Course Authors
Anna Broder, M.D., and Peter Barland, M.D.
Dr. Broder is Senior Fellow and Dr. Barland is Professor of Medicine (Emeritus), Albert Einstein College of Medicine, Bronx, NY.
Within the past 12 months, Drs. Broder and Barland report no commercial conflicts of interest;
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Discuss vitamin D metabolism and define vitamin D deficiency
List the experimental evidence that vitamin D effects the immune system
Review critically the evidence that vitamin D deficiency plays a role in the pathogenesis of rheumatologic and non-rheumatologic autoimmune diseases.
In recent years the role of vitamin D in immune diseases has become an area of great interest because of basic science discoveries of a diverse range of actions of vitamin D on cell differentiation, cell growth, and immunomodulation. Recently, researchers have focused on the role of vitamin D deficiency or resistance to vitamin D in the pathogenesis of autoimmune rheumatologic diseases with the potential for using vitamin D as therapy. This Cyberounds® explores the basis for this interest.
Vitamin D and Calcium Homeostasis
Vitamin D plays an important role in calcium homeostasis and bone metabolism. The major source of pre-vitamin D is conversion in the skin of 7-dehydrocholesterol, a cholesterol derivative, to pre-vitamin D by UVB light. Pre-vitamin D is a pro-hormone, which gets rapidly converted into vitamin D3. Vitamin D3 is metabolized in the liver to 25-hydroxy vitamin D. 25-hydroxy vitamin D, 25(OH)D, is the most stable form of the vitamin D, and it is the form of the vitamin usually measured in serum to evaluate vitamin D status.
However, 25-hydroxy vitamin D is biologically inactive and gets further metabolized by the kidneys into 1, 25-dihydroxy vitamin D, the most active form of vitamin D . This last step is regulated by plasma parathyroid hormone (PTH) levels, serum calcium levels and fibroblast growth factor 23.
It is 1,25-dihydroxy vitamin D that increases intestinal and renal absorption of calcium. It also promotes expression of the receptor activator of nuclear factor-κB ligand (RANKL) osteoblasts. RANKL kbinds to RANK, its receptor on preosteoclasts, and induces their maturation into osetoclasts.(1)(2)
Increased levels of vitamin D hormone downregulate PTH production by suppressing the parathormone gene and by decreasing proliferation of parathyroid gland cells. This vitamin D hormone acts by activating its cellular receptor, vitamin D receptor (VDR), which alters the transcription rates of target genes responsible for its biological functions. The VDR gene, discovered on chromosome 12, has several allelic variants with substantial variations among different ethnic groups. The expression of the different VDR alleles is thought to be associated with differences in bone density, in predisposition to hyperparathyroidism, and in resistance to vitamin D therapy. (1)(4)
Vitamin Deficiency
Vitamin D deficiency is defined as a serum 25-hydroxyvitamin D level of less than 20 ng per milliliter, and vitamin D insufficiency is defined as a 25-hydroxyvitamin D level between 21 and 30 ng per milliliter. Based on several epidemiologic studies, an estimated 1 billion people around the world have vitamin D deficiency or insufficiency. Several groups have been identified to be at a higher risk for vitamin D deficiency including the elderly in the US and Europe, post-menopausal women, children and adolescents, dark-skinned individuals who live in the Northern hemisphere, and people in the countries where most of the skin is covered because of cultural norms.(2)
Patients with very low vitamin D levels often complain of diffuse generalized pain that can be reproduced on physical examination by applying light pressure to the chest or shins. These patients are often misdiagnosed as having fibromyalgia, myositis or polymyalgia rheumatica. The exact cause of the aching sensation is unknown, but it is thought to be from the edema of the osteoid tissue on the periosteal surface of the skeleton that is innervated with nocioceptors.(35)
The Role of Vitamin D Cellular Components of the Immune System
Vitamin D receptor has been identified on various cells of the immune system including dendritic cells, mononuclear cells, antigen presenting cell and activated B and T lymphocytes.(5) In vitro, addition of vitamin D was shown to decrease antibody production and secretion by B lymphocytes.(6) It also has been shown to inhibit the differentiation of monocytes into immature dendritic cells. Vitamin D also plays a role in dendritic cell maturation and survival by maintaining the immature dendritic cell phonotype and by promoting the spontaneous apoptosis of mature dendritic cells.(7)
Activated macrophages and dendritic cells contain the enzyme 1 α-hydroxylase, the same enzyme that is found in the kidney, which facilitates conversion of 25-hydroxy vitamin D into 1, 25-dihidroxy vitamin D. Unlike the renal enzyme, the level of enzyme activity in the immune cells is regulated by the immune signals such as IFNγ.(8) It has been demonstrated that activated CD4+ T cells have a five-fold increase in expression of VDRs compared to inactivated CD4+ T cells.
