Changes in Vitamin D Levels in Patients With Systemic Lupus Erythematosus: Effects on Fatigue, Disease Activity, and Damage
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Arthritis Care & Research Vol. 62, No. 8, August 2010, pp 1160 –1165 DOI 10.1002/acr.20186 © 2010, American College of Rheumatology ORIGINAL ARTICLE Changes in Vitamin D Levels in Patients With Systemic Lupus Erythematosus: Effects on Fatigue, Disease Activity, and Damage GUILLERMO RUIZ-IRASTORZA,1 SUSANA GORDO,2 NEREA OLIVARES,3 MARIA-VICTORIA EGURBIDE,3 AND CIRIACO AGUIRRE4 Objective. To analyze whether changes in serum 25-hydroxyvitamin D (25[OH]D) levels affect activity, irreversible organ damage, and fatigue in systemic lupus erythematosus (SLE). Methods. We performed an observational study of 80 patients with SLE included in a previous cross-sectional study of 25(OH)D, reassessed 2 years later. Oral vitamin D3 was recommended in those with low baseline 25(OH)D levels. The relationship between changes in 25(OH)D levels from baseline and changes in fatigue (measured by a 0 –10 visual analog scale [VAS]), SLE activity (measured by the Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]), and irreversible organ damage (measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]) were analyzed. Results. Sixty patients took vitamin D3. Mean 25(OH)D levels increased among all treated patients (P ⴝ 0.044), in those with baseline vitamin D levels
Vitamin D in SLE 1161 form) at the discretion of the attending physician. After 2 ence to treatment with oral vitamin D3 was addressed by years of therapy and clinical followup of our patients, we the patients self-reporting. We analyzed whether the 12 aimed to further deﬁne the role of vitamin D in modulating patients unavailable for this longitudinal part of the study the clinical expression of SLE. were different from the remaining cohort in terms of the variables measured at T1. The proportion of patients who achieved optimal levels of 25(OH)D at T2, i.e., at or above 30 ng/mg, was calcu- PATIENTS AND METHODS lated. Likewise, we calculated the proportion of patients with 25(OH)D levels below 20 ng/ml and 10 ng/ml at T2. Design and aims of the study. We designed a longitudi- The variations in 25(OH)D levels, the VAS, and the SLE- nal observational study with the objective of analyzing DAI and SDI scores between T1 and T2 were analyzed. whether changes in 25(OH)D levels relate to changes in The relationship between vitamin D and the ﬁnal clini- SLE activity, irreversible organ damage, and fatigue. Spe- cal variables (fatigue, activity, and damage) was analyzed ciﬁcally, we aimed to prospectively conﬁrm our previous using 2 different strategies. First, we assessed the associa- results, with the hypothesis of an improvement in fatigue tion between 25(OH)D levels and each of the correspond- following the increase in 25(OH)D levels. ing scores (VAS, SLEDAI, and SDI), all measured at T2. Second, we tested the correlation between the changes in Patients. The 92 patients from the Lupus-Cruces cohort 25(OH)D levels and the changes of each of the scores from that were included in our previous study (6) were con- T1 to T2. Subgroup analysis according to baseline (i.e., at tacted and invited to participate in this second, longitudi- T1) levels of serum vitamin D and according to whether or nal part of the study. Eighty patients were available for not treatment with oral vitamin D3 was received was also clinical evaluation during the 2 months (October and No- performed. vember 2008) in which the study took part. All of the The normality of continuous variables was established patients fulﬁlled at least 4 of the American College of by means of the Kolmogorov-Smirnov test. According to Rheumatology (ACR) classiﬁcation criteria for SLE (7) and normality, continuous variables