Coimbra protocol using high-dose Vitamin D is safe – April 2022

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Safety Data in Patients with Autoimmune Diseases during Treatment with High Doses of Vitamin D3 According to the “Coimbra Protocol”

Nutrients 2022, 14(8), 1575; https://doi.org/10.3390/nu14081575
Ulrich Amon 1, Raul Yaguboglu 1. Madeleine Ennis 2. Michael F. Holick 3. And Julian Amon 1

• 1 International Centre for Skin Diseases DermAllegra, Coimbra Protocol Certified Center, Am Markgrafenpark 6, 91224 Pommelsbrunn-Hohenstadt, Germany
• 2 The Wellcome-Wolfson Institute for Experimental Medicine, Queens University of Belfast, Belfast BT7 1NN, UK
• 3 Endocrinology, Diabetes, Nutrition & Weight Management, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA

Calcium similar before and after, often drops a litte

PTH drops a lot over time

Dose size drops over time with MS

60% of MS patients have an average of 6 Vitamin D gene problems

Principal Diagnoses: Vitiligo, MS, Psorasis, etc.

Background: In 2013, the group of Cicero Coimbra, Brazil, reported the clinical efficacy of high doses of vitamin D3 in patients suffering from autoimmune skin disorders (“Coimbra protocol”, CP). However, hypercalcemia and the subsequent impaired renal function may be major concerns raised against this protocol.

Methods: We report for the first time for a broad spectrum of autoimmune diseases in 319 patients (mean age (±SD) 43.3 ± 14.6 years, 65.5% female, 34.5% male) safety data for high doses of orally applied vitamin D3 (treatment period: up to 3.5 years) accompanied by a strict low-calcium diet and regular daily fluid intake of at least 2.5 L.

Results: Mean vitamin D3 dose was 35,291 ± 21,791 IU per day. The measurement of more than 6100 single relevant laboratory parameters showed all mean values (±SD) within the normal range for total serum calcium (2.4 ± 0.1 mmol/L), serum creatinine (0.8 ± 0.2 mg/dL), serum creatinine associated estimated GFR (92.5 ± 17.3 mL/min), serum cystatin C (0.88 ± 0.19 mg/L), serum TSH (1.8 ± 1 mIU/L), and for 24 h urinary calcium secretion (6.9 ± 3.3 mmol/24 h). We found a very weak relationship between the dosage of oral vitamin D3 and the subsequent calcium levels, both in serum and in urinary excretion over 24 h, respectively.

Conclusions: Our data show the reliable safety of the CP in autoimmune patients under appropriate supervision by experienced physicians.
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Discussion

