CLINICAL INVESTIGATION

Efficacy and Safety of Vitamin D

Supplementation in Patients With
Systemic Lupus Erythematosus: A
Meta-analysis of Randomized
Controlled Trials
Ronghao Zheng, MD1,2, Alex Gonzalez, BS2,3, Jing Yue, MD4,
Xiaolin Wu, MD1, Ming Qiu, BS1, Lin Gui, MD1, Songbai Zhu, MD1 and
Li Huang, MD1
1
Department of Nephrology, Rheumatology, and Immunology, Maternal and Child
Health Hospital of Hubei Province, Wuhan, People’s Republic of China;
2
Department of Pediatrics, University of California, San Diego, California; 3 Biology
undergraduate Program, University of California, San Diego, California; 4 Emergency
Department, Maternal and Child Health Hospital of Hubei Province, Wuhan,
People’s Republic of China

ABSTRACT
Background: The efficacy of vitamin D supplementation in patients with systemic lupus erythematosus (SLE) remains uncer-
tain. This meta-analysis aimed to systematically evaluate the efficacy and safety of vitamin D supplementation in patients with
SLE.
Materials and Methods: Randomized controlled trials (RCTs) were searched in PubMed, Embase, Cochrane CENTRAL
and Web of Science databases. The retrieved studies were subjected to meta-analysis using the fixed-effect or random-effect
model.
Results: Five eligible RCTs enrolling 490 participants were included. Compared to the placebo treatment, vitamin D supple-
mentation significantly increased the level of serum 25-hydroxyvitamin D (25(OH)D) (5 trials, 490 participants: standard mean
difference (SMD) = 2.072, 95% CI: 1.078-3.066, P < 0.001). The pooled result from 2 RCTs showed that vitamin D supplemen-
tation decreased the fatigue severity scale scores in patients with SLE (2 trials, 79 participants: SMD = ¡1.179, 95% CI: ¡1.897
to ¡0.460, P = 0.001). The SLE disease activity index scores and positivity of anti-double-stranded DNA antibodies (anti-dsDNA)
did not differ significantly (4 trials, 223 participants: SMD = ¡0.507, 95% CI: ¡1.055-0.041, P = 0.070; 3 trials, 361 participants:
Risk ratio = 0.880, 95% CI: 0.734-1.054, P = 0.165) between the vitamin D supplementation group and the placebo treatment
group. None of the included studies reported severe adverse events associated with vitamin D supplementation.
Conclusions: This meta-analysis suggested that vitamin D supplementation is effective in increasing the serum 25(OH)D
levels, may improve fatigue, and is well-tolerated in patients with SLE, however, it does not seem to have significant effects in
decreasing the positivity of anti-dsDNA and disease activity.
Key Indexing Terms: Meta-analysis; Vitamin D supplementation; Vitamin D; Systemic lupus erythematosus. [Am J Med Sci
2019;358(2):104–114.]

INTRODUCTION inverse correlation between serum vitamin D levels and

V
itamin D has been shown to have a wide range of disease activity of SLE.3 Furthermore, putative correlations
anti-inflammatory and immune-modulatory effects were established between low serum vitamin D levels and
in recent decades.1 Based on the novel immuno- comorbidities of SLE such as anti-dsDNA,4 fatigue,5 car-
modulatory function, the levels of vitamin D have been diovascular diseases,6 cutaneous and renal involvement7
associated with autoimmune rheumatic diseases such as and SLE flares.8 Additionally, the animal models and in
multiple sclerosis, rheumatoid arthritis and systemic lupus vitro experiments showed that vitamin D supplementation
erythematosus (SLE).1 Moreover, a high prevalence of vita- or intervention exerted some positive effects.9,10 In the
min D deficiency or insufficiency in SLE has been reported mouse strain MRLlpr/lpr, which is a spontaneous model of
worldwide.1,2 Another meta-analysis demonstrated an the SLE-like syndrome, administration of vitamin D

