Rheumatology Advance Access originally published online on October 17, 2008
Rheumatology 2009 48(3):210-212; doi:10.1093/rheumatology/ken394
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EDITORIALS |
Vitamin D and autoimmune rheumatic diseases
1Research Laboratories and Clinical Academic Unit of Rheumatology, University of Genova, Genova, Italy
Correspondence to: M. Cutolo, Research Laboratories and Clinical Academic Unit of Rheumatology, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy. E-mail: mcutolo{at}unige.it
Introduction
Vitamin D is classified as a secosteroid in which one of the rings has been broken, in this case by ultraviolet B sunlight, and the main source of vitamin D is de novo synthesis in the skin. Although vitamin D is consumed in food, dietary intake alone is often insufficient, supplying only 20% of the body's requirements.
In recent years, the discovery of the vitamin D receptor (VDR) in the cells of the immune system and the fact that several of these cells produce the vitamin D hormone suggested that it could have immunoregulatory properties.
However, vitamin D insufficiency is emerging as a clinical problem of global proportions and epidemiology has linked vitamin D status with autoimmune disease susceptibility and severity [1].
Therefore, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] the biologically active metabolite of Vitamin D3, not only regulates bone and calcium metabolism but also exerts immunomodulation via the nuclear VDR expressed in antigen-presenting cells and activated T/B cells [2]. In particular, this regulation is mediated through interference with nuclear transcription factors such as NF-AT and NF-
B or by direct interaction with vitamin D responsive elements in the promoter regions of cytokine genes.
The mechanisms of vitamin D immunomodulation
Dendritic cells (DCs) are primary targets for the immunomodulatory activity of 1,25(OH)2D3, as indicated by inhibited DC differentiation and maturation, leading to down-regulated expression of MHC-II, costimulatory molecules (CD40, CD80 and CD86) and decreased production of IL-12. Moreover, 1,25(OH)2D3 enhances IL-10 production and promotes DC apoptosis. Together, these effects of 1,25(OH)2D3 inhibit DC-dependent T-cell activation [2] (Fig. 1).
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In particular, the active synthesis of 1,25(OH)2D3 seems to exert an autoregulatory function by inhibiting the differentiation of monocyte precursors into immature DCs and the subsequent ability of the immature DCs to undergo terminal differentiation in response to maturation stimuli [3] (Fig. 1).
Tolerogenic DCs induced by a brief treatment with 1,25(OH)2D3 or its analogues can induce CD4+CD25+ T regulatory (Treg) cells that are able to mediate transplantation tolerance and arrest the development of autoimmunity (i.e. autoimmune diabetes) [4].
Tolerogenic DCs may not always be necessarily involved in the generation of Treg cells by VDR agonists, however, and a combination of 1,25(OH)2D3 and dexamethasone has been shown to induce naïve CD4+ T cells (Th0) to differentiate in vitro into IL-10-producing Treg cells, even in the absence of antigen-presenting cells [4] (Fig. 1).
VDR agonists not only favour induction of CD4+CD25+ Treg cells and enhance their suppressive activity, but can also promote their recruitment at inflammatory sites. Furthermore, 1,25(OH)2D3 treatments induced natural killer (NK) T-cell functions in vitro and in vivo [5] (Fig. 1).
NKT cells are early innate regulatory cells that can alter the outcome of autoimmunity. Therefore, two types of cells are induced by 1,25(OH)2D3, the Treg and the NKT cells; induction of these regulatory cells and direct inhibition of Th1 cells are the mechanisms by which 1,25(OH)2D3 suppresses experimental autoimmunity [5].
In addition, treatment with VDR agonists inhibits the T-cell production of IL-17, a pro-inflammatory cytokine that is produced by pathogenic T cells (Th17) in various models of organ-specific autoimmunity in the brain, heart, synovium and intestines [6] (Fig. 1).
Interestingly, IL-17 production is sustained by IL-23, an IL-12 family member consisting of p19 and p40 chains, the latter of which is strongly inhibited by VDR agonists [6].
Recently, 1,25(OH)2D3 treatment induced a significant inhibition of normal lymphoid cell progenitors growth of both T and B lineage and inhibited significantly also the growth of malignant B-cell lineage lymphoid progenitors, without inducing cytotoxic effect [7].
More recently, by testing the effects of 1,25(OH)2D3 on B-cell responses, it was found that it inhibited the ongoing proliferation of activated B cells and induced their apoptosis, whereas initial cell division was unimpeded [8] (Fig. 1).