Although the pathophysiological role and the therapeutic implications of vitamin D in autoimmunity are still under debate [6], the pleiotropic non-skeletal functions of vitamin D have been generally recognized for reducing the risk of complex non-communicable diseases (NCDs), including cardiovascular diseases, diabetes mellitus, depression, dementia, cancer, allergies, asthma as well as chronic infections [48-50].
While for most NCDs the putative pathophysiologic role of vitamin D as being an association or a cause-effect relationship is still unclear, recent evidence, using Mendelian randomization studies focusing on the genetic variants of vitamin D metabolism in order to reduce confounders, has confirmed an increased risk at least for MS in patients with vitamin D deficiency [51].
Therefore, MS might be the optimal "model" to study both the effects and safety parameters of the high-dose vitamin D treatment as offered with the CP [19]. To date, the treatment protocol of Cicero Coimbra in Brazil for a variety of autoimmune disorders, e.g., MS, psoriasis, and vitiligo, has only been published as pilot study [16], and randomized clinical trials are missing.
Patients with autoimmune diseases, especially MS, often look for holistic and alternative approaches in addition to symptomatic, immune suppressive and disease modifying treatments [52]. Nowadays, very extensive information is available in the World Wide Web [53-55]. There are many websites and personal case reports, which reflect the efficacy of CP as seen in social media by the patients [53-55].
Since the increasing interest in treatment with vitamin D and even ultra-high doses [7,56] results in the possible consequences of self-administering highly concentrated food supplements, we here primarily focus on the safety aspects of the CP.
In the pilot study of Coimbra's group published in 2013 [16], assessing the effect of the prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis, nine patients with psoriasis and sixteen patients with vitiligo received vitamin D3 35,000 IU once daily for six months in association with a consequent low-calcium diet (avoiding dairy products and calcium-enriched foods, such as oat, rice or soya "milk") and reliable hydration (minimum 2.5 L daily). In their study, serum creatinine and calcium (total and ionized) did not change and urinary calcium excretion increased within the normal range [16].
To our knowledge, we in this paper demonstrate for the first time for a broad spectrum of autoimmune diseases in over 300 patients with a treatment period of more than 3.5 years that high doses of orally applied vitamin D3 up to 1000 IU per kg bodyweight are safe in terms of calcium metabolism and renal function, when strict recommendations for diet and fluid intake are followed, up to a treatment period of 3.5 years.
With respect to our population, the mean daily dose of 35,000 IU Vitamin D3 is far higher than usual recommendations [57] and should be a contribution to the debate on the disparity of conclusions on what an "optimal" serum concentration of 25(OH)D is and how much supplementation is required to achieve a sufficient clinical response without long-term side effects.
For many years, we have been following clinically the recommendation of 25(OH)D ranging between 40 and 60 ng/mL being considered to be "optimal" (preferred range) for healthy people [9,58-60]. However, for autoimmune and inflammatory diseases, we have little knowledge about the variations of vitamin D metabolism and recognition, such as VDR polymorphisms, vitamin D binding protein polymorphisms, extrarenal 1 alpha hydroxylase activity, and micro RNAs [61].
Instead of solely focusing on 25(OH)D serum levels, different groups have recently elegantly worked out that, due to epigenetic and genetic differences, the individual immune responsiveness to vitamin D3 is rather complex [19,57,62,63]. Among other factors, this depends on the individual ability to convert vitamin D to its active metabolite 1,25(OH)2D and the interaction with VDR and the response elements [62-64]. Recently, it was shown that there is a dissociation between the calcemic and non-calcemic biologic actions of vitamin D3, especially on functions involved in immune activity [57].
Against this background, the suppression of PTH should be rather favored as a proxy for optimal vitamin D status as well as vitamin D3 treatment [65].
As expected [19], PTH levels dropped over time during CP treatment depending on the dose of vitamin D3 in our population. This confirms the preliminary results of Coimbra's group [16]: during a six month treatment period with a fixed daily dose of 35,000 IU vitamin D3 PTH levels significantly decreased from 57.8 ± 16.7 to 28.9 ± 8.2 pg/mL and from 55.3 ± 25.0 to 25.4 ± 10.7 pg/mL in patients with psoriasis and vitiligo, respectively.