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receptor agonists decreased proteinuria, improved the Information Sources and Search Strategy
knee joint arthritis and prolonged the average lifespan.9 We searched PubMed, Embase, Cochrane Central
Therefore, vitamin D deficiency may play a vital role in the Register of Controlled Trials (CENTRAL) and Web of Sci-
pathogenesis and progression of SLE. Vitamin D supple- ence databases. The search strategies are outlined in
mentation, especially the higher-dose vitamin D supple- Supplementary Table 2. The search was not limited by the
mentation that may better induce the immunomodulatory language and date. The search was conducted up to April
function,10,11 is considered to have potential benefits for 17, 2018.
the treatment of patients with SLE. However, the efficacy
is yet to be clarified.
Study Selection, Data Management, and Assessment
Although some clinical studies have explored the effi-
of the Risk of Bias
cacy and/or safety of vitamin D supplementation in
The eligible studies were identified, screened and
patients with SLE,5,12-27 several were observational trials,
data extracted independently by 2 authors. The data
which did not allow a precise conclusion. Although the
extraction was based on a template which included the
most rigorous method for a definite conclusion is the ran-
following: publication year, study design, age, sample
domized controlled trial (RCT), inconsistent conclusions
sizes, the initial condition that included the serum vitamin
still existed in RCTs.14-16,18-22,25,26 A randomized and pla-
D levels and disease activity, outcomes, outcomes
cebo-controlled clinical trial suggested that vitamin D sup-
measures, follow-up periods, and types, dosage and
plementation was effective in decreasing the disease
duration of intervention and comparison. The corre-
activity of patients with SLE.25 Another randomized and
sponding authors of the specific studies were contacted
double-blind study indicated that the SLE disease activity
if the required data were not presented directly in the
index (SLEDAI) scores did not differ significantly before
publications. Both authors utilized the Cochrane Collab-
and after vitamin D supplementation, implying that it did
oration’s risk of bias tool to assess the risk of bias in
not exert a positive effect in patients with SLE.26 Hence,
each of the included studies.30
the present study aimed to synthesize the results of the
The disagreements were resolved by discussions
available RCTs to systematically evaluate the efficacy and
with other authors, and the final decisions made by the
safety of vitamin D supplementation in patients with SLE.
consensus among all authors.

METHODS Statistical Analysis

This meta-analysis conformed to the Preferred All statistical analyses were performed using STATA
Reporting Items for Systematic Reviews and Meta-Anal- version 10.0 (STATA Co., College Station, TX). The stan-
yses (PRISMA) guidelines,28 and the PRISMA Checklist28 dard mean difference (SMD) is the difference in the mean
has been listed in the Supplementary Table 1. The proto- outcome between the groups divided by standard devia-
col for this meta-analysis was registered in PROSPERO tion of the outcome among the participants; it is used as a
(International Prospective Register of Systematic summary statistic in a meta-analysis when the trials all
Reviews; number CRD42018097063) prior to the analysis assess the same outcome but measure it in a variety of
of the current results. ways.30 Therefore, we used SMD as the pooled effect
estimate for continuous variables included in this meta-
Eligibility Criteria and Exclusion Criteria analysis, as they were not collected using the same scales.
Only RCTs that evaluated the efficacy and/or safety of The risk ratio (RR) was used as a pooled effect estimate for
vitamin D supplementation in SLE were included. The par- dichotomous variables. The subgroup analyses were
ticipants comprised of patients who were diagnosed with planned to be performed according to the different dura-
SLE, without any restrictions of age, race and region. The tions of vitamin D supplementation and sample sizes, and
types of interventions were supplementation of vitamin D sensitivity analyses were also expected to test the stability
or its analogs for at least 3 months as compared to the of the pooled results. I-squared (I2) and chi-squared test
identical placebo or placebo or no vitamin D or no vitamin were used for assessing the heterogeneity, and I2 > 50%
D analogs. The dose of vitamin D supplementation or its or P < 0.1 represented a significant heterogeneity. A ran-
analogs was ≥1,200 IU/day, which is 2-fold more than the dom-effects model was employed as the pooling method
current recommended dietary allowance (600 IU/day in 1- if there was significant heterogeneity; otherwise, the fixed-
70-year-old patients),29 while the other drugs and thera- effects model was adopted as the pooling method. Publi-
pies for SLE were matched between the intervention and cation bias was assessed using the Egger’s test. P values
the comparison groups. The serum 25(OH)D levels and < 0.05 were considered as statistically significant.
SLEDAI scores were the primary outcomes, and the posi-
tivity of anti-dsDNA, fatigue severity scale (FSS) scores,
RESULTS
and occurrence of adverse events were the secondary
outcomes. The in vitro trials, the studies conducted using Search Results and Study Characteristics
animal models, and those that assessed only the effect on A total of 5 eligible studies with 490 participants were
bone were excluded. analyzed in this meta-analysis. The selection process for

