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Abstract
Background Low serum vitamin D concentrations have been reported in several autoimmune disorders.
Objective To assess whether low serum vitamin D concentrations are related to disease activity of patients with systemic lupus erythematosus (SLE).
Methods 378 patients from several European and Israeli cohorts were pooled and their disease activity was measured by two different methods: 278 patients had SLE disease activity-2000 (SLEDAI-2K) scores and 100 patients had European Consensus Lupus Activity Measurement (ECLAM) scores. In order to combine the two systems the scores were converted into standardised values (z-scores), enabling univariate summary statistics for the two variables (SLEDAI-2K and ECLAM). The commercial kit, LIAISON 25-OH vitamin D assay (310900-Diasorin) was used to measure serum concentration of 25-OH vitamin D in 378 patients with SLE.
Results A significant negative correlation was demonstrated between the serum concentration of vitamin D and the standardised values (z-scores) of disease activity scores as measured by the SLEDAI-2K and ECLAM scales (Pearson's correlation coefficient r=−0.12, p=0.018).
Conclusions In a cohort of patients with SLE originating from Israel and Europe vitamin D serum concentrations were found to be inversely related to disease activity.
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Introduction
Vitamin D is the common name of a group of sterols that affect multisystem metabolism. The main source of vitamin D is from the conversion of 7-dehydrocholesterol to previtamin D3 in the skin, by solar ultraviolet B radiation. A smaller amount of vitamin D is consumed in food.
In the past few years, it has been recognised that vitamin D deficiency is widespread and also has a seminal role in preserving immune homoeostasis. Vitamin D promotes immune stability in the innate and adoptive immune systems, preventing lapses towards autoimmunity.1,–,6 The identification of vitamin D receptors on the membranes of immune cells as well as the existence of 1α-hydroxylase in these cells clearly underline the importance of vitamin D for immune regulation.2 4 Smolders et al7 suggested that the genetic polymorphisms of the vitamin D receptors may affect the their functionality and impact on immune regulation in autoimmunity.
Several reports have elaborated on the linkage between serum concentrations of vitamin D and the development and progression of autoimmune disorders. Using two large cohorts from the Nurses' Health Study, it was shown that women in the highest quintile of vitamin D intake had a 40% reduced rate of developing multiple sclerosis.8 A similar observation was also recorded in the Iowa Women's Health Study. Based on data from 29 368 women, the risk of developing rheumatoid arthritis was found to be inversely related to vitamin D intake.9
It is widely known that in the United States, Afro-Americans have a threefold increased incidence of systemic lupus erythematosus (SLE), which also develops at an earlier age and is associated with a more aggressive form of disease.10 This significant high prevalence of SLE in the black population cannot be attributed merely to genetics since the disease seems not to be more prevalent in the black population of West Africa. The difference therefore may also be related to the reduced sunlight exposure and to the decreased penetration of ultraviolet radiation through pigmented skin, resulting in low concentrations of serum vitamin D in black populations in Northern countries.11 In addition to these aspects, as clinicians, we instruct patients with SLE to avoid sunlight exposure and often prescribe steroids and antiepileptic agents that enhance vitamin D metabolism and decrease its absorption. Anti-vitamin D antibodies have also been reported in patients with SLE, probably contributing to the clearance of vitamin D from the patients' serum.12
In this study we retrospectively evaluated the possible association between serum vitamin D concentration and SLE disease activity levels in a large group of lupus patients.
Methods
Patients and statistical analysis
Altogether 378 patients from several European and Israeli cohorts were pooled. Their disease activity was measured by two different methods: 278 patients had SLE disease activity-2000 (SLEDAI-2K) scores and 100 patients had European Consensus Lupus Activity Measurement (ECLAM) scores. Both indices measure the global systemic activity of SLE.13
The disease activity scores were measured on the day the serum samples were drawn. To combine the data from the two systems, and assuming that the disease activity scores were of normal distribution we converted the scores into standardised values (z-scores), which enabled us to obtain univariate summary statistics for the two variables (SLEDAI-2K and ECLAM).
Vitamin D analysis was done using the commercial kit, LIAISON 25-OH vitamin D assay (310900) (Cardinal Health, Dublin, Ohio, USA). The method for quantitative determination of 25-OH vitamin D is a direct, competitive chemiluminescence immunoassay. Anti-DNA antibody measurement was conducted using the LIAISON dsDNA (310310) for the quantitative determination of the autoantibody titres. This is a two-step immunoluminometric sandwich assay using directly coated magnetic microparticles. All the blood samples were analysed at a single laboratory in DiaSorin SpA (Saluggia, Italy). Vitamin D concentrations >34 ng/ml were considered to be normal.
Statistical analysis was completed using the Student t test and correlations between parameters were calculated using Pearson's correlation coefficient.