Shirvani and co-workers [57] described a plateau in PTH levels in thirty randomized healthy adults at 16 weeks for a vitamin D3 dose of 4000 and 10,000 IU per day, but not for the group that received 600 IU per day, respectively, without changes in serum calcium. Interestingly, they observed a dose-dependent 25(OH)D alteration in broad gene expression with 162, 320 and 1289 genes up- or down-regulated in white blood cells, respectively [57].
However, due to higher oral vitamin D3 dosages in our patients suffering from MS, in our protocol, PTH plateaued at 15 pg/mL at approximately 6 months after start of treatment, which was different from non-MS autoimmune patients (Figure 5).
In comparison to healthy persons in autoimmunity genetic or epigenetic alterations of vitamin D metabolism differs both in quantity and quality of SNPs within genes of the vitamin D system (e.g., in activating enzymes, serum transport, and VDR) responsible for vitamin D status alterations, causing vitamin D resistance and reduced vitamin D responsiveness [7,19]. The influence of vitamin D3 high dose supplementation on genomewide expression in autoimmune patients remains unexplored.
As already stated in the pilot study of Finamor et al. [16], the daily requirements of vitamin D3 for patients with autoimmune disorders should be individually adapted to the profile of genetic polymorphisms of vitamin D metabolism.
The association between VDR, SNPs, and MS risk, for example, has been reported by many groups, whereas other vitamin D-related genes (including CYP2R1, CYP27B1, CYP24A1) have been less investigated [39].
In our population, the most frequent mutations were found in the genes encoding the enzymes 25-Hydroxylase (CYP2R1) and 1alpha-Hydroxylase (CYP27B1) with 75% of all patients, while SNPs in the regions of the VDR (BsmI, TaqI and FokI) were detected less frequently.
As previously shown, the genetic polymorphism of CYP27B1 associated with autoimmunity [66,67] causes a relative resistance to vitamin D requiring a higher level of circulating 25(OH)D3 to achieve biologically active 1,25(OH)2D3, resulting in normalized immune functions [16]. In order to achieve a physiologic rate of product formation in polymorphic enzyme variants, a higher Km (decreased affinity for substrate) and/or a lower Vmax require supra-physiologic concentrations of the substrate [16].
In patients with a combination of polymorphisms within different sections of vitamin D metabolism, this effect is potentiated. Supra-physiologic doses as applied according to CP may compensate for this genetic-related status of relative vitamin D resistance establishing tolerance to auto-antigens and may with respect to our safety data also increase tolerability in patients with autoimmune disorders [16]. This might explain the far lower PTH plateau in our patients in comparison with healthy subjects studied by Shirvani and co-workers [57].
According to Lemke et al. and the hypothesis of Cicero Coimbra of an acquired vitamin D resistance in autoimmune diseases [19], PTH concentrations could be used as a hallmark for individual adaption of oral vitamin D3 dosages. For an optimal physiological response of 1,25(OH)2D3, a low PTH plateau should reached and maintained within the lower third of the reference range [19]. With respect to our own experiences during the last four years, the degree of inflammation in autoimmune processes seem to influence the need to further decrease the PTH level by higher daily doses of vitamin D3.
A seven-year experience of McCullough et al. with oral vitamin D3 up to 50,000 IU per day did not reveal a linear or exponential relationship between vitamin D and calcium blood levels [68]. They did not observe cases of vitamin D3 induced hypercalcemia or any adverse events attributable to vitamin D3 supplementation in any patient.
Historically, many reports were published during the last century describing the successful use of vitamin D3, for example, in treating psoriasis, asthma, or rheumatoid arthritis with daily doses ranging from 60,000 to 300,000 IU [68]. Due to serious concerns following complications from vitamin-D-induced hypercalcemia after the prolonged daily intake of these supra-physiologic daily doses, vitamin D was then labelled as toxic [68].
With our current detailed knowledge about vitamin D metabolism, central cofactors (e.g., magnesium [69]), the influence of SNPs according to (epi)genetic studies [39], and worldwide experience of several thousands of patients treated with the CP from 2012 onwards with daily doses up to 340,000 IU [70], we are able to develop an individualized vitamin D3 treatment for autoimmune patients by the careful planning and determination of reliable mechanisms for regular laboratory controls. Based on our findings, hypercalcemia does not appear to be a first line risk of high-dose vitamin D3 therapy.
