Rheumatology Advance Access originally published online on April 14, 2008
Rheumatology 2008 47(6):920-923; doi:10.1093/rheumatology/ken121
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Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences
Department of Internal Medicine, Hospital de Cruces, University of the Basque Country, Bizkaia, Spain.
Correspondence to: G. Ruiz-Irastorza, Servicio de Medicina Interna, Hospital de Cruces, 48903-Bizkaia, Spain. E-mail: r.irastorza{at}euskalnet.net; r.irastorza{at}hcru.osakidetza.net
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Abstract |
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Objectives. We aimed to establish the prevalence, predictors and clinical consequences of vitamin D deficiency in patients with SLE.
Methods. Cross-sectional study including patients fulfilling ACR criteria for the classification of SLE. Serum 25(OH)D levels at 30 and 10 ng/ml were the cut-off values for vitamin D insufficiency and vitamin D deficiency, respectively. SLE activity was measured by SLEDAI and irreversible organ damage by the SLICC-ACR index. Fatigue was quantified using a 0–10 visual analogue scale (VAS).
Results. Ninety-two patients (90% women, 98% white) were included in the study. Sixty-nine (75%) and 14 (15%) patients presented with vitamin D insufficiency and deficiency, respectively. 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 [odds ratio (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, SLEDAI or SLICC-ACR indexes.
Conclusions. Vitamin D insufficiency and deficiency are common in patients with SLE and are associated with sun avoidance. HCQ prevented vitamin D deficiency. Vitamin D deficiency was related to a higher degree of fatigue. Vitamin D levels had no relation with SLE severity.
KEY WORDS: Calcidiol, Calcitriol, Cholecalciferol, Hydroxychloroquine, Damage, Prognosis, Systemic lupus erythematosus
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Introduction |
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Vitamin D is the common denomination of a group of sterols with a crucial role in phospho-calcic metabolism. The main source of vitamin D is the conversion of 7-dehydrocholesterol to pre-vitamin D3 in the skin, by means of solar ultraviolet B radiation. Conversion to vitamin D3, or cholecalciferol, also takes place in the skin through a heat-mediated process [1]. A lesser amount of vitamin D is obtained from food, particularly fish like salmon and tuna. Vitamin D3 undergoes a 25-hydroxylation in the liver, with the resulting product, 25-OH-vitamin D [25(OH)D] or calcidiol, being the main circulating form of vitamin D [1]. 25(OH)D levels are therefore used to determine the vitamin D status of a given individual. The fully active form, 1, 25(OH)2D, is synthesized in the kidneys by the 25(OH) vitamin D-1
hydroxylase, an enzyme which is manly induced by PTH [2]. The main metabolic effect of 1, 25(OH)2D, which is mediated through the interaction with vitamin D receptors (VDRs), is promoting the intestinal absorption and renal resorption of calcium in order to increase its circulating levels [1, 2]. Deficient levels of vitamin D promote PTH synthesis that results in bone resorption. Long-lasting depletion of vitamin D causes rickets and osteomalacia, with skeletal deformities in children and bone pain and increased risk of fractures in adults, respectively [1].
However, many other cells and tissues harbour VDR. Muscle is one of the most important tissues, with vitamin D deficiency producing weakness and fatigue [1, 3]. Also, vitamin D deficiency has been implicated in the development of neoplasms and cardiovascular disease as well as in an increased susceptibility to infections and autoimmune diseases [1, 4].
Lupus patients are frequently photosensitive, which makes this population at risk for developing vitamin D deficiency. In fact, suboptimal vitamin D levels have been frequently found in patients with SLE [5–8]. Some authors propose a relation between SLE activity and a deficient vitamin D status [8]. However, the clinical consequences of vitamin D deficiency have not yet been established.
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Methods |
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Design and aims of the study
We designed a cross-sectional study with the following objectives:
- To determine the prevalence of vitamin D insufficiency and deficiency in patients with SLE.
