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Keywords:

  • disease modifying agent;
  • immunomodulatory;
  • rheumatoid arthritis;
  • supplementation;
  • 1,25 dihydroxy vitamin D3

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXISTING EVIDENCE FOR THE POSSIBLE ROLE OF 1,25 DIHYDROXY VITAMIN D3 IN AUTOIMMUNE DISEASES
  5. CONCLUSION
  6. REFERENCES

Rheumatoid arthritis predisposes to osteoporosis and most physicians supplement calcium and 1,25 dihydroxy vitamin D3 along with the standard treatment with disease modifying drugs. Advances in the understanding of physiological actions of 1,25 dihydroxy vitamin D3 suggest that this molecule plays an important role in modulating the immune response of the body. Vitamin D receptor has been found in many cells of the immune system including promyelocytes, myelocytes and macrophages. Experiments in animal models of rheumatoid arthritis have shown amelioration of the disease after administration of 1,25 dihydroxy vitamin D3. This article reviews the available data regarding the role of 1,25 dihydoxy vitamin D3 in rheumatoid arthritis.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXISTING EVIDENCE FOR THE POSSIBLE ROLE OF 1,25 DIHYDROXY VITAMIN D3 IN AUTOIMMUNE DISEASES
  5. CONCLUSION
  6. REFERENCES

Rheumatoid arthritis (RA) affects about 0.5–1% of the population.1 The standard treatment of RA includes combination disease-modifying anti-rheumatic drugs (DMARDs) initially and tapering of these later in the course of the disease after achieving remission, or an escalation approach if there is no clinical improvement.2 The recent trend in the West includes a change-over to immunological agents like infliximab, rituximab or etanercept along with methotrexate as combination therapy. The cost of these biologic agents is prohibitive and is presently out of reach for most of the global population. The need of the day is cost-effective interventions to improve disease outcome.

Rheumatoid arthritis is known to predispose to osteoporosis and most physicians prescribe supplementary calcium and vitamin D. Recent advances in the understanding of physiological actions of vitamin D suggest that there may be other actions of this vitamin including immunomodulatory action.

This review article explores the existing data available which supports the potential of 1,25-dihydroxy vitamin D3 being considered for use as a disease-modifying agent in RA.

Traditional functions of vitamin D

1,25-dihydroxy vitamin D3 is a principal component of the calcium metabolism of the body. Cholecalciferol can be obtained by converting 7-dehydrocholestrol in the skin to cholecalciferol or by absorption from the diet. Cholecalciferol undergoes conversion to 25-hydroxy vitamin D3 by the liver and to 1,25 dihydroxy vitamin D3 (calcitriol) by the kidney. Calcitriol increases the absorption of calcium from the diet and is also involved in the efflux of calcium from the bone. Calcitriol also increases reabsorption of calcium from the renal tubules.

Vitamin D deficiency causes rickets in children and osteomalacia in adults. The levels of 25-hydroxy vitamin D are indicative of the status of storage in the body. The normal range of 25-hydroxy vitamin D is usually taken as between 9 and 36 ng/mL, but this range undermines the pickup of asymptomatic cases of vitamin D deficiency, which would manifest only as a raised parathyroid hormone (PTH) level. Levels of 25-hydroxy vitamin D more than 16 ng/mL are required to keep PTH in the normal range and so this level should be ideally considered as the lower limit of normal.3

Non-traditional functions of 1,25-dihydroxy vitamin D3

The first insight into functions of 1,25-dihydroxy vitamin D3 beyond its actions in the regulation of calcium and phosphorus came as a result of studies involving the cellular and subcellular localization of radio-labelled 1,25-dihydroxy vitamin D3 in the nuclei of the islet cells of the pancreas, keratinocytes of skin, ovarian tissue, mammary epithelium, epididymis, neuronal tissue, promyelocytes, macrophages, and T-lymphocytes.4,5 The widespread distribution of the vitamin D receptor (VDR) in cells of predominantly immune actions raised the hypothesis that there could be a role of 1,25-dihydroxy vitamin D3 in immune modulation. The presence of the VDR in activated T-lymphocytes was reported by Provvedini et al.6 who also showed that resting lymphocytes do not express the VDR. Among the antigen-presenting cells, the macrophage which is derived from the monocyte has receptors for 1,25-dihydroxy vitamin D3.7

Vitamin D receptor has been localized in the fibroblasts, macrophages, lymphocytes and endothelial cells of lesions in patients with RA,8 but the receptor is not expressed by the normal healthy human synovium.8 1,25-dihydroxy vitamin D3 has been hypothesized to increase chondrolysis by interleukin-mediated production of matrix metalloproteinases (MMPs) and this could be one of the triggers for cartilage damage in RA.9

T helper-1 (Th1) cells secrete interferon γ (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factor (TNF). Th1 cell activation is essential for cell-mediated immune responses. In autoimmune diseases, like RA, Th1 cells are directed against self-antigens. Other examples of Th1 cell-driven diseases include multiple sclerosis, type 1 diabetes mellitus, and inflammatory bowel disease.