were summarized by the signed the informed consent form. The local institutional mean ⫾ SD or the median and range. Univariate compar- review board approved the study protocol and the in- isons between nominal variables were done by chi-square formed consent form (study code CEIC E07/38) in compli- test with Yates’ correction or Fisher’s exact test, as appro- ance with the Helsinki Declaration. priate. Comparisons of continuous variables between 2 groups were done using a Student’s 2-tailed t-test in the Study variables. At the time of signing the informed case of normal variables and the Mann-Whitney U test in consent form, the following variables were recorded for the case of non-normal variables. Variations in variables this study: age, sex, ethnicity, disease duration, smoking between T1 and T2 were analyzed using McNemar’s test, status, current treatment for SLE (prednisone and dose, the Student’s paired t-test, or Wilcoxon’s test, as required. hydroxychloroquine, immunosuppressive drugs), and the The associations between continuous variables were dose and duration of treatment with oral vitamin D3 since tested by linear regression. Adjustment for potential con- the previous study (maximum 24 months). The Systemic founders was performed by means of multiple linear re- Lupus Erythematosus Disease Activity Index (SLEDAI) gression. score (8) and the Systemic Lupus International Collaborat- All of the statistical calculations were done using SPSS ing Clinics/ACR Damage Index (SDI) score (9) were calcu- software, version 11.0.4, for Mac OS X (SPSS). lated at that point. In addition, each patient was asked to reﬂect the degree of fatigue using the same 0 –10 visual analog scale (VAS) used in the previous study (where 0 ⫽ no fatigue and 10 ⫽ intense fatigue) (10). Levels of RESULTS 25(OH)D were determined using the Liaison 25OH Vita- min D Total Assay (DiaSorin), as previously described (6). Demographic and SLE-related variables. Eighty pa- This is a competitive 2-step chemiluminescence assay, tients, 72 (90%) of them women and 78 (98%) of them with a measuring range of 4.0 –150 ng/ml. The reported white, agreed to participate in the study. The mean ⫾ SD analytical sensitivity is ⬍1.0 ng/ml and the functional age at the time of inclusion was 43 ⫾ 14 years. The median sensitivity is ⬍4.0 ng/ml. The reported speciﬁcity is 104% disease duration was 9.5 years (range 2–29 years). Sixty- for 25(OH)D2 and 100% for 25(OH)D3. The reliability of seven patients (84%) were taking hydroxychloroquine, 44 this assay in our laboratory has been regularly assessed by (55%) were taking prednisone at a median dosage of 2.5 participating in the Vitamin D External Quality Assess- mg/day (range 0 –15), and 16 (20%) were receiving immu- ment Scheme, the largest vitamin D quality assurance pro- nosuppressive drugs at T2. The clinical characteristics of gram worldwide (11). the study group at T1 and T2 are shown in Table 1. Statistical analysis. Herein, we designate T1 as the time Patients lost to followup. Twelve patients (13%) in- when the previous study was done in 2006, and T2 as the cluded in the ﬁrst study group were not available for a time of the current evaluation in October and November second clinical and biochemical evaluation within the 2 2008. The clinical assessment of patients was done at T1 months in which this study was performed. No signiﬁcant by GR-I and M-VE and at T2 by GR-I and SG. The adher- differences in the baseline variables at T1 were found