- To identify the clinical and analytical variables related to vitamin D insufficiency and deficiency.
- To establish the relation between vitamin D levels and fatigue in patients with SLE.
- To establish the association between vitamin D levels and disease severity.
Patients
Consecutive patients attending the Lupus Clinic at Hospital de Cruces, University of the Basque Country, from January to December 2006, were invited to join the study. In order to be included, patients had to fulfil at least four of the ACR criteria for the classification of SLE [9] and sign the informed consent, according to the Declaration of Helsinki. The local institutional review board approved the study protocol and the informed consent form (study code CEIC E07/38).
Variables studied
The following variables were recorded at the time of inclusion: age, sex, ethnicity, disease duration, previous presence of anti-Ro antibodies, history of photosensitivity, current use of photoprotection, current treatment (prednisolone and dose, HCQ, immunosuppressive drugs, calcium plus vitamin D and time on calcium and vitamin D), current smoking, SLEDAI score [10], SLICC damage index (SDI) score [11] and season at the time of protocol (winter-fall and spring-summer). In addition, each patient was asked to reflect in a 0–10 visual analogue scale (VAS; 0 = no fatigue; 10 = intense fatigue) the degree of fatigue, as described in reference [12].
Within 15 days after the informed consent was signed and the fatigue VAS was completed, the following blood tests were done: full blood count, serum levels of ferritin, thyroid stimulating hormone (TSH), PTH and 25(OH)D. PTH levels were determined by Immulite 2000 Intact PTH (Siemens Diagnostics, Los Angeles, CA, USA), a solid-phase, two-site chemoluminiscent enzyme-labelled immunometric assay. The 25(OH)D levels were determined by the Liaison 25OH Vitamin D Assay (DiaSorin Inc., Stillwater, MN, USA), a direct, competitive chemiluminescence immunoassay in which either human serum or ethylenediaminetetraacetic acid-plasma may be used. According to current recommendations, serum 25(OH)D levels <30 and 10 ng/ml were defined as vitamin D insufficiency and vitamin D deficiency, respectively [1, 2].
Statistical analysis
All the statistical calculations were done using the statistical software SPSS 11.0.4 for Mac OS X (SPSS Inc., Chicago, IL, USA).
The normality of continuous variables was established by means of the Kolmogorov–Smirnov test. Normally distributed variables were summarized using the mean and S.D. The median and range were used for non-normally distributed variables.
The prevalence of vitamin D insufficiency and deficiency was calculated as the ratio between the number of patients with 25(OH)D levels below the specified cut-off values (30 and 10 ng/ml, respectively) and the total cohort.
Univariate comparisons between nominal variables were performed by chi-square test with Yate's correction. Comparisons of continuous variables between two groups were done using two-tailed Student's t-test in the case of normal variables and Mann–Whitney U-test in the case of non-normal variables. For correlations between two continuous variables, we used Pearson's or Spearman's coefficients for normal or non-normal variables, respectively.
Independent predictors of 25(OH)D levels were identified using a multiple backward stepwise linear regression. The following independent variables were entered in the baseline model, with 25(OH)D levels as the dependent variable: sex, age, disease duration, season, photosensitivity, photoprotection, anti-Ro, treatment with HCQ, treatment with prednisolone, treatment with calcium and vitamin D, smoking, SLEDAI and SDI scores.
The same independent variables were entered in two conditional logistic regression models with vitamin D insufficiency (yes/no) and vitamin D deficiency (yes/no) as dependent variables.
To investigate the relation between vitamin D deficiency and fatigue, a multiple backward stepwise linear regression model was fitted using the fatigue score as the dependent variable, with age, smoking, HCQ, prednisolone, SLEDAI, SDI, haemoglobin levels, ferritin levels and vitamin D <10 ng/ml (yes/no) as independent variables. TSH levels were not included in the initial model given that all patients had normal values.
