systemic lupus erythematosus ( sle ) is an autoimmune disease with wide - ranging clinical manifestations and the potential to affect multiple organ systems in the body .
healthy immune responses help prevent or overcome harmful antigens and infections but immune dysfunction with loss of self - tolerance can lead to autoimmunity with self - antigens becoming the target of immune attack .
patients with sle develop t and b cell - mediated autoimmune responses manifested by the production of autoantibodies . the actual mechanism of autoimmunity , and factors that contribute the progression to clinical autoimmune disease ,
vitamin d deficiency has been implicated as one of the environmental factors contributing to the prevalence of several autoimmune diseases , including sle .
vitamin d is an essential steroid hormone with well - established effects on mineral metabolism , skeletal health , and more recently described effects on cardiovascular and immune health .
it has become recently apparent that vitamin d deficiency contributes to the morbidity and mortality of multiple chronic diseases .
lifestyle factors have led to an increased prevalence of vitamin d deficiency in the general population , while improved availability and reliability of the serum 25-hydroxyvitamin d [ 25(oh)d ] test have led to better awareness of the widespread deficiency . because patients with sle are advised to avoid direct sunlight , a common trigger of disease flares but also the primary source of vitamin d3
, the risk of vitamin d deficiency is even higher among sle patients than in the general population . without oral supplementation ,
the primary source of vitamin d3 ( cholecalciferol ) is the skin upon exposure to ultraviolet - b radiation ( uvb ) .
vitamin d2 ( ergocalciferol ) from dietary sources is typically a minor contributor to overall vitamin d status .
interestingly , solar radiation , particularly uvb ( 280315 nm ) , is a risk factor for sle and sle - related mortality .
one study found over 90% of patients with sle exposed to uv radiation had an abnormal reaction .
the importance of vitamin d in immune regulation has gained increased interest over the past decade with the discovery of the vitamin d receptor ( vdr ) being expressed by cells of the immune system and manipulation of 1,25-dihydroxyvitamin d [ 1,25(oh)2d ] having downstream immune effects .
the effects of 1,25(oh)2d are mediated by complex nuclear receptor and the binding of the activated complex to regulatory dna sequences of target genes .
the vdr gene is a direct target of its own receptor , thus facilitating an upregulation of the vdr protein in certain target tissues .
several hundred vitamin d - regulated genes have been identified , including multiple genes involved with the innate and adaptive immune system .
the overall immunologic effects of 1,25(oh)2d include downregulating th1 immune responses , modulating the differentiation of dendritic cells ( dcs ) , and lowering proliferation of activated b cells , while upregulating regulatory t cells and preserving innate immune responses .
each of the immune pathways influenced by 1,25(oh)2d has profound potential implications for patients with sle . in general , 1,25(oh)2d promotes the development of dcs with tolerogenic properties .
1,25(oh)2d inhibits dc il12 production and secondarily limits the development of th1 helper cells shifting to a th2 phenotype .
interferon  ( ifn ) , primarily produced by activated plasmacytoid dcs , plays a key role in sle , with activation of the ifn pathway being associated with increased anti - dsdna antibodies and increased disease activity among patients with sle . in vitro and ex vivo studies have shown the ability of 1,25(oh)2d to inhibit dc maturation and the  ifn signature  typical of active sle .
vitamin d deficiency also contributes to b - cell hyper - activation and autoantibody production in genetically susceptible individuals .
linker - israeli et al . showed that 1,25(oh)2d and its analogs inhibit polyclonal and anti - dsdna igg production by stimulated peripheral blood mononuclear cells from patients with sle .
compared 32 female patients with sle to 32 healthy matched controls and found 25(oh)d deficiency to be associated with antinuclear antibody ( ana ) positivity among controls and with increased b cell activation among patients .
additional immune modulating actions of 1,25(oh)2d of importance in suppressing autoimmunity include increasing treg cells , decreasing autoantibody production , suppressing the release of inflammatory mediators and the potential reestablishment of immune tolerance .
vitamin d deficiency is a global health problem being detected at all ages , particularly among populations with darker skin pigmentation living further from the equator .
african americans have a 3-fold increased prevalence of sle , develop sle at an earlier age , and have increased sle - related morbidity and mortality compared with caucasians .
it is notable that the same ethnic disparities seen in the prevalence of vitamin d deficiency are seen in the prevalence of sle .