Quiescent T cells express VDRs in low concentrations, but the expression increases five times after activation.10 1,25-dihydroxy vitamin D3 decreases the production of IFN-γ, IL-2, and IL-5 in Th-1 cells and inhibits Th-1 proliferation.10 1,25-dihydroxy vitamin D3 increases the production of IL-4, is increased in Th-2 cells, which results in an immumosupressive action.10 Th-1 repsonse is blunted by the production of tolerogenic dendtritic cells that increase suppressor T cell action.11 Studies done in murine models with experimental autoimmune encephalomyelitis has shown that Th-1 cell apoptosis is facilitated by 1,25-dihydroxy vitamin D3.12

Effect of VDR polymorphism on RA

The presence of certain VDR genotypes has been associated with low bone mineral density (BMD) in elderly populations as well as with accelerated bone loss in patients with RA. Four VDR gene polymorphisms, namely Fok1, BsmI, ApaI and Taq1 have been studied. Fok1 polymorphism is a restriction fragment length polymorphism in exon II region, BsmI and ApaI polymorphisms are in the intron VIII region, and the Taq1 variant in exon IX region. Fok1 polymorphism is found in a greater frequency in the RA population as compared to controls and it is speculated that this polymorphism may contribute to disease susceptibility but the mechanisms are yet to be elucidated.13 The polymorphisms by themselves alone do not increase susceptibility to RA, but there is a slight predilection to early RA among female patients who have the the BB/tt genotype, defined by the BsmI and TaqI restriction site polymorphisms.14 The BB polymorphism BsmI of VDR gene in RA results in clinically more severe disease as evidenced by higher erythrocyte sedimentation rate (ESR) values, disease activity counts, number of DMARDs used and amount of glucocorticoids taken,15 a higher degree of bone loss and osteoclastic acitivity, a lower bone mineral density score16 and higher titre values of rheumatoid factor16 as compared to patients without the polymorphism.

EXISTING EVIDENCE FOR THE POSSIBLE ROLE OF 1,25 DIHYDROXY VITAMIN D3 IN AUTOIMMUNE DISEASES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXISTING EVIDENCE FOR THE POSSIBLE ROLE OF 1,25 DIHYDROXY VITAMIN D3 IN AUTOIMMUNE DISEASES
  5. CONCLUSION
  6. REFERENCES

Animal models

Rheumatoid arthritis is characterized by infiltration of the synovium with neutrophils, macrophages, T and B cells, and dendritic cells, resulting in subsequent tissue damage. The collagen-induced arthritis model is the most commonly used arthritis model for human RA. In a study done by Cantorna et al.17 two different animal models of arthritis were tested, namely murine Lyme arthritis and collagen-induced arthritis. Infection of mice with Borrelia burgdorferi, the causative agent of human Lyme arthritis, produced acute arthritic lesions, mainly footpad and ankle swelling. Supplementation with dietary 1,25-dihydroxy vitamin D3 to mice infected with B. burgdorferi minimized or prevented arthritis. The symptoms of arthritis induced by type II collagen were prevented by dietary supplementation with 1,25-dihydroxy vitamin D3. 1,25-dihydroxy vitamin D3 given to mice with early symptoms of collagen-induced arthritis prevented the progression to severe disease in comparison to the untreated controls.

This immune modulatory action of 1,25-dihydroxy vitamin D3 is not mediated by increasing serum calcium, because in these experiments, the serum calcium was within normal limits. In established collagen- induced arthritis, 1,25-dihydroxy vitamin D3 produced a rapid improvement. This suggests a direct action on arthritogenic cells. The above experiments show prevention of collagen-induced arthritis and amelioration of symptoms of arthritis in the mouse model by 1,25-dihydroxy vitamin D3.