1162 Ruiz-Irastorza et al Table 1. Clinical characteristics of the study group (n ⴝ 80) at T1 and T2* T1 T2 P Female sex 72 (90) 72 (90) N/A Age, mean ⫾ SD years 41.2 ⫾ 13.8 43 ⫾ 14 N/A Disease duration, median (range) years 8 (0–27) 9.5 (2–29) N/A Photosensitivity 54 (67) 54 (67) N/A Anti-Ro antibodies 31 (39) 31 (39) N/A Renal disease 23 (29)† 23 (29)† N/A Prednisone 42 (52) 44 (55) 0.8 Prednisone dosage, median (range) mg/day 2.5 (0–10) 2.5 (0–15) 0.7 Immunosuppressive drugs 13 (16) 16 (20) 0.45 Hydroxychloroquine 66 (82) 67 (84) 1.0 Smoking 20 (25) 23 (29) 0.45 SLEDAI score, median (range) 0 (0–18) 2 (0–21) 0.015 SDI score, median (range) 0 (0–5) 0 (0–6) 0.044 25(OH)D level ⬍30 ng/ml 62 (77) 57 (71) 0.42 25(OH)D level ⬍20 ng/ml 38 (48) 26 (33) 0.06 25(OH)D level ⬍10 ng/ml 13 (16) 5 (6) 0.06 VAS for fatigue, mean ⫾ SD 4.1 ⫾ 3.0 3.3 ⫾ 2.6 0.015 * Values are the number (percentage) unless otherwise indicated. T1 ⫽ previous study (2006); T2 ⫽ current study (2008); N/A ⫽ not applicable; SLEDAI ⫽ Systemic Lupus Erythematosus Disease Activity Index; SDI ⫽ Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; 25(OH)D ⫽ 25-hydroxyvitamin D; VAS ⫽ visual analog scale. † No patients in this cohort developed renal disease between T1 and T2. between active and missing patients, except for a clinically Despite the signiﬁcant increase in mean 25(OH)D levels irrelevant difference in the SDI score (data not shown). at T2, it is noteworthy that as many as 57 patients (71%) still had vitamin D levels ⬍30 ng/ml, 26 (33%) had Effects of therapeutic intervention. Sixty patients 25(OH)D levels ⬍20 ng/ml, and 5 (6%) had 25(OH)D levels (75%) in the entire group took oral vitamin D3 for a median ⬍10 ng/ml (Table 1). Among patients with 25(OH)D levels period of 24 months (range 7–24 months). Among the 62 ⬍30 ng/ml at T1 who took oral vitamin D3, 34 (72%) did patients with 25(OH)D levels ⬍30 ng/ml at T1, 47 (76%) not accrue optimal levels, with 13 (27%) and 2 (4%) pa- took vitamin D3 at a median dosage of 800 IU/day (range tients in this subgroup having 25(OH)D levels ⬍20 ng/ml 400 –1,200) during a median period of 24 months (range and ⬍10 ng/ml at T2, respectively. Only 2 of 10 treated 5–24 months). Ten (77%) of 13 patients with 25(OH)D patients with 25(OH)D levels ⬍10 ng/ml at T1 attained levels ⬍10 ng/ml at T1 received oral vitamin D3 at a optimal levels at T2, with 4 (40%) and 2 (20%) of them median dosage of 600 IU/day (range 400 –1,200) for a me- still having 25(OH)D levels ⬍20 ng/ml and ⬍10 ng/ml, dian period of 24 months (range 7–24 months). respectively. Mean 25(OH)D levels of the entire cohort increased from 21.7 ng/ml at T1 to 24.8 ng/ml at T2 (P ⫽ 0.044). The same Relationship between 25(OH)D levels and fatigue. Fa- was true for patients with 25(OH)D levels ⬍30 ng/ml at T1 tigue improved in the entire cohort according to the reduc- (from 16.6 to 23.6 ng/ml; P ⬍ 0.001) and for patients with tion seen in the mean ⫾ SD VAS score between T1 and T2 25(OH)D levels ⬍10 ng/ml at T1 (from 6.4 to 20.1 ng/ml; P (4.1 ⫾ 3.0 versus 3.3 ⫾ 2.6; P ⫽ 0.015) (Table 3). However, ⫽ 0.001). A signiﬁcant increase in 25(OH)D levels was an improvement in VAS score was seen only among pa- seen only among patients who took oral vitamin D3 (Ta- tients who took oral vitamin D3, although the differences ble 2). in the subgroups of treated patients with 25(OH)D levels Table 2. Levels of 25(OH)D at T1 and T2 by subgroups of patients* 25(OH)D level at T1, 25(OH)D level at T2, Subgroup mean ⴞ SD ng/ml mean ⴞ SD ng/ml P Total cohort (n ⫽ 80) 21.7 ⫾ 12.2 24.8 ⫾ 10.1 0.044 Total cohort, treated (n ⫽ 60)† 20.7 ⫾ 11.5 25.8 ⫾ 9.6 0.005 Total cohort, untreated (n ⫽ 20)‡ 24.8 ⫾ 13.8 21.8 ⫾ 11.6 0.27 25(OH)D level ⬍30 ng/ml at T1, treated (n ⫽ 47)† 16.1 ⫾ 7.4 25.1 ⫾ 9.8 ⬍ 0.001 25(OH)D level ⬍30 ng/ml at T1, untreated (n ⫽ 15)‡ 18.5 ⫾ 8.0 19.0 ⫾ 7.7 0.84 25(OH)D level ⬍10 ng/ml at T1, treated (n ⫽ 10)† 5.9 ⫾ 1.9 21.1 ⫾ 13.2 0.005 25(OH)D level ⬍10 ng/ml at T1, untreated (n ⫽ 3)‡ 8.0 ⫾ 2.6 16.9 ⫾ 4.4 0.16 * 25(OH)D ⫽ 25-hydroxyvitamin D; T1 ⫽ previous study (2006); T2 ⫽ current study (2008). † Patients who took oral vitamin D3. ‡ Patients who did not take oral vitamin D3.