multiple studies have shown that the majority of patients with sle have insufficient levels of 25(oh)d , especially among african american and hispanic patients with sle . to examine whether vitamin d deficiency is a potential environmental trigger of sle ,
nurses health study ii prospective analysis of over 180,000 women followed for up to 22 y found no significant evidence of association between dietary vitamin d intake and subsequent development of sle .
there were limitations which include use of self - reported exposure data without serum 25(oh)d measurements , observational study design and applicability of results to caucasian female populations only .
there was also limited power to detect a small effect of vitamin d intake on sle development and the confidence intervals were relatively wide ( 0.51.4 ) . in the population - based carolina lupus inception - cohort study
it was noted that lower 25(oh)d levels were found in 123 cases with newly diagnosed sle compared with 240 controls , which was statistically significant in caucasians ( p = 0.04 ) , controlling for age , sex , season and smoking .
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 .
these baseline results within an inception - cohort of sle suggest vitamin d deficiency as a possible risk factor for the development of sle .
many , but not all , studies of 25(oh)d among patients with established sle have shown an association of 25(oh)d deficiency with increased sle disease activity .
a summary of the studies which have examined the relationship between sle and vitamin d status is presented in table 1 .
patients with sle have a higher risk for osteoporosis and fragility fractures , compared with age - matched controls .
the increased osteoporosis and fracture risk among young patients with sle is attributed to systemic inflammation , frequent corticosteroids use , and more recently the high prevalence of vitamin d deficiency .
low levels of 25(oh)d results in the calcium reserves in bone being depleted in an attempt to correct for the reduced calcium that will be absorbed from the gut . as
the reduction in intestinal calcium absorption associated with low levels of 25(oh)d triggers the release of parathyroid hormone ( pth ) , which stimulates the absorption of calcium through increased production of 1,25(oh)2d .
pth also mediates the mobilization of calcium from bone by stimulating bone resorption , which results in a reduction in bone mineral density .
vitamin d deficiency is one of several osteoporosis risk factors common among patients with sle , including high disease activity , renal disease , corticosteroid use , and premature ovarian failure from cytotoxic medications such as cyclophosphamide .
since most patients with sle have multiple disease - associated and traditional osteoporosis risk factors , bone mineral density loss tends to run a rapid course , making vitamin d status even more important .
sle is associated with higher incidence of cardiovascular problems at a younger age . a leading cause of morbidity and mortality in women with sle , including those who are premenopausal , is cvd .
patients with sle have an increased incidence of myocardial infarction up to 5 times that of the general population , with an age - specific incidence in young women up to 50 times higher .
there is evidence to show that , like diabetes , sle itself is an independent risk factor for the development of atherosclerosis . the excess cardiovascular risk , which may be up to 52 times in sle , is not explained by traditional cardiovascular risk factors .
excess mortality in sle follows a bimodal pattern , with the early peak predominantly a consequence of active sle or its complications , and the later peak largely attributable to atherosclerosis .
patients with sle are also at increased risk of nonfatal ischemic heart disease . as overall survival for patients with sle
improves with better , more targeted , immune suppression therapies , the prevention of morbidity and mortality from atherosclerosis becomes an increasingly critical need .
vascular stiffness can be partly driven by inflammation , and better disease control in patients with inflammatory arthritis results in a reduction in pulse wave velocity ( pwv ) noted that inflammatory biomarkers in sle were particularly associated with aortic pwv . in study by reynolds et al . , the association between 25(oh)d and stiffness was at least in part accounted for by disease activity since in a regression model that includes sledai score the association was no longer significant .
the results suggest that the association between 25(oh)d and disease activity is strongest in those patients with the most active disease / lowest vitamin d. vitamin d deficiency may therefore augment the inflammatory response in sle , underpinning both increased disease activity and vascular stiffness . a recent study by zhao et al .