1,25-dihydroxy vitamin D3 has also been advocated as a therapeutic modality in multiple sclerosis (MS). 1,25-dihydroxy vitamin D3 is postulated to act by decreasing the proliferation of T-lymphocytes and decreasing the production of cytokines, both of which contribute to the pathogenesis of MS. In experimental allergic encephalomyelitis (EAE), the mouse model of MS, treatment with 1,25-dihydroxy vitamin D3 prevented the disease in asymptomatic mice.18 In mice with active EAE, the progression of disease was retarded.19 1,25-dihydroxy vitamin D3 has also been shown to prolong the survival of allogenic transplanted hearts in murine models.20

Supplementation of 1,25-dihydroxy vitamin D3 to interleukin-10 knockout mice, which is an experimental model for inflammatory bowel disease, for 2 weeks, showed amelioration of the disease.21

The animal data presented above shows the amelioration of autoimmunity in animal models by the administration of 1,25-dihydroxy vitamin D3; however, it is worth mentioning that these models are over a decade old and the work has not been replicated independently by other investigators.

Epidemiological studies

The environment in which the immune system encounters the antigen determines whether tolerance, infectious immunity, or autoimmunity results. Geographical areas with low supplies of vitamin D, for example Scandinavia, correlate with higher occurrences of MS, RA and diabetes.22 Autoimmune diseases like MS,23 type 1 diabetes,22 and to a lesser extent, RA24 in the northern hemisphere, particularly in Western Europe and North America, display a latitudinal gradient in disease frequency, with the prevalence of these disorders increasing at higher latitudes. MS exhibits a similar prevalence gradient in the southern hemisphere, but RA does not show any difference in prevalence in studies done in the southern hemisphere.25 Prevalence of RA is higher in Italy as compared to Finland by 0.5% and this has been attributed to a higher latitude, but the interplay of genetic factors cannot be completely ruled out.26 But generally RA, MS and juvenile diabetes are more prevalent in higher latitudes of the northern hemisphere than in the tropics and subtropics where sunlight is abundant and vitamin D deficiency is presumed to be low. Whether these geographical variations in vitamin D status are linked to predilection for autoimmunity is not clear at this point of time. If they are linked, vitamin D deficiency could be a possible explanation for the increased prevalence of autoimmunity in these regions.

Vitamin D levels in patients with RA

The initial work done dates back to 1987 in which Christiansen et al.27 studied 102 patients with RA, divided into three treatment groups, namely those on (i) gold salts, (ii) penicillamine and (iii) glucocorticoids. Blood samples were drawn between November and January and four different metabolites of vitamin D (25-hydroxy vitamin D3, 24,25-dihydroxy vitamin D3, 25,26-dihyrdroxy vitamin D3 and 1,25-dihydroxy vitamin D3) were measured. These values were then compared to values from normal controls. The mean serum concentrations of 25-hydroxy vitamin D in all three patient groups were significantly lower than those of the controls (P-value ranged from < 0.01 to < 0.001). The study concluded that low levels of vitamin D are found in patients with RA and this could be due to less exposure to sunlight caused by immobility. The major drawback of this study was that it used patients undergoing treatment and that there was no control made for sunlight exposure.

In a study done in Finland in 1993 by Kroger et al.28 calcium and vitamin D metabolism was studied in 143 women with RA. Mean age of the study population was 50.7 years and serum calcium was normal. Serum alkaline phosphatase was increased in one-third of cases. In 16% of the patients, serum 25-hydroxy vitamin D levels were low, that is, < 12.5 nmol/L (5 ng/mL), which was arbitrarily considered as the lower limit for vitamin D levels in this study. The lowest values were found in patients with the highest disease activity. This could suggest a negative correlation between disease activity and vitamin D levels.28

In a study done in Iowa29 a prospective cohort of 29 368 normal women of ages 55–69 years were followed up for 11 years from 1986 onwards. Diet was ascertained using a self-administered questionnaire which gathered information on vitamin D intake including information on supplemental 1,25 dihydroxy vitamin D3 intake.

Through 11 years of follow-up, 152 cases (0.5%) of RA were detected from medical records. Greater intake of 1,25-dihydroxy vitamin D3 was inversely associated with risk of RA (relative risk 0.67). The protective effect was found only due to supplementation of 1,25-dihydroxy vitmain D and not by adequate dietary intake alone. The limitations of the study were that the effect of sunlight was not taken into consideration and that pure dietary assessment may not be a good indicator of the status of vitamin D in the body. There was no difference in the baseline serum 25-hydroxy vitamin D levels of patients who developed RA later and those who remained healthy. The conclusion was that supplementation of 1,25-dihydroxy vitamin D3 seemed to protect against RA in older Caucasian women.

