducing Calcium intake.
Your doctor will monitor these and might increase your intake of Vitamins B2, C, as well as Omega-3
MS updates from Brazil
- Treatment with daily high doses of vitamin D Overcoming MS May 2013
Of course, this is not a cure it's a life-long treatment.. but at least it stops the progression and in many cases even revert back some (sometimes all) of the brain lesions.
- Huge page - all in Portuguese about Coimbra's work
- Web site of patients who have been cured by Dr. Coimbra Australia 150 ng is the target
Great sequential posts, over a year. by an Australian patient whose MS was reversed by Dr. Coimbra
- I Have Multiple Sclerosis: I Am Treating My MS With High Doses Vitamin D experienceproject. May 2013
Gives a fair amount of details, such as taking lots of water and monitoriing for excess Calcium.
Note A home test kit for excess Calcium in the urine is available $10 for 10 tests
- Dr. Holick visited with the patients in Brazil Sept 2013