, has shown that concentrations of 25(oh)d were inversely associated with all - cause and cvd mortality among adults with hypertension in the united states . due to the high prevalence of vitamin d deficiency seen worldwide and the conditions associated with deficiency , we recommend all patients at risk for sle or with established disease be screened for vitamin d deficiency .
the only lab test usually required to ascertain the patient s status is the 25(oh)d level .
ideal  level of 25(oh)d for the general population and in subpopulations with certain health conditions such as sle .
as our knowledge expands , we may find out that higher thresholds are needed for optimal health , however at this time the minimally adequate level of 25(oh)d is 30 ng / ml .
achieving sufficient levels of vitamin d is a particularly complex issue for patients with sle because they are told to avoid the sun , the primary source of vitamin d. there is good evidence that even 
sensible  sun exposure of 1 minimal erythema dose daily could trigger a disease flare .
for that reason , there will be an even greater dependence on adequate dietary vitamin d intake . unlike other vitamins , currently very little of our daily vitamin d comes from food .
many experts are recommending increased vitamin d fortification of common foods to help counteract widespread deficiency .
but for now , oral vitamin d supplementation is needed for most , if not all , patients with sle .
oral vitamin d supplementation is recommended in the form of vitamin d3 ( cholecalciferol ) rather than d2 ( ergocalciferol ) .
vitamin d3 is preferred over vitamin d3 due to vitamin d2 being less efficacious in raising serum 25(oh)d , having diminished metabolite binding to vitamin d binding protein ( dbp ) and a shorter shelf life .
the dose of oral vitamin d3 required to achieve adequate 25(oh)d levels can be difficult to predict and will depend on the patient s baseline serum level and the presence of other risk factors for deficiency , such as obesity and corticosteroid use .
the american college of rheumatology published guidelines in 2001 recommending calcium and vitamin d supplementation for all patients starting corticosteroids .
therefore patients on corticosteroids often require higher daily doses of vitamin d to maintain adequate levels .
a phase i study of daily oral vitamin d3 showed that doses up to 4,000 iu / day for 3 mo was safe and well - tolerated among african american patients with sle , and other trials among non - sle patients have shown similar safety of vitamin d3 4,000 iu / day . until further prospective trial results in patients with sle are available , we recommend correcting vitamin d deficiency with 50,000 iu capsule of vitamin d3 weekly for 8 weeks , followed by 2,0004,000 iu of vitamin d3 daily .
the dose required to achieve and maintain adequate levels of 25(oh)d depends on the starting level , with roughly 100 iu of additional daily oral vitamin d3 required to raise the serum 25(oh)d level by 1 ng / ml .
it takes approximately 3 mo to achieve steady - state once supplementation is started , but higher doses achieve steady - state sooner .
individual responses may vary and known risk factors for deficiency should be taken into account .
the importance of vitamin d in immune regulation has gained increased interest over the past decade with the discovery of the vitamin d receptor ( vdr ) being expressed by cells of the immune system and manipulation of 1,25-dihydroxyvitamin d [ 1,25(oh)2d ] having downstream immune effects .
the effects of 1,25(oh)2d are mediated by complex nuclear receptor and the binding of the activated complex to regulatory dna sequences of target genes .
the vdr gene is a direct target of its own receptor , thus facilitating an upregulation of the vdr protein in certain target tissues .
several hundred vitamin d - regulated genes have been identified , including multiple genes involved with the innate and adaptive immune system .
the overall immunologic effects of 1,25(oh)2d include downregulating th1 immune responses , modulating the differentiation of dendritic cells ( dcs ) , and lowering proliferation of activated b cells , while upregulating regulatory t cells and preserving innate immune responses .
each of the immune pathways influenced by 1,25(oh)2d has profound potential implications for patients with sle . in general , 1,25(oh)2d promotes the development of dcs with tolerogenic properties .
1,25(oh)2d inhibits dc il12 production and secondarily limits the development of th1 helper cells shifting to a th2 phenotype .
interferon  ( ifn ) , primarily produced by activated plasmacytoid dcs , plays a key role in sle , with activation of the ifn pathway being associated with increased anti - dsdna antibodies and increased disease activity among patients with sle . in vitro and ex vivo studies have shown the ability of 1,25(oh)2d to inhibit dc maturation and the  ifn signature  typical of active sle .
vitamin d deficiency also contributes to b - cell hyper - activation and autoantibody production in genetically susceptible individuals .
linker - israeli et al . showed that 1,25(oh)2d and its analogs inhibit polyclonal and anti - dsdna igg production by stimulated peripheral blood mononuclear cells from patients with sle .
compared 32 female patients with sle to 32 healthy matched controls and found 25(oh)d deficiency to be associated with antinuclear antibody ( ana ) positivity among controls and with increased b cell activation among patients .
additional immune modulating actions of 1,25(oh)2d of importance in suppressing autoimmunity include increasing treg cells , decreasing autoantibody production , suppressing the release of inflammatory mediators and the potential reestablishment of immune tolerance .