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Zheng et al

FIGURE 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram of study selection process.

eligible studies, including a PRISMA flow diagram,28 is studies16,18,20,26 were considered to have a low risk of
shown in Figure 1. The reasons for the exclusion of full- bias for “blinding of participants and personnel” and
text studies are included in Supplementary Table 3. In “blinding of outcome assessment,” and 4 (80%) stud-
the included studies, the dosage of vitamin D supple- ies18,20,25,26 were assessed to have a low risk of bias for
mentation varied from 1,200 to 7,143 IU/day and the “random sequence generation.” Detailed assessments of
maximal duration of vitamin D supplementation was 12 the risk of bias are depicted in Supplementary Table 4.
months. The detailed general characteristics of the
included studies are shown in Table 1. Results of Individual Studies
The results of individual studies, analyzed quantita-
Risk of Bias in Included Studies tively, are shown in Supplementary Table 5.
Overall, the included studies were of moderately high
quality. All 5 (100%) of the included studies16,18,20,25,26 Synthesis of Serum 25(OH)D Levels
were judged to have a low risk of bias for “incomplete All the included studies reported that the serum 25
outcome data” and “other bias.” Of these, 4 (80%) (OH)D levels after vitamin D supplementation increased

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Copyright © 2019 Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation.

Table 1. General characteristic of included studies.

Studies Nation/ethnicity Age Population Initial condition Study design Intervention Comparison Outcomes Follow
up (months)
Type n Type n
Abou-Raya A Egypt/no mention 38.8 § 5.7(IG) 325 identified, 267 SLEDAI ≥1 and Randomized, double- 2000IU cholecalciferol/day 178 Identical placebo 89 Serum 25(OH)D 12
2013 38.9 § 3.5(PG) randomized, 25(OH)D blind, and placebo- levels, SLEDAI,
236 completed <30 ng/mL controlled anti-dsDNA,
and pro-inflam-
matory
cytokines
Karimzadeh H Iran/no mention 33.78 § 6.2(IG) 97 identified, 90 25(OH)D Randomized, double- Vitamin D3 50000 unit/ 45 Identical placebo 45 Serum 25(OH)D 9
2017 35.69 § 6.8(PG) randomized, 90 <30 ng/mL blind, and placebo- weekly for 12 weeks and levels, and
completed controlled then 50000 unit/monthly SLEDAI
for 6 months
Aranow C 2015 USA /African American, 38.3 § 12.88(IG1) 125 identified, 57 SLEDAI≤4 and 25 Multicenter, random- Vitamin D3 2000IU daily 17(IG1) Identical placebo 19 IFN signature, 3
Hispanic and other 36.5 § 10.90(IG2) randomized, 54 (OH)D ized, double-blind, (IG1) and vitamin D3 18(IG2) serum 25(OH)D

Vitamin D Supplementation in Systemic Lupus Erythematosus

38.7 § 12.27(PG) mITT, 31 <20 ng/mL and placebo- 4000IU daily (IG2) levels, SLEDAI,
per-protocol controlled and anti-dsDNA
Lima GL 2016 Brazil/Caucasian and 18.5§3.5(IG) 60 identified, 45 SLEDAI<12 and Randomized, double- 50000IU cholecalcipherol/ 20 Identical placebo 20 Serum 25(OH)D 6
Non-Caucasian 19.3§3.3(PG) randomized, 40 95% patients blind, and placebo- week levels, SLEDAI,
completed with 25(OH) controlled anti-dsDNA,
D<30ng/ml and FSS
Rifa’i A 2016 Indonesian/no 28.25§6.97(IG) 39 randomized, 39 SLEDAI≥5 and Randomized, open and Vitamin D3 cholecalciferol 20 Placebo 19 Serum 25(OH)D 3
mention 27.26§6.76(PG) completed vitamin D placebo-controlled 1200IU/day or 30mg/day levels, SLEDAI,
deficiency and FSS