The generation of plasma cells and post-switch memory B cells was significantly inhibited by 1,25(OH)2D3 although the up-regulation of genetic programmes involved in B-cell differentiation was only modestly affected. B cells expressed mRNAs for proteins involved in vitamin D activity, including 1
-hydroxylase, 24-hydroxylase and the VDR, each of which was regulated by 1,25(OH)2D3 and/or activation. Interestingly, 1,25(OH)2D3 up-regulated the expression of p27, but not of p18 and p21, which may be important in regulating the proliferation of activated B cells and their subsequent differentiation in plasma cells [8].
Vitamin D and autoimmune rheumatic diseases
The net effect of the vitamin D endocrine system on the immune response is an enhancement of innate immunity coupled with multifaceted regulation of adaptive immunity [9].
Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of autoimmune diseases, and clarification of the physiological role of endogenous VDR agonists in the regulation of autoimmune responses will support the pharmacological VDR agonists for use in the clinic. The anti-proliferative, pro-differentiative, immunomodulatory and anti-inflammatory properties of synthetic VDR agonists could be exploited to treat a variety of autoimmune rheumatic diseases, from RA to SLE, and possibly also multiple sclerosis, type 1 diabetes or IBDs [9].
Low serum levels of vitamin D3 might be partially related, among other factors, to prolonged daily darkness (reduced activation of the pre-vitamin D by the ultraviolet B sunlight), different genetic background (i.e. vitamin D receptor polymorphism) and nutritional factors, and explain to the latitute-related prevalence of autoimmune diseases such as RA, by considering the potential immunosuppressive roles of vitamin D [10]. Treatment of vitamin D deficiency could be particularly important in SLE patients due to concomitant insults on their tissues such as bone, and in view of the discovered immunomodulatory effects exerted by vitamin D [11].
RA
Regarding RA, a recent study evaluated the association of dietary and supplemental vitamin D intake with RA incidence [12]. Through 11 yrs of follow-up, 152 cases of RA were validated against medical records. Greater intake (highest versus lowest tertile) of vitamin D was inversely associated with risk of RA (P for trend = 0.05). Inverse associations were apparent for both dietary (P for trend = 0.16) and supplemental (P for trend = 0.03) vitamin D. No individual food item, high in vitamin D content and/or calcium was strongly associated with RA risk, but a composite measure of milk products was suggestive of an inverse association with risk of RA (P for trend = 0.06). In conclusion, greater intake of vitamin D may be associated with a lower risk of RA in older women, although this finding is hypothesis-generating [12].
An older study in 19 RA patients evaluated the effects of oral -calcidiol 2 µg/day added to regular drug regimen [13].
After 3 months, high-dose oral -calcidiol therapy showed a positive effect on disease activity in 89% of the patients (45% or nine patients with complete remission and 44% or eight patients with a satisfactory effect). Only two patients (11%) showed no improvement, but no new symptoms occurred. No side-effects were observed. These results suggest that -calcidiol is a powerful immunomodulatory agent with fairly low hypercalcaemic activity. Clinical improvement was strongly correlated with the immunomodulating potential of this agent; in fact, dual effects on lymphocyte proliferation and apoptosis according to the prior cell activation state were observed. -Calcidiol could therefore possibly be used as an adjunct therapy with DMARDs in patients with active RA [13].
Therefore, greater intake of vitamin D has been associated with a lower risk of RA but low serum vitamin D together with higher prevalence of RA seem common among North European people when compared with Southern Europe. A recent study evaluated serum 25(OH)D levels in female RA patients from North (Estonia) and South (Italy) Europe and to correlate them with the disease activity score (DAS28) during winter and summer [14].
The 25(OH)D levels were found significantly higher in south vs north (P = 0.0116) both in winter and in summer time. Differences were observed also in controls. The variations (increase) of 25(OH)D levels between winter and summer were found to be significant (P = 0.0005) in both south and north. Differences were also observed in controls. No significant differences were found concerning 25(OH)D levels between RA patients and their controls in either country. Interestingly, a significant negative correlation between 25(OH)D and DAS28 was found in summer only in south (r = –0.57, P < 0.0001) and in winter in north (r = –0.40, P < 0.05). In conclusion, significantly lower 25(OH)D serum levels were observed in RA patients from north vs south Europe with a circannual rhythm in winter and summer time. In addition, 25(OH)D values showed a significant correlation (negative) with RA clinical status (DAS28) in both North and South European RA patients, suggesting possible effects of vitamin D among other factors on disease activity [14].
More recently, it was investigated if serum vitamin D metabolites may be inversely associated with current disease activity, severity and functional disability in patients with early RA [15].