Vitamin D hormone functions by stimulating Th-2 cells to produce the cytokines transforming growth factor-γ 1 and IL-4 which suppress TNF-α and IFN production by Th-1 cells, ultimately decreasing Th-1 cell proliferation.(9) Vitamin D also increases production of IL-5 and IL-10 leading to increased proliferation of Th2 cells. Vitamin D inhibits production of the proinflammatory cytokine, IL-6, which stimulates the differentiation of Th17 cells that play an important role in autoimmunity.(10)
Vitamin D and Non-rheumatologic Autoimmune Diseases
Some of the evidence supporting a relationship between vitamin D deficiency and autoimmune diseases comes from epidemiological and observational studies. Multiple sclerosis and inflammatory bowel disease are more prevalent in areas with decreased sun exposure. The prevalence of multiple sclerosis increases with increasing latitude in both hemispheres.(11) A study of bone metabolism in patients with multiple sclerosis demonstrated low serum levels of 25(OH)D in 77% of patients.(12)
Similarly, newly diagnosed patients with inflammatory bowel disease were shown to have lower levels of vitamin D compared to healthy controls.(13) In an experimental animal model of inflammatory bowel disease, the disease has been shown to be accelerated by vitamin D deficiency and suppressed by 1,25(OH)2D treatment.(14) In murine experimental autoimmune encephalitis, an animal model of multiple sclerosis, administration of vitamin D prevented the induction of the disease. Vitamin D also reversed the signs of experimental autoimmune encephalitis in mice with established disease.(15)
Vitamin D in Rheumatic Autoimmune Diseases
Systemic Lupus Erythematosus (SLE)
Vitamin D deficiency in association with SLE has been a subject of great interest in rheumatology. Several studies from the US, Europe and China demonstrated that patients with SLE have lower levels of vitamin D compared with healthy controls and rheumatoid arthritis patients.(16)(17)(18)(33) In a population-based cohort of 123 newly diagnosed SLE patients and 240 controls, 67% of SLE patients were vitamin D deficient. Vitamin D levels were significantly lower among African-Americans compared to caucasians.
Interestingly, in the US, African-Americans have a higher incidence of SLE associated with increased morbidity and mortality. While vitamin D levels were statistically significantly lower among caucasian patients with SLE compared with the population-based caucasian controls, the levels of vitamin D were not significantly different in African-American patients with SLE compared with the population-based African-American controls. The presence of renal disease and photosensitivity were the strongest predictors of vitamin D deficiency in the lupus patients, which suggests that vitamin D deficiency could be a consequence of the disease and not a cause.(16) In addition, most of these patients are receiving steroid treatment that could alter vitamin D metabolism.
When 25 patients with SLE were compared with 25 patients with fibromyalgia in a study from Canada, no statistically significant differences were found between vitamin D levels. In both groups about half of the patients were vitamin D deficient.(19)
Several cross-sectional studies have explored the relationship between vitamin D deficiency and disease activity in SLE with contradictory results. In a recent study from Spain of 92 patients with SLE, 75% had vitamin D insufficiency and 15% had vitamin D deficiency. No association was found between vitamin D levels and disease activity or severity measured by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC-ACR) index. However, in this study, vitamin D deficiency was associated with a higher degree of fatigue measured by a visual analog scale.(20) Similar results were demonstrated in some earlier studies. Other large studies showed an association between vitamin D deficiency and higher disease activity measured by SLEDAI and European Consensus Lupus Activity Measurement (ECLAM) scores was noted in European patients.(21)(22)
There are some experimental data suggesting that vitamin D replacement may have beneficial effects on SLE activity. In one study, administration of vitamin D to MRL/lpr mice, a murine model of SLE, resulted in improvement in dermatologic manifestations but had no effect on renal disease; however, in another study, improvement in proteinuria and survival were observed.(8) To date, there are no prospective or randomized studies to evaluate the effect of vitamin D supplementation on the course of human SLE.
