Background: Until 2003, at the Lynchburg Rheumatology Clinic, vitamin D deficiency was associated with metabolic bone disorders; osteomalacia in adults or rickets in children. The accepted normal range for 25-hydroxyvitamin D was 8 to 50 ng/ml (nanograms (ng) per millilitre (mL). With the introduction of bisphosphonate treatment for osteoporosis, there was interest in the role of vitamin D as part of the osteoporosis treatment regimen.
But the article in 2003 by Plotnikoff and Quigley, relating musculoskeletal pain to “hypovitaminosis D,” stimulated great interest for looking at vitamin D levels in all our rheumatology patients (1). Was low vitamin D associated with fibromyalgia or other causes of musculoskeletal pain? Using new accepted normal levels for 25-hydroxyvitamin D of 32 to 100 ng/ml, low vitamin D levels were found in over 70% of our patients. The following case demonstrates the importance of monitoring yearly vitamin D levels in the patient with Sjögren’s.
Case study: A 56-year-old, white, married, female was followed over 10 years for Sjögren’s. The 25-hydroxyvitamin D levels in 2003 (43 ng/ml) and 2004 (37 ng/ml) were normal. In 2005 her level was less than 4 ng/ml. For over 25 years the patient carried the diagnosis of irritable bowel syndrome (IBS). Subsequent testing included a tissue transglutaminase IgA level of more than 250 U (normal 0 to 30 U), and a small bowel biopsy confirmed the diagnosis of celiac disease. Her clinical symptoms of IBS resolved with the usual dietary modifications for celiac disease.
This case reminds us that the vitamin D level should be checked at least yearly. When low levels are discovered after prior normal levels, it may be a clue to the onset of disorders seen more frequently in Sjögren’s patients, such as celiac disease or primary biliary cirrhosis. It also is a reminder to remain vigilant, especially in Sjögren’s patients, for other autoimmune diseases developing such as hypothyroidism or B12 deficiency.
Michael Holick raised the general awareness of vitamin D insufficiency in 2006(2,3). Over the next decade, vitamin D was touted as a panacea for cardiovascular disease, cancer, diabetes, falls in the elderly, neurologic diseases like multiple sclerosis, and autoimmune diseases. Studies over the last five years have not shown beneficial effects in preventing cardiovascular disease, cancer, or falls in the elderly, but confirmed vitamin D’s role in protecting against osteoporosis.
General information: Vitamin D is unique in being produced by the skin’s exposure to the sun. “Vitamin” is derived from “vital amine” implying something coming from exogenous sources; notmanufactured by our bodies. The increased frequency of vitamin D insufficiency relates partly to success of sunscreens, less outdoor exposure for children playing indoors, the anti-sun exposure skin cancer-melanoma education by dermatology, and something I suspect; with aging, our skin no longer manufactures adequate vitamin D on sun exposure. For years, in the office, I would see retired, elderly white male patients who never learned about sunscreens, never used them, were playing golf three times a week in the summer and looked like red lobsters. They could not have had more sun exposure. Yet, on testing, they had deficient or insufficient vitamin D levels. Learn more about the sun and Sjögren's.
An antimicrobial effect of vitamin D is suggested by the history of tuberculosis (TB) sanatoriums in the early 1900’s, before anti-TB meds existed. Improvement of patients may have been partly due to sun exposure boosting vitamin D levels. An unintended experiment was the failure of a TB sanatorium in Mammoth Cave where, of course, there was no sun exposure.
Coronavirus/ COVID-19, hydroxychloroquine& vitamin D: One of the first controversial ideas that arose as part of the COVID-19 pandemic was the use of hydroxychloroquine(Plaquenil/HCQ) as a treatment for active infection or as a preventive medication. Studies so far have shown no benefit. Instead, many of our rheumatology patients had trouble obtaining their prescribed hydroxychloroquine; scarce due to the increased demand.
The action of hydroxychloroquine has never been clearly identified as a remittive agent or perhaps as an immune modulator like vitamin D. Retrospective analysis of the COVID-19 experience in our rheumatology patients already on hydroxychloroquine will be of interest in finding out if the medication had a role in preventing initial infection or if hydroxychloroquine decreased morbidity and mortality of infected patients.
An article by WebMD, May 18, 2020, reviews reports from different countries around the world of increased morbidity and mortality in patients of all races associated with low vitamin Dlevels. The role of vitamin D in immune modulation is considered. While we do not want our immune system suppressed, failing to react to acute infection, we likewise do not want an over-reactive immune response resulting in hyper-inflammatory manifestations such as cytokine storm, which may harm the patient. Hopefully, vitamin D supplementation will modulate the immune system helping resist infection initially or decreasing the autoimmune induced reactions associated with greater morbidity and mortality.
Vitamin D deficiency is very common in African American blacks and other dark-skinned people. The melanin in the skin acts as a natural sun block. For over twenty years, the majority of black patients seen at the Lynchburg Rheumatology Clinic were found to have low levels of vitamin D. Normal levels of vitamin D, measured by 25-hydroxyvitamin D blood tests, are greater than 30 ng/ml; vitamin insufficiency ranges from 21 to 29 ng/ml; and levels less than 20 ng/ml indicate deficiency of vitamin D. Extremely low levels (less than 10 ng/ml) were often seen in patients with autoimmune disorders like Sjögren’s and lupus. Pharmacogenetics relate to inherited tendency to these extremely low vitamin D levels and to family histories of connective tissue and other autoimmune diseases.
The pandemic has also brought attention to the increased cases, hospitalizations, morbidity, and mortality among African Americans. While representing 13.4% of the U.S. population, Black Americans make up 25% of individuals testing positive for Covid-19 and 39% of fatalities. This has been attributed to many factors such as poverty, decreased access to health care, increased exposure related to employment, housing density, and lower vitamin D levels (5). While these factors merit societal attention and social justice, they will involve long term, slow societal changes, but vitamin D supplementation can be added now for all individuals, as well as African Americans.
Treatment for vitamin D insufficiency: Initial therapy depends on the level of vitamin D and family history (pharmacogenetics). I usually begin with prescription D2—50,000 IU weekly for 12 weeks and repeat the 25-hydroxyvitamin D. Final vitamin D replacement regimens are unpredictable. They must be individualized according to follow-up 25-OH Vitamin D levels.
Some patients may maintain normal levels on 50,000 IU of D2 monthly. The most extreme regimen has been 50,000 IU D2 twice a week and 4000 IU D3 daily. Several of my young patients with lupus were on that regimen.
In hopes of increasing resistance to Covid-19 for anyone not on vitamin D, I recommend 4000 IU D3 daily and a baby aspirin (with respect to hypercoagulable complications reported).
Toxicityfrom vitamin D supplementation is rare. 50,000 IU of prescription D2 daily for 3 months would be required. I saw one patient from a nursing home who accidentally was given this regimen by medication error. Her vitamin D level was 141 ng/ml. However, she felt fine, her serum calcium level was normal (hypercalcemia is the best indicator of toxicity) and subsequent bone density was normal.
Summary: While vitamin D does not appear to be a panacea, it continues with an important role in metabolic bone diseases such as osteomalacia and osteoporosis. The COVID-19 pandemic reemphasizes the importance of vitamin D as an immune modulator, decreasing infectivity of the virus (incidence of cases) and decreasing morbidity and mortality of infected patients, which are disproportionately high in African Americans.
by Jeffrey W. Wilson, M.D.
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