Vitamin D in SLE 1163 Table 3. Variations in the VAS for fatigue according to 25(OH)D levels at T1 and treatment with vitamin D3* VAS at T1, VAS at T2, Subgroup mean ⴞ SD mean ⴞ SD P Total cohort (n ⫽ 80) 4.1 ⫾ 3.0 3.3 ⫾ 2.6 0.015 Total cohort, treated (n ⫽ 60)† 4.0 ⫾ 3.0 3.0 ⫾ 2.6 0.012 Total cohort, untreated (n ⫽ 20)‡ 4.6 ⫾ 3.0 4.0 ⫾ 2.5 0.53 25(OH)D level ⬍30 ng/ml at T1, treated (n ⫽ 47)† 3.9 ⫾ 2.8 3.2 ⫾ 2.6 0.09 25(OH)D level ⬍30 ng/ml at T1, untreated (n ⫽ 15)‡ 4.3 ⫾ 3.2 4.4 ⫾ 2.2 0.98 25(OH)D level ⬍10 ng/ml at T1, treated (n ⫽ 10)† 5.5 ⫾ 2.6 4.6 ⫾ 1.6 0.23 25(OH)D level ⬍10 ng/ml at T1, untreated (n ⫽ 3)‡ 4.6 ⫾ 1.6 4.7 ⫾ 1.4 0.97 * VAS ⫽ visual analog scale; 25(OH)D ⫽ 25-hydroxyvitamin D; T1 ⫽ previous study (2006); T2 ⫽ current study (2008). † Patients who took oral vitamin D3. ‡ Patients who did not take oral vitamin D3. ⬍30 ng/ml and ⬍10 ng/ml at T1 did not reach the level of 25(OH)D levels between T1 and T2 (P ⫽ 0.87 and P ⫽ 0.63, statistical signiﬁcance (P ⫽ 0.09 and P ⫽ 0.23, respec- respectively). This was also true for the subgroups of pa- tively), probably due to the lack of power related to the tients with 25(OH)D levels at T1 ⬍30 ng/ml (P ⫽ 0.84 and small numbers of patients (Table 3). P ⫽ 0.64 for the SLEDAI and SDI, respectively), ⬍20 ng/ml We found an inverse signiﬁcant association between (P ⫽ 0.58 and P ⫽ 0.64, respectively), and ⬍10 ng/ml (P ⫽ 25(OH)D levels and the VAS score at T2 (P ⫽ 0.001). This 0.64 and P ⫽ 0.85, respectively). relationship was independent of the effect of other vari- ables shown to inﬂuence tiredness in our ﬁrst study, such as age, SLEDAI score, and treatment with hydroxychloro- DISCUSSION quine (P ⫽ 0.001). In this observational longitudinal study, we have found a Using different cutoff points for 25(OH)D levels at T2, high prevalence of suboptimal 25(OH)D serum levels de- the mean ⫾ SD VAS score was different in those with spite therapy with standard doses of oral vitamin D3. values above or below 30 ng/ml (2.4 ⫾ 2.5 versus 3.6 ⫾ 2.5; Changes in serum 25(OH)D levels were inversely associ- P ⫽ 0.057), above or below 20 ng/ml (2.5 ⫾ 2.4 versus ated with fatigue, as measured using a 0 –10 VAS. On the 4.8 ⫾ 2.1; P ⬍ 0.001), and above or below 10 ng/ml (3.2 ⫾ other hand, no relationship was found between absolute 2.5 versus 4.5 ⫾ 3.5; P ⫽ 0.2). values or variations in 25(OH)D serum levels and scores Changes in the VAS score between T1 and T2 were not measuring SLE activity (SLEDAI) or damage accrual (SDI). associated with changes in 25(OH)D levels in the entire Low serum 25(OH)D levels in patients with SLE have cohort (P ⫽ 0.41). However, a signiﬁcant inverse correla- been demonstrated in a number of studies performed in tion was found after restricting this analysis to patients different populations from countries at variable latitudes with 25(OH)D levels ⬍30 ng/ml at T1 (P ⫽ 0.017). The (6,12–17). Rather unsurprisingly, photosensitivity has results did not change (P ⫽ 0.017) after controlling for been found to predict vitamin D deﬁciency (6,13). potential confounders such as treatment with hydroxy- Besides its well-known effects on calcium homeostasis, chloroquine at T2, dose of prednisone at T2, SLEDAI score vitamin D exerts several additional effects. Vitamin D re- at T2, SDI score at T2, SLEDAI score variation between T1 ceptors (VDRs) have been found in muscle cells, with a and T2, and SDI score variation between T1 and T2, none well-recognized relationship between vitamin D deﬁ- of which was statistically related to variations in the VAS ciency and muscle weakness (3,18), as well as with car- score. diovascular disease (19). With respect to autoimmunity, the presence of VDRs is protean among immunologic cells, Relationship between 25(OH)D levels, disease activity, and irreversible damage. Regarding the relationship be- Table 4. Lupus activity and irreversible damage at T2 tween 25(OH)D levels and disease severity, we obtained according to different cutoff points of serum 25(OH)D* results akin to our previous study. Serum levels of 25(OH)D at T2 did not correlate with either SLEDAI or SDI SLEDAI SDI values (P ⫽ 0.5 and P ⫽ 0.3, respectively). Likewise, me- Median Median dian values for both the SLEDAI and SDI did not signiﬁ- (range) P (range) P cantly differ whether the patients had 25(OH)D levels be- low or above the different cutoff points (Table 4). 