Abbreviations: anti-dsDNA, anti−double-stranded DNA antibodies; FSS, Fatigue Severity Scale; IG, intervention group; IFN, interferon; mITT, modified intent-to-treat; PG, placebo group; SLEDAI, Systemic Lupus Erythe-
matosus Disease Activity Index; 25(OH)D, 25-hydroxyvitamin D.
107
Zheng et al

as compared to the placebo treatment group or baseline by vitamin D supplementation as compared to the pla-
before vitamin D supplementation. The pooled result of cebo treatment, and the study by Rifa’i et al25 showed
the 5 studies showed that vitamin D supplementation significant differences in all the items of FSS before and
significantly increased the levels of serum 25(OH)D as after vitamin D supplementation.
compared to the placebo treatment (SMD = 2.072, 95%
CI: 1.078-3.066, P < 0.001), although high heterogeneity
(I2 = 93.2%, P < 0.001) was detected among these stud- Safety
ies (Figure 2a). Adverse events were reported in the 4 included stud-
ies,16,18,20,25 and no severe adverse events were found
to be associated with vitamin D supplementation (range:
Synthesis of the SLEDAI Scores 1200-7143 IU/day). The study by Karimzadeh et al26 did
The SLEDAI scores after vitamin D supplementation not mention any information regarding the adverse
were reported in all the included studies. The study by events and safety of vitamin D supplementation. We syn-
Aranow et al18 suggested that SLEDAI scores did not dif- thesized the data of serum calcium levels from 2 included
fer significantly over a period among intervention groups studies.16,18 The pooled result suggested that vitamin D
after adjustment for the baseline scores. The study by supplementation did not influence the serum calcium lev-
Karimzadeh et al26 demonstrated that there was not a els in patients with SLE (SMD = 0.347, 95% CI: 0.072-
significant difference in the SLEDAI scores before and 0.765; P = 0.105), and no significant heterogeneity was
after vitamin D supplementation. The study by Lima observed (I2 = 0.0%, P = 0.523) (Figure 3c). Also, we ana-
et al16 showed that the SLEDAI scores after intervention lyzed some common adverse events, and no significant
were not significantly different between the vitamin D differences were observed in the events of hypercalciuria
supplementation and the placebo treatment groups, (RR = 4.525, 95% CI: 0.246-83.129, P = 0.309), constipa-
although the changes of SLEDAI scores after 6 months tion (RR = 1.750, 95% CI: 0.371-8.251, P = 0.479),
of intervention in comparison with the respective base- anorexia (RR = 2.000, 95% CI: 0.227-17.631, P = 0.533)
line were significantly different between the vitamin D and hypercalcemia (RR = 4.525, 95% CI: 0.246-83.129,
supplementation and the placebo treatment groups. The P = 0.309) in the study by Abou-Raya et al20 and epigas-
study by Rifa’i et al25 demonstrated that the SLEDAI tric pain (RR = 2.000, 95% CI: 0.412-9.712, P = 0.390) in
scores decreased significantly before and after interven- the study by Lima et al16 between the vitamin D supple-
tion in both the vitamin D supplementation and the mentation and placebo treatment groups.
placebo treatment groups. Abou-Raya et al20 reported
the SLEDAI scores in the vitamin D insufficiency and
vitamin D deficiency groups, whereas we could not Subgroup Analysis
extract the data from the vitamin D supplementation and Subgroup analysis was performed according to the
placebo treatment groups. Therefore, data were synthe- different durations of vitamin D supplementation for the
sized from the 4 included studies,16,18,25,26 and the pooled analyses of serum 25(OH)D levels and SLEDAI
pooled result indicated that vitamin D supplementation scores respectively. The results did not indicate the dura-
did not decrease the SLEDAI scores as compared to the tion of vitamin D supplementation as the cause of hetero-
placebo treatment (SMD = ¡0.507, 95% CI: ¡1.055-0.041, geneity because the heterogeneity was not eliminated from
P = 0.070) (Figure 2b). any of the subgroups. However, the pooled effect esti-
mates of each subgroup were statistically significant for the
serum 25(OH)D levels (SMD = 2.338, 95% CI: 0.595-4.081,
Synthesis of the Positivity of Anti-dsDNA P = 0.009; SMD = 1.693, 95% CI: 0.892-2.495, P < 0.001),
The positivity of anti-dsDNA after vitamin D supple- but insignificant for the SLEDAI scores (SMD = ¡0.328,
mentation was reported in 3 included studies,16,18,20 and 95% CI: ¡0.726-0.069, P = 0.106; SMD = ¡0.685, 95% CI:
the pooled result did not show a significant difference ¡2.060-0.690, P = 0.329), which was consistent with the
between the vitamin D supplementation and the placebo respective overall pooled results (Figure 2a and 2b). Due to
treatment groups (RR = 0.880, 95% CI: 0.734-1.054; a small number of studies in each pooled analysis, further
P = 0.165) (Figure 3a). subgroup analysis could not be performed by different
sample sizes according to the previous protocol or other
criteria.
Synthesis of the FSS Scores
The FSS scores were analyzed in the 2 included
studies,16,25 and the pooled result demonstrated that the Sensitivity Analysis
FSS scores were significantly reduced by vitamin D sup- The results of the sensitivity analysis are shown in
plementation as compared to the placebo treatment Table 2. For the serum 25(OH)D levels and the SLEDAI
(SMD = ¡1.179, 95% CI: ¡1.897 to ¡0.460; P = 0.001), scores, the pooled results of the remaining studies were
and moderate heterogeneity was observed (I2 = 54.6%, consistent with the overall pooled result after the
P = 0.138) (Figure 3b). Furthermore, the study by Lima sequential exclusion of each study, indicating the robust-
et al16 indicated that 4 items of FSS could be improved ness of the 2 pooled results. For the FSS scores and

