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Vitamin D is a hormone implicated in calcium homeostasis, with additional effects on other organs and systems such as the muscles, endothelium, and immune cells (1). Apart from effects on bone metabolism, vitamin D deficiency has been related to an increased risk of cardiovascular disease and a higher risk of all-cause mortality in the general population (2). Also, an increased risk for autoimmune diseases, including type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus (SLE), in relation to low vitamin D levels and/or intake, has been reported (3, 4). In the case of lupus, vitamin D deficiency has been advocated as one of the causes explaining the increased prevalence and severity of SLE among African Americans (5). However, the relationship between vitamin D levels and the clinical course of SLE is still controversial.
Between January and December 2006, we performed a cross-sectional study including 92 patients from the Lupus-Cruces cohort in whom serum 25-hydroxyvitamin D (25[OH]D) levels were measured. Our results showed a high prevalence of vitamin D insufficiency and deficiency that was related to sun avoidance. A relationship between vitamin D deficiency and fatigue, but not with lupus activity or irreversible organ damage, was found (6).
Thereafter, patients were treated with oral vitamin D3 (in the form of tablets containing fixed combinations of calcium and cholecalciferol or with calcidiol in liquid form) at the discretion of the attending physician. After 2 years of therapy and clinical followup of our patients, we aimed to further define the role of vitamin D in modulating the clinical expression of SLE.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
In this observational longitudinal study, we have found a high prevalence of suboptimal 25(OH)D serum levels despite therapy with standard doses of oral vitamin D3. Changes in serum 25(OH)D levels were inversely associated with fatigue, as measured using a 0–10 VAS. On the other hand, no relationship was found between absolute values or variations in 25(OH)D serum levels and scores measuring SLE activity (SLEDAI) or damage accrual (SDI).
Low serum 25(OH)D levels in patients with SLE have been demonstrated in a number of studies performed in different populations from countries at variable latitudes (6, 12–17). Rather unsurprisingly, photosensitivity has been found to predict vitamin D deficiency (6, 13).
Besides its well-known effects on calcium homeostasis, vitamin D exerts several additional effects. Vitamin D receptors (VDRs) have been found in muscle cells, with a well-recognized relationship between vitamin D deficiency and muscle weakness (3, 18), as well as with cardiovascular disease (19). With respect to autoimmunity, the presence of VDRs is protean among immunologic cells, including T and B lymphocytes, macrophages, and dendritic cells (1). An immunoregulatory role of vitamin D has been proposed, with an increased risk of developing autoimmune diseases among vitamin D–deficient individuals (20). Moreover, “prophylactic” treatment with this compound has been advocated by some authors in order to prevent the development of SLE (21).
Yet, the specific effects of vitamin D on SLE are far from clear. Four cross-sectional studies found an inverse relationship between 25(OH)D levels and lupus activity, measured by means of the SLEDAI and/or Systemic Lupus Activity Measure (13, 22–24). However, other authors have not found such an association (14–17). Our previous cross-sectional study did not show any relationship between 25(OH)D levels and SLEDAI scores, either as a continuous variable or taking into account different cutoff points. Moreover, damage accrual, as measured by the SDI, was not associated with vitamin D deficiency (6).
It is important to note that 1,25-dihydroxyvitamin D (1,25[OH]2D) is the active form of the hormone, which has been shown to inhibit proliferation and differentiation and enhance apoptosis of activated B cells in in vitro studies (14). In one study, it was 1,25(OH)2D, but not 25(OH)D, that correlated with SLE activity (14). The fact that this active form of the hormone is not routinely measured due to fluctuations of its serum levels further complicates the interpretation of the clinical effect of vitamin D on SLE activity. Moreover, conversion of 25(OH)D into 1,25(OH)2D is reduced by drugs such as hydroxychloroquine as well as by renal disease (3, 25).
In this study, we offer a dynamic view of the problem. After recommendation to take oral vitamin D3, which was followed by 75% of patients, the mean serum 25(OH)D levels of our population with SLE increased significantly, although a high number of patients still had values below 30 ng/ml. However, an inverse decrease in SLEDAI values was not found; rather, mean SLEDAI scores increased parallel to 25(OH)D levels between T1 and T2, although with no significant correlation. Patients accrued little damage within the study period despite the improvement in vitamin D levels, again without a statistical association between these 2 variables. Therefore, these data confirm our previous results that showed no relationship between 25(OH)D levels and lupus severity, and neither activity nor irreversible damage (6).
On the other hand, our previous finding of improved fatigue with higher 25(OH)D levels has now been confirmed prospectively. We found an independent association between 25(OH)D and the VAS score, both as continuous variables. The median VAS was also higher (reflecting more tiredness) in patients with levels below 30 ng/ml, 20 ng/ml, and 10 ng/ml as compared with those patients with levels above these values, although with a lack of statistical significance in the latter comparison, probably due to the low number of patients in this subgroup (n = 5). Indeed, in patients with vitamin D levels below 30 ng/ml at T1, increasing 25(OH)D levels were inversely and significantly correlated with a decrease in the VAS score. Therefore, with fatigue being a complex and multifactorial manifestation of lupus, our results confirm a potential role of vitamin D deficiency in SLE.
Measuring fatigue in SLE is a difficult task. In 2007, the Ad Hoc Committee on Systemic Lupus Erythematosus Response Criteria for Fatigue reviewed the available instruments to measure fatigue in patients with lupus (26). Fifteen different scales were used in 34 studies. More than 50% of the studies used the Fatigue Severity Scale, a 9-item scale with a 1–7 possible score in each item, which was the instrument recommended by the authors. A VAS similar to that used in this study has also been tested in SLE and employed to measure fatigue in other clinical settings (10). This scale was used in our 2006 cohort and again in this study in order to analyze its variations. However, the actual clinical impact of the reduction of fatigue seen in this study is uncertain and our results should be further validated using more accurate instruments.
The nonrandomized design of this study also limits our findings. Moreover, although most patients were treated with oral vitamin D3, with 25(OH)D levels significantly increasing in the cohort, many of them did not reach optimal levels, which constitutes an additional problem. The possible influence of obesity in the final 25(OH)D levels could not be established because we did not calculate the body mass index of our patients. We did not find any association between 25(OH)D levels and the SLEDAI, either in absolute values or in terms of change over time. It is possible that achieving higher final 25(OH)D levels would have resulted in more striking differences in activity. Likewise, larger variations in SLEDAI scores would have resulted in an increased potency of the study. However, even the trends were not suggestive of an inverse association, since both 25(OH)D levels and the SLEDAI increased significantly over time. On the other hand, despite the same limitation of insufficient vitamin D repletion in many patients, a significant and consistent reduction in fatigue was noted parallel to increasing 25(OH)D levels.
In summary, this study supports the use of dosages of vitamin D3 higher than 800 IU/day for lupus patients with vitamin D insufficiency or deficiency. Dose adjustments should be based on monitoring of serum 25(OH)D levels. In the general population, levels above 30 ng/ml are the recommended goal in order to avoid parathyroid hormone activation (3). However, it is not clear whether these are also the optimal levels in patients with lupus. Increasing 25(OH)D levels may have a beneficial effect in reducing fatigue in patients with SLE. The relationship between vitamin D and lupus activity is complex and still poorly understood, needing further studies to clarify the clinical consequences of vitamin D deficiency and repletion. However, our results do not support any improvement of SLE activity following treatment, and subsequent increase of serum 25(OH)D levels, with oral vitamin D3.