25(OH)D level ⬍30 ng/ml 2 (0–21) 0.41 0 (0–5) 0.89 Both the SLEDAI and SDI scores signiﬁcantly increased 25(OH)D level ⬎30 ng/ml 2 (0–8) 1 (0–5) between T1 and T2, although this increase was small in 25(OH)D level ⬍10 ng/ml 2 (0–17) 0.88 2 (0–5) 0.35 25(OH)D level ⬎10 ng/ml 2 (0–21) 0 (0–5) clinical terms (SLEDAI: median 0 [range 0 –18] versus median 2 [range 0 –21]; P ⫽ 0.015, and SDI: median 0 * T2 ⫽ current study (2008); 25(OH)D ⫽ 25-hydroxyvitamin D; [range 0 –5] versus median 0 [range 0 – 6]; P ⫽ 0.044). SLEDAI ⫽ Systemic Lupus Erythematosus Disease Activity Index; SDI ⫽ Systemic Lupus International Collaborating Clinics/Ameri- However, no signiﬁcant association was found between can College of Rheumatology Damage Index. the variation of SLEDAI or SDI values and the variation in
1164 Ruiz-Irastorza et al including T and B lymphocytes, macrophages, and den- Measuring fatigue in SLE is a difﬁcult task. In 2007, the dritic cells (1). An immunoregulatory role of vitamin D has Ad Hoc Committee on Systemic Lupus Erythematosus Re- been proposed, with an increased risk of developing auto- sponse Criteria for Fatigue reviewed the available instru- immune diseases among vitamin D– deﬁcient individuals ments to measure fatigue in patients with lupus (26). Fif- (20). Moreover, “prophylactic” treatment with this com- teen different scales were used in 34 studies. More than pound has been advocated by some authors in order to 50% of the studies used the Fatigue Severity Scale, a prevent the development of SLE (21). 9-item scale with a 1–7 possible score in each item, which Yet, the speciﬁc effects of vitamin D on SLE are far from was the instrument recommended by the authors. A VAS clear. Four cross-sectional studies found an inverse rela- similar to that used in this study has also been tested in tionship between 25(OH)D levels and lupus activity, mea- SLE and employed to measure fatigue in other clinical sured by means of the SLEDAI and/or Systemic Lupus settings (10). This scale was used in our 2006 cohort and Activity Measure (13,22–24). However, other authors have again in this study in order to analyze its variations. How- not found such an association (14 –17). Our previous cross- ever, the actual clinical impact of the reduction of fatigue sectional study did not show any relationship between seen in this study is uncertain and our results should be 25(OH)D levels and SLEDAI scores, either as a continuous further validated using more accurate instruments. variable or taking into account different cutoff points. The nonrandomized design of this study also limits our Moreover, damage accrual, as measured by the SDI, was ﬁndings. Moreover, although most patients were treated not associated with vitamin D deﬁciency (6). with oral vitamin D3, with 25(OH)D levels signiﬁcantly It is important to note that 1,25-dihydroxyvitamin D increasing in the cohort, many of them did not reach (1,25[OH]2D) is the active form of the hormone, which has optimal levels, which constitutes an additional problem. been shown to inhibit proliferation and differentiation and The possible inﬂuence of obesity in the ﬁnal 25(OH)D enhance apoptosis of activated B cells in in vitro studies levels could not be established because we did not calcu- (14). In one study, it was 1,25(OH)2D, but not 25(OH)D, late the body mass index of our patients. We did not ﬁnd that correlated with SLE activity (14). The fact that this