The effect of supplementing vitamin D in RA

Andelkovic et al.30 studied the supplementation of vitamin D as 25-hydroxy vitamin D (alpha calcidiol) in 19 patients with RA. The patients were divided into two subgroups based on ESR and the Ritchie arthritis index (RAI), into those with severe disease and those with moderately active RA. The patients with severe disease were on methotrexate and steroids while those with moderately active disease were on methotrexate only. Disease activity was established by articular examination (RAI, Lee index, morning and night pain) and laboratory measurements (ESR, C-reactive protein [CRP], rheumatoid factor [RF]). The criteria for improvement were: (i) complete effect (remission): no swollen or painful joints, no morning stiffness, ESR < 17/h; (ii) satisfactory effect: pain or swelling in eight or fewer joints, morning stiffness < 20 min. ESR < 28 mm/h; and (iii) no effect: same disease activity or new symptoms.

All patients had an observation period of 3 months and then alpha calcidiol was added for another 3 months. There was a significant improvement in disease activity, the number of swollen joints, the ESR and the CRP in 89% of patients (9 had complete remission and 8 had satisfactory effect). No significant side-effects were noticed and the serum calcium levels were seen to be within normal limits for all the patients during the period of the study. The main drawbacks of this study were the small sample size, lack of blinding and lack of controls.

The role of 1,25-dihydroxy vitamin D3 in other autoimmune diseases

1,25-dihydroxy vitamin D3 has been considered as a therapeutic modality in MS. Adequate sunlight exposure in childhood has been found to be protective against the development of MS later in life based on a study done on monozygotic twins and this protective effect was independent of genetic suseptiblility.31 Supplementation of 1,25-dihydroxy vitamin D3 has been found to be protective against MS in adult Caucasian women.32 Low levels of 25-hydroxy vitamin D have been associated with an increased risk for MS in Whites.33 1,25-dihydroxy vitamin D3, when supplemented for 1 year for patients with relapsing and remitting MS decreases the number of relapses.34

Low levels of 25-hydroxy vitamin D have also been found in patients with inflammatory bowel disease.35 1,25-dihydroxycholecalciferol treatment (0.2 µg/day) for 2 weeks blocked the progression and ameliorated symptoms in murine models of inflammatory bowel disease21 and this is probably by inhibiting the TNF-α pathway.36 A recent meta analysis showed that supplementation of 1,25-dihydroxy vitamin D3 in infants reduced the risk of development of type I diabetes later in life.37 1,25-dihydroxy vitamin D3 is being considered as a therapeutic or preventive modality in all these autoimmune diseases, but large-scale randomized controlled trials need to be done before substantial conclusions of benefit can be drawn.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXISTING EVIDENCE FOR THE POSSIBLE ROLE OF 1,25 DIHYDROXY VITAMIN D3 IN AUTOIMMUNE DISEASES
  5. CONCLUSION
  6. REFERENCES

The role of 1,25-dihydroxy vitamin D3 in the immune system seems to be that of an immune suppressor in the setting of an autoimmune disease. The amieloration of autoimmune disease seems to be by the inhibition of Th-1 cells. Murine models done nearly a decade ago have shown that experimental arthritis can be prevented by administration of 1,25-dihydroxy vitamin D3. Supplementation of 1,25-dihydroxy vitamin D3 has been shown to be protective against RA in older Caucasian women. An uncontrolled study on patients with active RA showed a significant decrease in the disease activity scores on addition of alpha calcidiol to methrotrexate with or without steroids.

Take-home message

The evidence presented above suggests that 1,25-dihydroxy vitamin D3 has a definite role in the immune system and this vitamin has the potential to be used as a DMARD. However there are no large-scale trials which have assessed the supplementation of 1,25-dihydroxy vitamin D3 in patients with RA. To prove or disprove this hypothesis, large-scale randomized controlled trials which assess the effect of supplementation of vitamin D in patients with RA need to be done. The parameters that could be assessed are clinical parameters like disease activity scores prior to and after a certain period of therapy, and laboratory parameters like ESR and CRP. The dose of 1,25-dihydroxy vitamin D3 can be varied in the study arms to see if there is a dose–response relationship between disease activity and the drug. As for now, we can only speculate that this versatile molecule may one day turn out to be a part of the standard treatment of RA.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXISTING EVIDENCE FOR THE POSSIBLE ROLE OF 1,25 DIHYDROXY VITAMIN D3 IN AUTOIMMUNE DISEASES
  5. CONCLUSION
  6. REFERENCES