Results
Patient characteristics
This cohort comprised 31 male and 347 female patients. Vitamin D levels did not differ between genders; the vitamin D serum concentration was 21.7±13.2 ng/ml versus 20.5±14.4 ng/ ml in men versus women, respectively (p value not significant, p=0.67). The average age of the patients was 40.2±14.2 years (mean±SD), range 13–77 years. Disease duration was 9.7±7.5 years. Neither age nor disease duration were correlated with vitamin D serum concentration (Pearson's correlation coefficient (r)=−0.07, p=0.15 and r=−0.05, p=0.31, respectively).
Of 274 patients, 161 were treated with corticosteroids (66%) but we did not have accurate data about the exact dosage of the drugs on the date on which the disease activity score was calculated. We had no solid data for the use of vitamin D supplements by the patients. Disease activity scores of the patients with SLE measured by SLEDAI-2K and ECLAM scales are presented in table 1. Not all the demographic and clinical data were extractable; therefore our analysis was limited to the available data.
Disease activity scores of patients with systemic lupus erythematosus measured by SLEDAI-2K and ECLAM scales
Vitamin D analysis and relation to disease activity
A total of 278 patients originating from Hungary, Slovakia and Israel were assessed by SLEDAI-2K and 100 patients from Italy by the ECLAM scale. The Italian group had a higher mean serum vitamin D concentration than the other patients (27.6±13.9 ng/ ml vs. 23.9±14.0 ng/ml, p<0.01). A significant negative correlation was demonstrated between the serum concentration of vitamin D and the standardised values (z-scores) of disease activity scores as measured by the SLEDAI-2K and ECLAM scales (r=−0.12, p=0.018). In other words the more active the disease, the lower the vitamin D concentration.
When we analysed the data for patients with active disease, defined by SLEDAI-2K scores >3 or ECLAM scores >1, a similar pattern was detected. Patients with active disease had lower vitamin D serum concentrations than patients with quiescent disease (17.8±12.8 ng/ml vs 24.3±15.3 ng/ml, respectively (p<0.0001)). As a comparator, we analysed serum anti-DNA antibodies in these two groups of patients and observed a higher titre in patients with active disease, according to the chemiluminescence immunoassay units (113.5±212.9 ng/ml vs 22.3±38.7 ng/ml, respectively, (p<0.001)). However, anti-DNA antibody titres did not correlate with disease activity (r=−0.05, p=0.54).
The exact composition of the disease activity scores of the two systems was not available. However, we had data on the 24 h urinary protein excretion of 100 Italian patients and found that patients who had >3 g proteinuria daily had a trend towards a lower mean serum vitamin D concentration than patients who had <3 g of protein (7.8±4.6 ng/ml vs 12.5±11.6 ng/ml, respectively (p=0.17)).
Discussion
It has become abundantly clear that vitamin D is an essential nutrient for many tissues and is involved in numerous biological processes beyond bone metabolism. A recent meta-analysis suggested a reduced all-cause mortality with vitamin D supplementation.14 A single 20 min exposure to the summer sun of a fair-skinned individual may produce 20 000 units of vitamin D, an amount that is equivalent to 200 glasses of milk.15 Yet, our modern life activities are mostly indoors, preventing adequate sunlight exposure and, consequently, vitamin D synthesis.
Significant epidemiological evidence indicates that low serum vitamin D concentrations are associated with various medical conditions, particularly autoimmune diseases.2 Patel et al16 noted that serum vitamin D was inversely related to the tender joint count, 28-joint count Disease Activity Score and Health Assessment Questionnaire score in patients with rheumatoid arthritis.
In this report, we demonstrated a significant inverse relationship between the degree of SLE activity and serum vitamin D concentration. Although the relationship was weak, it was statistically significant, implying that vitamin D insufficiency, among other factors, probably contributes to the development of active disease in patients with SLE. Previous reports failed to demonstrate this association.17 18 It is likely that the large number of patients included in this report helps to explain why an association was detected between vitamin D levels and disease activity.
Borba et al19 recently reported that increased disease activity, expressed by SLEDAI-2K scores, was associated with increased serum interleukin (IL)6, soluble IL6 receptor, IL1, tumour necrosis factor α and low 25-OH vitamin D levels in 36 patients with SLE. Furthermore, multiple regression analysis showed that low 25-OH vitamin D levels were also associated with elevated levels of osteocalcin and bone-specific alkaline phosphatase.
Cutolo and et al4 20 reported that low 25-OH vitamin D was highly prevalent in patients with SLE originating from different regions of Europe (Estonia vs Italy). In his study, other factors such as intake of vitamin D, treatment with hydroxychloroquine and/or prednisolone and clinical status affected serum 25-OH vitamin D levels more significantly than geographical latitude. This observation apparently underlines the concept that a darkly pigmented integument rather than a fair complexion is significantly more important and additive to latitude as a cause of vitamin D deficiency.11
Further interventional studies focusing on vitamin D supplementation are warranted in order to determine whether vitamin D has therapeutic value, also. However, many centres including ours advocate supplementing patients with relatively high dosages of vitamin D (2000 units).
In conclusion, this report underlines the observational association between low serum vitamin D levels and disease activity in SLE.
References
Footnotes
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Competing interests None.
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Provenance and peer review Not commissioned; externally peer reviewed.