vitamin d deficiency is a global health problem being detected at all ages , particularly among populations with darker skin pigmentation living further from the equator .
african americans have a 3-fold increased prevalence of sle , develop sle at an earlier age , and have increased sle - related morbidity and mortality compared with caucasians .
it is notable that the same ethnic disparities seen in the prevalence of vitamin d deficiency are seen in the prevalence of sle .
multiple studies have shown that the majority of patients with sle have insufficient levels of 25(oh)d , especially among african american and hispanic patients with sle . to examine whether vitamin d deficiency is a potential environmental trigger of sle ,
prospective studies and inception cohorts are needed . in the nurses health study and nurses health study ii prospective analysis of over 180,000 women followed for up to 22 y found no significant evidence of association between dietary vitamin d intake and subsequent development of sle .
there were limitations which include use of self - reported exposure data without serum 25(oh)d measurements , observational study design and applicability of results to caucasian female populations only .
there was also limited power to detect a small effect of vitamin d intake on sle development and the confidence intervals were relatively wide ( 0.51.4 ) . in the population - based carolina lupus inception - cohort study
it was noted that lower 25(oh)d levels were found in 123 cases with newly diagnosed sle compared with 240 controls , which was statistically significant in caucasians ( p = 0.04 ) , controlling for age , sex , season and smoking .
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 .
these baseline results within an inception - cohort of sle suggest vitamin d deficiency as a possible risk factor for the development of sle .
many , but not all , studies of 25(oh)d among patients with established sle have shown an association of 25(oh)d deficiency with increased sle disease activity .
a summary of the studies which have examined the relationship between sle and vitamin d status is presented in table 1 .
patients with sle have a higher risk for osteoporosis and fragility fractures , compared with age - matched controls .
the increased osteoporosis and fracture risk among young patients with sle is attributed to systemic inflammation , frequent corticosteroids use , and more recently the high prevalence of vitamin d deficiency .
low levels of 25(oh)d results in the calcium reserves in bone being depleted in an attempt to correct for the reduced calcium that will be absorbed from the gut . as
the reduction in intestinal calcium absorption associated with low levels of 25(oh)d triggers the release of parathyroid hormone ( pth ) , which stimulates the absorption of calcium through increased production of 1,25(oh)2d .
pth also mediates the mobilization of calcium from bone by stimulating bone resorption , which results in a reduction in bone mineral density .
vitamin d deficiency is one of several osteoporosis risk factors common among patients with sle , including high disease activity , renal disease , corticosteroid use , and premature ovarian failure from cytotoxic medications such as cyclophosphamide .
since most patients with sle have multiple disease - associated and traditional osteoporosis risk factors , bone mineral density loss tends to run a rapid course , making vitamin d status even more important .
a leading cause of morbidity and mortality in women with sle , including those who are premenopausal , is cvd .
patients with sle have an increased incidence of myocardial infarction up to 5 times that of the general population , with an age - specific incidence in young women up to 50 times higher .
there is evidence to show that , like diabetes , sle itself is an independent risk factor for the development of atherosclerosis .
the excess cardiovascular risk , which may be up to 52 times in sle , is not explained by traditional cardiovascular risk factors . excess mortality in sle follows a bimodal pattern , with the early peak predominantly a consequence of active sle or its complications , and the later peak largely attributable to atherosclerosis .
patients with sle are also at increased risk of nonfatal ischemic heart disease . as overall survival for patients with sle
improves with better , more targeted , immune suppression therapies , the prevention of morbidity and mortality from atherosclerosis becomes an increasingly critical need .
vascular stiffness can be partly driven by inflammation , and better disease control in patients with inflammatory arthritis results in a reduction in pulse wave velocity ( pwv ) noted that inflammatory biomarkers in sle were particularly associated with aortic pwv . in study by reynolds et al . , the association between 25(oh)d and stiffness was at least in part accounted for by disease activity since in a regression model that includes sledai score the association was no longer significant .
the results suggest that the association between 25(oh)d and disease activity is strongest in those patients with the most active disease / lowest vitamin d. vitamin d deficiency may therefore augment the inflammatory response in sle , underpinning both increased disease activity and vascular stiffness . a recent study by zhao et al .