Several small studies from Asia examined a potential link between VDR polymorphisms and susceptibility to SLE with mixed results. Large studies are needed to determine if VDR polymorphisms are linked with disease susceptibility or severity and whether specific VDR polymorphisms are predictive of a better response to vitamin D supplementation.(23)
Rheumatoid Arthritis (RA)
Similar to other autoimmune diseases, RA is more prevalent in Northern Europe where vitamin D deficiency is also more prevalent. In Finland prevalence of RA is 0.8% of the population compared with 0.3% in Italy.(24)
The VDR has been demonstrated in macrophages, chondrocytes and synoviocytes in rheumatoid synovium and sites of cartilage erosion in RA patients, but not in the corresponding tissues from control subjects.(25) When mice with collagen induced arthritis were supplemented with 1,25 dihydroxyvitamin D, the initiation and progression of inflammatory arthritis was prevented.(26)
A large epidemiological study involving >180,000 women from the Nurses' Health Study did not find any association between vitamin D intake and the risk of developing either SLE or RA. In the Iowa Women's Health Study of over 29,000 healthy women ages between 55- and 69-years old, borderline significant association was found between increased intake of vitamin D and decreased risk for developing RA. However, this study collected vitamin D information based on self-reported dietary intake without taking sun exposure into consideration.(28) When vitamin D levels were measured in patients who later developed RA, no significant differences were found compared with healthy controls.(29)
One small uncontrolled open-label study from the former Yugoslavia in patients with established RA demonstrated reduction in disease activity with 1,25(OH)2D supplementation. In that study, 19 patients treated for RA with DMARDs were treated for three months with a vitamin D analog, alphacalcidiol (not available in the US), 2 micrograms per day. According to this study, 9 patients (45%) were in complete remission and 44% showed substantial improvement in symptoms after three months of treatment. Two patients (11%) did not show improvement, but they did not get worse. There were no side effects reported in that study.(27)
Vitamin D in Other Rheumatologic Autoimmune Diseases
The term 'undifferentiated connective tissue disease' (UCTD) has been used to describe a constellation of inflammatory and rheumatic signs and symptoms that don't meet criteria for any of the established autoimmune connective tissue diseases. Patients with UCTD may present with polyarthritis, rash, sicca symptoms, Raynaud's phenomenon or serositis. After several years of follow-up, about 30% to 40% of patients with UCTD progress to a defined connective tissue disease including SLE, systemic sclerosis, RA, Sjogren's syndrome or systemic vasculitis. One study reported that patients with UCTD had lower levels of vitamin D compared with healthy controls. In addition patients who progressed to a known connective tissue disease over the follow up period of two years had significantly lower levels of vitamin D compared with patients with UCTD who did not progress to a known connective tissue disease.(30)
In a small case series, six of seven children with linear scleroderma treated with calcitriol, the active form of vitamin D, demonstrated significant improvement.(31) Calcitriol in combination with UVA therapy has been used in patients with morphea.(34)
Topical vitamin D analogs in combination with betamethasone are the first line therapy for plaque psoriasis.(32) Based on our review of the dermatologic literature, oral vitamin D analogs are not widely used for treating psoriasis, and there are no recent studies evaluating oral vitamin D supplementation in psoriasis.
Future Vitamin D Studies
There is much experimental evidence that vitamin D is a potent immunomodulator. However, the evidence from the epidemiologic studies in human subjects is not as robust. While the studies reviewed herein provide useful information about the prevalence of vitamin D deficiency in autoimmune diseases, they do not address the causal relationships between the vitamin D deficiency and the disease in question or the etiology of vitamin D deficiency. For example, vitamin D levels could be a measure of UV light exposure, overall nutritional status or a measure of general health, all of which could be altered by the presence of a chronic debilitating disease. Prospective cohort studies are needed to determine if there is a causal relationship between vitamin D deficiency and development of autoimmune diseases. Randomized trials are needed to determine if vitamin D replacement can improve outcomes in autoimmune diseases.
Based on our review of the literature, we do not feel that there is enough evidence to conclude that vitamin D supplementation can be considered as accepted treatment of autoimmune disease, though maintenance of normal levels is probably indicated to maintain good bone health. Vitamin D supplementation is safe and inexpensive and, given potential benefits, deserves further study.
The amount of vitamin D required to modulate the immune response may be different from the amount required to maintain calcium homeostasis. There may be a higher vitamin D requirement for patients at risk for developing autoimmune diseases and for patients who already have an autoimmune disease.(34) Interestingly, the only two studies that showed a significant improvement in symptoms in patients with rheumatoid arthritis and linear scleroderma used the active form of vitamin D, calcitriol (or its analog), to treat the study patients. This may represent a real treatment effect or a publication bias. Further studies are needed to determine the optimal vitamin D levels and the best way to supplement vitamin D in patients with autoimmune diseases with either the active or the inactive form of vitamin D. Alternatively, VDR receptor agonists other than vitamin D may become potential novel treatments in autoimmune diseases.