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Demographic and SLE-related variables
Ninety-two patients were requested to enter the study: all of them signed the written consent and were thus included in the study. Eighty-three (90%) were women and 90 (98%) were white. Mean (S.D.) age at the time of the study was 41 (18) yrs, with a median disease duration of 7 yrs (range 0–30 yrs).
Seventy-three patients (79%) were taking HCQ and 48 (52%) prednisolone, at a median dose of 5 mg/day (range 2.5–30). Fifteen patients (16%) were taking immunosuppressive drugs. Forty-five patients (49%) were on calcium 1000 mg/day plus vitamin D 800 IU/day, for a median period of 27 months (range 2–180).
The SLEDAI score was 0 in 49 patients (53%), 1–3 in 26 patients (28%) and >3 in the remaining 17 patients (19%). Fifty-seven patients (62%) had not accrued any damage (SDI = 0), 29 (31%) had moderate damage (SDI 1 or 2) and 6 (7%) had severe damage (SDI 
3). The Clinical and laboratory characteristics of the cohort are shown in Table 1.
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Prevalence of vitamin D deficiency
Mean (S.D.) 25(OH)D values were 22 (12) ng/ml. Sixty-nine patients (75%) had 25(OH)D levels <30 ng/ml (insufficiency) and 14 patients (15%) had 25(OH)D levels 10 ng/ml (deficiency). Of the 69 patients 31 (45%) with vitamin D insufficiency and 5/14 patients (35%) with vitamin D deficiency were taking calcium and vitamin D at the time of study entry.
PTH levels were not significantly different between patients with and without 25(OH)D insufficiency (P = 0.11). However, median PTH levels were significantly higher in patients with vitamin D deficiency (72 vs 42 pg/ml, P = 0.02).
Predictors of 25(OH)D levels
The following variables were independent predictors of higher 25(OH)D levels: female sex (P = 0.001), treatment with HCQ (P = 0.014) and treatment with calcium and vitamin D (P = 0.049). Photosensitivity (OR 3.5; 95% CI 1.9, 6.4) predicted vitamin D insufficiency and photoprotection (OR 5.7; 95% CI 0.9, 32.1) predicted vitamin D deficiency. On the other hand, increasing age (OR 0.95; 95% CI 0.90, 0.98) and treatment with HCQ (OR 0.29; 95% CI 0.08, 1.1) protected against vitamin D deficiency. The distribution of clinical and laboratory variables according to vitamin D status are shown in Table 2.
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Patients taking calcium plus vitamin D were older (mean age 44 vs 39 yrs, P = 0.07), whilst patients taking HCQ tended to be younger (mean age 39 vs 49 yrs, P = 0.02). SLEDAI score was similar between patients taking and not taking HCQ (P = 0.9).
Vitamin D and fatigue
The mean (S.D.) fatigue score in the whole population was 4.2 (3.0). There was no correlation between serum 25(OH)D levels and the fatigue score (P = 0.71). Likewise, mean levels of fatigue score did not differ between patients with or without vitamin D insufficiency (4.13 vs 4.50, P = 0.8). However, patients with critically low levels of vitamin D had higher values in the fatigue scale than patients with 25(OH)D levels >10 ng/ml (mean 5.32 vs 4.03, P = 0.08). Age (P = 0.001), vitamin D deficiency (P = 0.04), HCQ (P = 0.05) and SLEDAI (P = 0.05) were independent predictors of a higher score in the fatigue scale.
Relationship between vitamin D and SLE severity
Serum levels of 25(OH)D did not correlate with the values of either SLEDAI (P = 0.94) or SDI (0.18). Indeed, neither of these two variables were statistically significant predictors of vitamin D levels in the multiple regression model (see above). Likewise, no difference in SLEDAI or SDI was seen whether patients had critically low vitamin D levels or not (P = 0.46 and P = 0.61, respectively).