However, since hypervitaminosis D leads to increased calcium absorption via the upregulation of intestinal VDR, a strict calcium-reduced diet is mandatory to protect patients from hypercalcemia. At baseline, patients must be informed in great detail about this central aspect. Restrictions in milk, dairy products and calcium-enriched food stuff have contributed to minimize the calciotropic effects of high daily doses of vitamin D3 in the current study, which confirms the data of the pilot study of Coimbra's group [16]. We strongly recommend that CP is always used in the hands of qualified and experienced physicians and strongly advise against the use of CP by patients themselves based on Internet information.
Among all the chronic inflammatory skin diseases we previously studied (Amon U et al., 2018), the average 25(OH)D serum level was lowest in patients with plaque psoriasis (psoriasis vulgaris), only in patients with severe acute or chronic recurrent skin infections on the skin did we find significantly lower levels. Since the 1930s [71], successful oral substitution of vitamin D in psoriasis patients has been demonstrated in different studies [72]. Since for psoriasis, an increased incidence of other inflammatory comorbidities (e.g., psoriatic arthritis, arteriosclerosis, diabetes mellitus, obesity, non-alcoholic steatohepatitis, inflammatory bowel diseases, and depression) has been described [73], for which—independent of psoriasis—a modulating role of vitamin D has also been discussed in recent publications [74], we strongly recommend that physicians consider using the CP for patients suffering from psoriasis [16].
Perez and co-workers observed an improvement of 88% after oral 1,25(OH)2D3 treatment in 85 patients with psoriasis, with approximately 27% of patients healing completely, 36% having a moderate and 25% showing a slight improvement without causing hypercalcemia [75]. High oral doses of vitamin D3 (35,000 IU once daily) for six months led to a significant improvement of Psoriasis Area and Severity Index (PASI) score in nine patients with psoriasis without significant side effects [75]. Earlier work has also demonstrated a drastic improvement following the oral administration of vitamin D2 in severe cases [71] and following the use of 1a-hydroxyvitamin D3 and 1,25(OH)D3 [76,77].
In our analysis, vitiligo was the dominant diagnosis. Vitiligo is a polygenic autoimmune disease, characterized by localized or generalized depigmentation of the skin as a result of melanocyte destruction by immunologic dysfunction [78]. Two recent metaanalyses identified a significant positive relationship between lower 25(OH)D serum levels and the incidence of vitiligo [79,80]. In our recent study, among 113 patients with vitiligo, 41.2% had a 25(OH)D serum level below 20 ng/mL at baseline before treatment [11].
Zhang et al. performed a meta-analysis with 17 studies on VDR gene polymorphisms (BsmI, ApaI, TaqI, and FokI) in vitiligo, resulting in an increased susceptibility risk of vitiligo only for the Apal polymorphism of the VDR; BsmI, TaqI, and FokI loci had no obvious correlation [80]. In our study, FokI (rs2228570) was most often mutated in comparison to BsmI and TaqI.
When Finamor et al. treated 16 vitiligo patients with daily doses of 35,000 IE vitamin D3 over a period of six months, no repigmentation of the affected areas was observed in only five patients, but the others did develop repigmentation up to 75% without further dermatological treatment [16]. In our center, the combination of CP with topical treatment (calcineurin inhibitors) and/or 311 nm narrow band UVB or 308 nm excimer laser regularly leads to repigmentation in all patients, of course to a varying extent, which will be reported elsewhere. With respect to the data presented here, the vast majority of our vitiligo patients had a daily dose of vitamin D3 not higher than 40,000 IE. For non-inflammatory autoimmune skin diseases (such as vitiligo or alopecia areata), in general, a lower vitamin D3 dose appears to be sufficient for a good clinical response (drop of PTH levels in patients with vitiligo: baseline vs. >365 days p < 0.001, non-vitiligo patients: baseline vs. >365 days p < 0.001), as has been suggested elsewhere [16,19].
Despite our evidence that high-dose vitamin D3 application according to CP is generally well tolerated without signs for long term toxicity, this therapeutic approach of vitamin D3 supplementation should be embedded in a holistic treatment package. Against this background, fascinating new findings from gut microbiome research demonstrated variations in the vitamin D receptor also influence the large functional network of gut microbiota [81].
Finally, further possible significant factors influencing vitamin D sensitivity and metabolism as well as disease activity of autoimmune processes, such as gender differences [82] and the degree of chronic psychoneuroimmunologic impact [83], should be elaborated in further studies, when the clinical efficacy of CP is evaluated in detail. It will be also particularly important to differentiate the clinical effects between the different autoimmune diseases treated by the regimen.