, has shown that concentrations of 25(oh)d were inversely associated with all - cause and cvd mortality among adults with hypertension in the united states .
due to the high prevalence of vitamin d deficiency seen worldwide and the conditions associated with deficiency , we recommend all patients at risk for sle or with established disease be screened for vitamin d deficiency .
the only lab test usually required to ascertain the patient s status is the 25(oh)d level .
ideal  level of 25(oh)d for the general population and in subpopulations with certain health conditions such as sle .
as our knowledge expands , we may find out that higher thresholds are needed for optimal health , however at this time the minimally adequate level of 25(oh)d is 30 ng / ml .
achieving sufficient levels of vitamin d is a particularly complex issue for patients with sle because they are told to avoid the sun , the primary source of vitamin d. there is good evidence that even 
sensible  sun exposure of 1 minimal erythema dose daily could trigger a disease flare . for that reason , there will be an even greater dependence on adequate dietary vitamin d intake . unlike other vitamins , currently very little of our daily vitamin d comes from food .
many experts are recommending increased vitamin d fortification of common foods to help counteract widespread deficiency . but for now , oral vitamin d supplementation is needed for most , if not all , patients with sle .
oral vitamin d supplementation is recommended in the form of vitamin d3 ( cholecalciferol ) rather than d2 ( ergocalciferol ) .
vitamin d3 is preferred over vitamin d3 due to vitamin d2 being less efficacious in raising serum 25(oh)d , having diminished metabolite binding to vitamin d binding protein ( dbp ) and a shorter shelf life .
the dose of oral vitamin d3 required to achieve adequate 25(oh)d levels can be difficult to predict and will depend on the patient s baseline serum level and the presence of other risk factors for deficiency , such as obesity and corticosteroid use .
the american college of rheumatology published guidelines in 2001 recommending calcium and vitamin d supplementation for all patients starting corticosteroids .
therefore patients on corticosteroids often require higher daily doses of vitamin d to maintain adequate levels .
a phase i study of daily oral vitamin d3 showed that doses up to 4,000 iu / day for 3 mo was safe and well - tolerated among african american patients with sle , and other trials among non - sle patients have shown similar safety of vitamin d3 4,000 iu / day . until further prospective trial results in patients with sle are available , we recommend correcting vitamin d deficiency with 50,000 iu capsule of vitamin d3 weekly for 8 weeks , followed by 2,0004,000 iu of vitamin d3 daily .
the dose required to achieve and maintain adequate levels of 25(oh)d depends on the starting level , with roughly 100 iu of additional daily oral vitamin d3 required to raise the serum 25(oh)d level by 1 ng / ml . it takes approximately 3 mo to achieve steady - state once supplementation is started , but higher doses achieve steady - state sooner .
individual responses may vary and known risk factors for deficiency should be taken into account .
it is well established that many people worldwide have inadequate levels of 25(oh)d , particularly patients with sle who often have additional risk factors for deficiency inherent to their disease .
there is mounting evidence that vitamin d plays a key role in the pathogenesis and progression of autoimmunity .
the hope is that something as nontoxic , inexpensive and widely available as vitamin d turns out to be effective as a disease suppressing intervention for patients with sle .
in addition to the potential benefit of vitamin d replacement on sle activity , patients will also avoid the excess morbidity and mortality associated with long - term deficiency of vitamin d. continued research will help us better understand the immunomodulatory role of vitamin d and determine the ideal range of serum 25(oh)d for immune health .
 systemic lupus erythematosus ( sle ) is a complex multi - system autoimmune disease . 
 vitamin d deficiency has been proposed as an environmental trigger of disease onset and as a contributor to increased sle activity . 
 sle patients are prone to develop vitamin d deficiency because of photosensitivity leading to sun avoidance and other sun protective measures . 
 the impact of vitamin d on immune function previously seen in vitro and in cross - sectional studies has now been shown in prospective human studies , strengthening the evidence that there is a connection between sle and vitamin d status . 
 this review describes the role of vitamin d on immune function , prevalence of vitamin d deficiency in patients with sle , identify risk factors for deficiency , describe the consequences of deficiency in sle patients , and review current vitamin d recommendations for patients with sle . 
Introduction
Vitamin D and the immune system
Prevalence of vitamin D deficiency in SLE
Vitamin D and musculoskeletal manifestations of SLE
Vitamin D and cardiovascular manifestations of SLE
Vitamin D recommendations for patients with SLE
Conclusions