At baseline, there was an inverse relationship between 25(OH)D levels and the tender joint count, DAS28 score and HAQ score. The only inverse relationship with 1,25(OH)2D3 was with the HAQ score. Each 10-ng/ml increase in the level of 25(OH)D was associated with a decrease in the DAS28 score of 0.3 and in the CRP level of 
25%. At 1 yr, the only significant result was an inverse association between baseline vitamin D metabolite levels and the HAQ score; that is, those with higher metabolite levels had lower HAQ scores. These data provide further support that vitamin D plays an immunomodulatory role in inflammatory arthritis and, if confirmed, the vitamin D supplementation should be also examined in early RA [15].
SLE
A number of recent studies have highlighted the association between SLE and vitamin D deficiency. Vitamin D deficiency skews the immunological response towards loss of tolerance. Adding vitamin D in vitro reverses immunological abnormalities characteristic of SLE.
Serum 25(OH)D levels between recently diagnosed SLE cases and matched controls, as well as disease characteristics in relationship to 25(OH)D among cases, were recently studied [16].
Data from a population-based cohort of 123 recently diagnosed SLE patients and 240 controls were used. A trend towards lower 25(OH)D levels in SLE cases compared with controls, which was statistically significant in Caucasians (P = 0.04), controlling for age, sex, season and smoking was detected. Overall, 67% of the subjects were vitamin D deficient, with mean levels significantly lower among African Americans (15.9 ng/ml) compared with Caucasians (31.3 ng/ml). Critically low vitamin D levels (<10 ng/ml) were found in 22 of the SLE cases, with the presence of renal disease being the strongest predictor [odds ratio (OR) 13.3, P < 0.01] followed by photosensitivity (OR 12.9, P < 0.01). These results further suggest vitamin D deficiency as a possible risk factor for SLE and provide guidance for future investigations looking at a potential role of vitamin D in the prevention and/or treatment of SLE [16].
Recently, serum levels of 25(OH)D were measured in 37 female SLE patients and correlated with clinical and immunological measures [17].
Approximately 65% of the SLE patients had values <80 nmol, which is accepted as the lower limit of vitamin D adequacy. In addition, 20% of the patients had levels of 25(OH)D that were lower than the normal range for the assay (<47.7 nmol/l). The group of SLE patients with these lowest levels showed disease activity measures, including global assessment scores, that were higher than in those with levels considered normal in the assay (P 
0.003). However, in this study, levels of autoantibodies including dsDNA were higher in the group with levels of vitamin D that were >47.7 nmol/l (P = 0.0069) [17].
The increased disease symptoms present in SLE patients with very low levels of vitamin D suggest a role for supplementation with exogenous vitamin D to optimize therapeutic outcomes. However, the possibility that such treatment could lead to increased autoantibody levels requires further study.
In a further study in 92 SLE patients (90% women, 98% white) 69 (75%) and 14 (15%) patients presented with vitamin D insufficiency and deficiency, respectively [18].
Female sex (P = 0.001), treatment with HCQ (P = 0.014) and treatment with calcium and vitamin D (P = 0.049) predicted higher levels of 25(OH)D. Photosensitivity (OR 3.5) and photoprotection (OR 5.7) predicted vitamin D insufficiency and deficiency, respectively. Higher age (OR 0.95) and HCQ use (OR 0.29) protected against vitamin D deficiency. Patients with vitamin D deficiency had a higher degree of fatigue as quantified by a 0–10 VAS (mean 5.32 vs 4.03, P = 0.08). No relation was seen between vitamin D insufficiency or deficiency and disease duration. This recent study further showed that vitamin D insufficiency and deficiency are common in patients with SLE and are associated with sun avoidance. Vitamin D deficiency was related to a higher degree of fatigue, but vitamin D levels had no significant relation with SLE severity [18].
Conclusions
The vitamin D endocrine system is recognized as an important immune modulatory factor involved in autoimmune rheumatic diseases.
VDR agonists seem primarily to inhibit DC differentiation, pathogenic pro-inflammatory T cells such as Th1 and Th17 cells and, under appropriate conditions, they seem to favour a deviation to the Th2 pathway.
These immunomodulatory and anti-inflammatory activities might be particularly efficient in RA patients and support a therapeutic role of 1,25(OH)2D3 in such a disease.
In addition, vitamin D may play an important role in the maintenance of B-cell homeostasis, and the correction of vitamin D deficiency may be useful in the treatment of B cell-mediated autoimmune rheumatic disorders such as SLE.
Disclosure statement: The author has declared no conflicts of interest.
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