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Conclusions

In summary, to our knowledge, our work provides the first long-term documentation of selected critical laboratory parameters during the application of the CP using a high-dose oral vitamin D3 in a broad spectrum of different autoimmune diseases, demonstrating that this procedure is well tolerated with respect to renal function and calcium metabolism. In terms of individualized treatment, we suggest to further use serum levels of PTH as biomarker for an individual response to vitamin D3, the individual ability to convert vitamin D to the active metabolite, the 1,25(OH)2D's interaction with its receptor and the response elements and finally the differential supplementation with vitamin D3. In further studies, possible differences of the clinical outcome of CP treatment should be investigated.

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• 66. Pani, M.; Regulla, K.; Segni, M.; Krause, M.; Hofmann, S.; Hufner, M.; Herwig, J.; Pasquino, A.; Usadel, K.; Badenhoop, K. Vitamin D lalpha-Hydroxylase (CYPlalpha) Polymorphism in Graves' Disease, Hashimoto's Thyroiditis and Type 1 Diabetes Mellitus. Eur. J. Endocrinol. 2002,146, 777-781. [CrossRef]
• 67. Sundqvist, E.; Bäärnhielm, M.; Alfredsson, L.; Hillert, J.; Olsson, T.; Kockum, I. Confirmation of Association between Multiple Sclerosis and CYP27B1. Eur. J. Hum. Genet. 2010,18,1349-1352. [CrossRef] [PubMed]
• 68. McCullough, P.J.; Lehrer, D.S.; Amend, J. Daily Oral Dosing of Vitamin D3 Using 5000 to 50,000 International Units a Day in Long-Term Hospitalized Patients: Insights from a Seven Year Experience. J. Steroid Biochem. Mol. Biol. 2019,189, 228-239. [CrossRef] [PubMed]
• 69. Deng, X.; Song, Y.; Manson, J.E.; Signorello, L.B.; Zhang, S.M.; Shrubsole, M.J.; Ness, R.M.; Seidner, D.L.; Dai, Q. Magnesium, Vitamin D Status and Mortality: Results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III. BMC Med. 2013,11,187. [CrossRef] [PubMed]
• 70. Coimbra, C.G.; (University of Sao Paulo, Sao Paulo, Brazil). Personal Communication. 2018. Recording of the lecture at the Congress of Human Medicine, Frankfurt, 14 April 2018. Available online: https://www.youtube.com/watch?v=w1XT0btvVSg (accessed on 31 January 2022).
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• 76. Morimoto, S.; Yoshikawa, K.; Kozoka, T.; Kitano, Y.; Imanaka, S.; Fukuo, K.; Koh, E.; Kumahara, Y. An Open Study of Vitamin D3 Treatment in Psoriasis Vulgaris. Br. J. Dermatol. 1986,115, 421-429. [CrossRef]
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• 81. Wang, J.; Thingholm, L.B.; Skieceviciene, J.; Rausch, P.; Kummen, M.; Hov, J.R.; Degenhardt, F.; Heinsen, F.-A.; Rühlemann, M.C.; Szymczak, S.; et al. Genome-Wide Association Analysis Identifies Variation in Vitamin D Receptor and Other Host Factors Influencing the Gut Microbiota. Nat. Genet. 2016, 48,1396-1406. [CrossRef]
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36+ VitaminDWiki pages with COIMBRA in title

This list is automatically updated

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67+ VitaminDWiki pages with HIGH-DOSE in title

This list is automatically updated

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• 1 (current)
• 2
• »

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VitaminDWiki - Multiple Sclerosis (412 studies)