any association between 25(OH)D levels and the SLEDAI, active form of the hormone is not routinely measured due either in absolute values or in terms of change over time. It to ﬂuctuations of its serum levels further complicates the is possible that achieving higher ﬁnal 25(OH)D levels interpretation of the clinical effect of vitamin D on SLE would have resulted in more striking differences in activ- activity. Moreover, conversion of 25(OH)D into ity. Likewise, larger variations in SLEDAI scores would 1,25(OH)2D is reduced by drugs such as hydroxychloro- have resulted in an increased potency of the study. How- quine as well as by renal disease (3,25). ever, even the trends were not suggestive of an inverse In this study, we offer a dynamic view of the problem. association, since both 25(OH)D levels and the SLEDAI After recommendation to take oral vitamin D3, which was increased signiﬁcantly over time. On the other hand, de- followed by 75% of patients, the mean serum 25(OH)D spite the same limitation of insufﬁcient vitamin D reple- levels of our population with SLE increased signiﬁcantly, tion in many patients, a signiﬁcant and consistent reduc- although a high number of patients still had values below tion in fatigue was noted parallel to increasing 25(OH)D 30 ng/ml. However, an inverse decrease in SLEDAI values levels. was not found; rather, mean SLEDAI scores increased par- In summary, this study supports the use of dosages of allel to 25(OH)D levels between T1 and T2, although with vitamin D3 higher than 800 IU/day for lupus patients with no signiﬁcant correlation. Patients accrued little damage vitamin D insufﬁciency or deﬁciency. Dose adjustments within the study period despite the improvement in vita- should be based on monitoring of serum 25(OH)D levels. min D levels, again without a statistical association be- In the general population, levels above 30 ng/ml are the tween these 2 variables. Therefore, these data conﬁrm our recommended goal in order to avoid parathyroid hormone previous results that showed no relationship between activation (3). However, it is not clear whether these are 25(OH)D levels and lupus severity, and neither activity also the optimal levels in patients with lupus. Increasing nor irreversible damage (6). 25(OH)D levels may have a beneﬁcial effect in reducing On the other hand, our previous ﬁnding of improved fatigue in patients with SLE. The relationship between fatigue with higher 25(OH)D levels has now been con- vitamin D and lupus activity is complex and still poorly ﬁrmed prospectively. We found an independent associa- understood, needing further studies to clarify the clinical tion between 25(OH)D and the VAS score, both as contin- consequences of vitamin D deﬁciency and repletion. How- uous variables. The median VAS was also higher ever, our results do not support any improvement of SLE (reﬂecting more tiredness) in patients with levels below 30 activity following treatment, and subsequent increase of ng/ml, 20 ng/ml, and 10 ng/ml as compared with those serum 25(OH)D levels, with oral vitamin D3. patients with levels above these values, although with a lack of statistical signiﬁcance in the latter comparison, ACKNOWLEDGMENT probably due to the low number of patients in this sub- group (n ⫽ 5). Indeed, in patients with vitamin D levels We thank Dr. Mugica for his help in deﬁning the reliability below 30 ng/ml at T1, increasing 25(OH)D levels were of the 25(OH)D assay in our hospital. inversely and signiﬁcantly correlated with a decrease in the VAS score. Therefore, with fatigue being a complex AUTHOR CONTRIBUTIONS and multifactorial manifestation of lupus, our results con- All authors were involved in drafting the article or revising it ﬁrm a potential role of vitamin D deﬁciency in SLE. critically for important intellectual content, and all authors ap-
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