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Discussion |
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Our results show that low vitamin D levels are frequent in lupus patients—75% had levels <30 ng/ml and 15% had <10 ng/ml—despite the fact that our population resides in a south European country with plenty of sunny days. It is noteworthy that treatment with calcium and vitamin D did not completely protect against 25(OH)D deficiency. As expected, photosensitivity and photoprotection were associated with vitamin D insufficiency and deficiency, while female sex and treatment with HCQ protected against low 25(OH)D levels. Critically low vitamin D values were associated with a higher degree of fatigue in SLE patients. On the other hand, we did not find any statistical association between vitamin D insufficiency or deficiency and lupus severity (either activity or irreversible damage) or with disease duration.
Being a population in whom photosensitivity and the use of photoprotection are frequent, patients with SLE are at a clear risk of developing 25(OH)D deficiency. However, the actual prevalence and the role of vitamin D in the pathogenesis and clinical course of lupus are largely unknown. Three recent studies have found lower serum vitamin D levels in patients with SLE as compared with those with OA [6], fibromyalgia [7] or healthy controls [6, 8]. Patients with RA also had higher vitamin D levels than lupus patients (median 24 vs 13 ng/ml, respectively), although the differences were not statistically significant [6].
We have found mean serum levels of vitamin D similar to those seen among SLE patients from South Carolina [8] and Ontario [7] (22, 21.6 and 18.6 ng/ml, respectively). Even lower levels were found in a lupus population from Denmark (median 13 ng/ml) [6]. Likewise, the prevalence of critically low vitamin D levels (<10 ng/ml) has also been similar (15, 16 and 18%, respectively). Therefore, published data agree in showing a high prevalence of vitamin D deficiency among SLE patients. However, several epidemiological studies have also found vitamin D levels <20 ng/ml in as many as 30% of healthy young individuals [2].
Another interesting finding of our study is the incomplete protection offered by treatment with oral calcium plus vitamin D against vitamin D deficiency. Low therapeutic adherence to calcium compounds is frequent due to bad taste, and may explain in part this lack of preventive effect. Other possible factors are the use of photoprotectors and high-dose steroid therapy [13]. Given the low dose of prednisolone taken by most of our patients (median 5 mg/day, 48% not on steroids), the latter does not seem to be a major issue in our cohort.
The role of HCQ in vitamin D metabolism is somewhat complex. We have found that patients on anti-malarial treatment had higher levels of 25(OH)D and were less likely to have critically low vitamin D levels. Anti-malarials inhibit the 1-hydroxylation of 25(OH)D, thus decreasing the levels of the most active form of vitamin D [13]. This well-known property is the basis of the treatment with HCQ of 1, 25(OH)2D-dependent hypercalcaemia seen in granulomatous disorders, such as sarcoidosis [14], although renal synthesis of calcitriol could be regulated in a different way. Huisman et al. [7] found lower 1, 25(OH)2D levels in patients with lupus treated with HCQ, although circulating 25(OH)D levels did not differ between treated and untreated patients. Therefore, it could be argued that anti-malarials spuriously increase 25(OH)D levels, at the expense of reducing the metabolically active form 1, 25(OH)2D.
However, published data point to similar clinical effects of both vitamin D and anti-malarials. A recent study has shown higher values of BMD among lupus women treated with HCQ [15]. The incidence of cardiovascular events [16] and cancer [1] and even total mortality [17] have shown an inverse relationship with 25(OH)D levels in the general population. Likewise, anti-malarials protecting SLE patients from thrombotic events [18], could have some anti-neoplastic properties [19] and increase long-term survival of patients with lupus [18, 20]. Whether some of these effects could be explained in part by increasing 25(OH)D serum levels is still speculative.