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FIGURE 2. Forest plot showing the pooled effect estimates for vitamin D supplementation versus placebo treatment on the serum 25(OH)D lev-
els (a) and SLEDAI scores (b). Abbreviations: SD, standard deviation; SLEDAI, systemic lupus erythematosus disease activity index; SMD, stan-
dard mean difference.

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Zheng et al

FIGURE 3. Forest plot showing the pooled effect estimates for vitamin D supplementation versus placebo treatment on the positivity of anti-
dsDNA (a), FSS scores (b) and serum calcium levels (c). anti-dsDNA, anti−double-stranded DNA antibodies; Abbreviations: FSS, Fatigue Sever-
ity Scale; RR, risk ratio; SD, standard deviation; SMD, standard mean difference.

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TABLE 2. Sensitivity analyses for the serum 25(OH)D levels, SLEDAI scores and positivity of anti-dsDNA.

Outcomes No. of studies SMD or RR (95%CI) P value I2 (%) P value for heterogeneity
For the serum 25(OH)D levels
All pooled studies 5 2.072 (1.078, 3.066) <0.001 93.2 <0.001
Exclude the study of Rifa’i A 4 2.273 (1.010, 3.535) <0.001 94.8 <0.001
Exclude the study of Karimzadeh H 4 1.560 (1.021, 2.099) <0.001 74.1 0.015
Exclude the study of Lima GL 4 2.094 (0.874, 3.314) 0.001 94.8 <0.001
Exclude the study of Abou-Raya A 4 2.338 (1.208, 3.469) <0.001 90.0 <0.001
Exclude the study of Aranow C 4 2.070 (0.829, 3.311) 0.001 94.6 <0.001
For the SLEDAI scores
All pooled studies 4 ¡0.507 (¡1.055, 0.041) 0.070 73.3 0.010
Exclude the study of Rifa’i A 3 ¡0.225 (¡0.520, 0.069) 0.134 4.7 0.350
Exclude the study of Lima GL 3 ¡0.488 (¡1.223, 0.247) 0.193 81.3 0.005
Exclude the study of Karimzadeh H 3 ¡0.649 (¡1.439, 0.140) 0.107 78.7 0.009
Exclude the study of Aranow C 3 ¡0.689 (¡1.383, 0.005) 0.052 76.9 0.013
For the positivity of anti-dsDNA
All pooled studies 3 0.880 (0.734, 1.054) 0.165 62.0 0.072
Exclude the study of Lima GL 2 0.885 (0.726, 1.079) 0.228 79.0 0.029
Exclude the study of Aranow C 2 0.810 (0.700, 0.937) 0.005 0.0 0.845
Exclude the study of Abou-Raya A 2 0.905 (0.735, 1.115) 0.348 2.7 0.311
Abbreviations: anti-dsDNA, anti−double-stranded DNA antibodies; RR, risk ratio; SMD, standard mean difference, which equals difference in mean outcome between
groups divided by standard deviation of outcome among participants; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; 25(OH)D, 25-hydroxyvitamin D.