Overview MS and vitamin D
Multiple Sclerosis and (lots of) Vitamin D - book by patient on Coimbra protocol - Feb 2016
Multiple Sclerosis 32 percent less likely among those with more than 32 ng of vitamin D – Dec 2019

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VitaminDWiki - Autoimmune category (204 studies)

• 204 items in Autoimmune category
• Vitamin D and   MS    Asthma    RA    Diabetes    Gut   Allergy    Hay Fever    Lupus    Psoriasis
• Predicted 95% autoimmune cured by HIGH-DOSE vitamin D - 2014
• 10% of the UK have Autoimmune Diseases - Lancet May 2023 PDF is behind a paywall
  • Increase in 20 years : coeliac disease 2.19 X. Sjogren's syndrome 2.09, and Graves' disease 2.07
  • All 43 references are FREE on-line
• Autoimmune diseases fought by Vitamin D, especially if have more than 40 ng – Sept 2022
• The BEST Nutrient for Autoimmune Conditions (Vitamin D) - video May 2022
• The number 1 Deficiency behind All Autoimmune Diseases (Vitamin D) video - Dec 2023
• Autoimmune disease clusters run in families having low D
• How Vitamin D reduces inflammation, improves immunity and fights autoimmunity – review Dec 2018
• 120 doctors and 20,000 MS patients using high dose Vitamin D Dec 2018
• Vitamin D has treated Multiple Sclerosis and autoimmune diseases for 16 years – Coimbra April 2018
• Vitamin D Receptor is associated in over 58 autoimmune studies
• More autoimmune disease if higher pollution or lower UVB - Feb 2023
• Many autoimmune diseases associated with low vitamin D or poor Vit D genes – July 2019
  

See also web: consensus that ~50 diseases are autoimmune, ~50 more are suspected:

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VitaminDWiki - Genetics category (343 studies)

343 articles in the Genetics category

see also

• Vitamin D Receptor has 530 items
• Vitamin D Binding Protein = GC has 178 items
• CYP27B1 has 63 items
• CYP24A1 in title of 39+ items
• CYP2R1 25+ items
• Calcidiol has 48 items
• Calcitriol has 62 items
• Topical Vitamin D
• Nanoemulsion Vitamin D may be a substantially better form
• 1289 genes changed with higher doses of Vitamin D - RCT Dec 2019
• CYP3A4 (7 as of Dec 2022)
• Getting Vitamin D into your body
• 

Vitamin D blood test misses a lot

• Vitamin D from coming from tissues (vs blood) was speculated to be 50% in 2014, and by 2017 was speculated to be 90%
• Note: Good blood test results (> 40 ng) does not mean that a good amount of Vitamin D actually gets to cells
• A Vitamin D test in cells rather than blood was feasible (2017 personal communication)   Commercially available 2019
  • However, test results would vary in each tissue due to multiple genes
• Good clues that Vitamin D is being restricted from getting to the cells
  1) A vitamin D-related health problem runs in the family
      especially if it is one of 51+ diseases related to Vitamin D Receptor
  2) Slightly increasing Vitamin D shows benefits (even if conventional Vitamin D test shows an increase)
  3) DNA and VDR tests - 100 to 200 dollars $100 to $250
  4) PTH bottoms out ( shows that parathyroid cells are getting Vitamin d)
     Genes are good, have enough Magnesium, etc.
  5) Back Pain
     probably want at least 2 clues before taking adding vitamin D, Omega-3, Magnesium, Resveratrol, etc
  • The founder of VitaminDWiki took action with clues #3&5

Vitamin D Receptor is associated in over 40 autoimmune studies

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VitaminDWiki - Some diseases reduce vitamin D getting to blood or cells

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The same study is also in VitaminDWiki at: Coimbra Protocol (using Vitamin D) is safe and effective for Multiple Sclerosis and Autoimmune diseases – April 2022