Likewise, the clinical consequences of vitamin D deficiency in patients with SLE are mostly unknown. VDRs are found on lymphocytes and monocytes. The normal response to macrophagic stimulation through Toll-like receptors up-regulate the expression of VDR on the surface of macrophages as well as the in situ conversion of 25(OH)D to the active form 1, 25(OH)2D, which has a co-stimulatory effect on lymphocytes [1]. Despite this well-established immunomodulatory effect, the final consequences of vitamin D deficiency on the immune system are uncertain. Basic studies have shown inhibitory properties of vitamin D on Th1 immunity and autoantibody production [21, 22]. Epidemiological studies suggest that adequate vitamin D levels decrease the risk of developing autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, RA and type I diabetes mellitus [1, 2, 23]. Recently, ‘preventive’ treatment with vitamin D of individuals considered at high risk for developing autoimmune diseases has been proposed [24].
In SLE, Kamen et al. [8] have suggested an association between vitamin D deficiency and early phases of disease as well as with lupus nephritis. Neither of these associations was found in our study. Disease duration was not a predictive variable of either 25(OH)D levels or the presence of vitamin D insufficiency or deficiency. Likewise, both SLEDAI and SDI scores were similar in patients with and without vitamin D deficiency. The study by Müller et al. [6] was in keeping with our results, showing no association between 25(OH)D levels and SLE disease activity or the number of ACR criteria accomplished. In addition, 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 [25]. Therefore, the role of vitamin D deficiency in the pathogenesis of SLE is far from clear. Thus, a protective effect of adequate vitamin D levels on the development of SLE or a more aggressive course of the disease cannot be advocated with the data currently available.
On the other hand, this study is the first one to show an association between vitamin D deficiency and fatigue in lupus patients. Fatigue is a frequent and troublesome symptom in patients with SLE, certainly multifactorial and often difficult to treat, with important consequences in the quality of life. In our cohort, age and SLE activity, along with critically low 25(OH)D levels (<10 ng/ml), were independent predictors of higher values in the VAS used to measure fatigue, which makes clinical sense. In fact, vitamin D deficiency has been identified as a cause of myalgia an weakness in elderly populations, with an increased risk for falls and fractures [3, 26]. Thus, vitamin D status should be checked in SLE patients experiencing tiredness.
A further step in our study would consist of demonstrating that improvement in the degree of fatigue follows repletion of vitamin D. Also, the role of vitamin D deficiency in the pathogenesis of autoimmune diseases in general, and SLE in particular, should be clarified before recommending the universal use of vitamin D compounds with the aim of preventing the development of such diseases [27].
Our study is limited by the homogeneity of our population, most of them white and with a mild form of disease at the time of enrolling the study. Despite the relatively high percentage of patients with vitamin D critical deficiency, the actual number of affected individuals was low. Whether a similar study in a population with a higher proportion of black patients, with more aggressive disease and higher numbers of patients with critically low 25(OH)D levels could find a relation between vitamin D deficiency and lupus severity remains speculative.
Our data disclosed two apparent contradictions. Older age was related with a lower frequency of vitamin D deficiency, while the opposite would be expected. This contradiction could be explained in part by the fact that older patients took vitamin D supplements more often. This was not the case with HCQ, whose effect was independent from age in regression models. The second paradox was the double relation of HCQ with both higher vitamin D levels and higher fatigue. A confounding by indication—HCQ is frequently given to treat tiredness in SLE—could be behind this contradiction, which also reflects the complex relation between HCQ and vitamin D metabolism, as previously discussed. Finally, the low absolute number of patients who did not take HCQ (n = 19) represents an additional limitation to interpret data related with this variable.
In summary, we have found a high prevalence of vitamin D deficiency in our cohort of lupus patients, related with avoidance from the sun and not always prevented by standard doses of oral calcium plus vitamin D compounds. Vitamin D deficiency was associated with a higher degree of fatigue, but not with a greater severity of SLE. Higher levels of 25(OH)D were seen in patients taking HCQ. Although the beneficial effects of HCQ and vitamin D overlap, the relation between both is still unclear.
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We thank Dr Mugica for his aid in describing the technical characteristics of the tests used to determine 25(OH)D and PTH.
Funding: This study was supported by a grant from Fundacion Gangoiti. N.O. was funded by Actelion and BIOEF.
Disclosure statement: The authors have declared no conflicts of interest.
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