serum calcium levels, sensitivity analysis could not be parameters and comorbidities of SLE. Thus, increasing
performed, as only 2 studies were included in those the level of vitamin D might be beneficial for the treat-
pooled analyses. ment of patients with SLE. A large sample cohort study
enrolling 1,006 patients with SLE showed that a
20 ng/mL increase in the serum 25(OH)D levels were
Publication Bias
associated with a 15% decrease in the odds of clinical
Each pooled analysis including 3 or more studies was
proteinuria.13 Currently, the optimal 25(OH)D levels for
assessed using Egger’s test, and no evidence of publica-
bone health are speculated to be 30 ng/mL, while that for
tion bias was detected (Egg’s test for the serum 25(OH)D
immunological homeostasis remain unknown. Further-
levels, P = 0.182; Egg’s test for the SLEDAI scores,
more, any published guidelines describing the dosage of
P = 0.265; Egg’s test for the positivity of anti-dsDNA,
vitamin D that can exert immunomodulatory function
P = 0.734).
in autoimmune rheumatic diseases are yet lacking,
although the in vitro experiments showed that a high
DISCUSSION dose of vitamin D could potentially induce the immuno-
To the best of our knowledge, this is the first meta- modulatory effect.11 In the current study, the dose of
analysis that systematically assessed the efficacy and vitamin D supplementation was ≥1,200 IU/day because
safety of vitamin D supplementation in patients with SLE. a review article suggested that at least 2-3-fold higher
The pooled results showed that vitamin D supplementa- dose of vitamin D should be administered to the patients
tion increases serum 25(OH)D levels and improves with the rheumatic disease than that recommended for a
fatigue in patients with SLE. However, vitamin D supple- given age.31 Hence, future studies should determine the
mentation was not shown to have significant effects on optimal dosage of vitamin D supplementation to exert
decreasing the positivity of anti-dsDNA and disease the immunomodulatory function in SLE.
activity. As for the safety, vitamin D supplementation is The pooled result from the 2 studies16,25 that
relatively safe, as no severe adverse events were assessed the FSS suggested that fatigue is improved by
reported in 4/5 included RCTs, and also, the serum cal- vitamin D supplementation in patients with SLE. Fatigue
cium levels were not affected significantly. is a common manifestation observed in approximately
As an expected result from certain observational 81% of patients with SLE.32 To date, only a small number
studies,5,27 evidence from RCTs reinforced that the vita- of studies have investigated the correlation between
min D supplementation significantly increased the serum serum vitamin D levels and fatigue in SLE,5,25,33,34 and
25(OH)D levels in patients with SLE. Moreover, 4 the mechanisms underlying the vitamin D deficiency-
included studies16,20,25,26 showed that the mean serum caused fatigue in patients with SLE are not yet clarified.
25(OH)D levels after vitamin D supplementation were Nonetheless, 1 key mechanism could be that vitamin
>30 ng/mL. As described previously, low serum vitamin D influences the expression of various components
D levels were significantly associated with various of inflammatory cascades, such as tumor necrosis

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Zheng et al

factor-alpha and nuclear factor kappa B, which are average dosage of vitamin D supplementation is up to
known to induce sleepiness, a common feeling associ- 4,097 IU/day, indicating that a high dose of vitamin D sup-
ated with fatigue.34 Our pooled result might also be plementation is still relatively safe in patients with SLE.
potentially explained by the following aspects. Firstly, Although moderate-to-high heterogeneity was
vitamin D receptors exist in skeletal muscle, which is the observed in some pooled analyses, the results of sensitiv-
basis for vitamin D-mediated improvement in muscle ity analysis verified the robustness of the serum 25(OH)D
fatigue. Secondly, vitamin D deficiency was associated levels and SLEDAI scores. Next, we attempted to explore
with muscle weakness.35 Moreover, an inverse correla- the origin of heterogeneity through subgroup and sensitiv-
tion occured between serum vitamin D levels and the ity analyses, whereas the causes of heterogeneity were
degree of fatigue in patients with SLE in specific not identified due to the limited analysis based on the small
studies.25,33 Therefore, other studies also showed that number of included studies. Nonetheless, the results of the
vitamin D treatment not only enhanced the muscle func- subgroup analysis further demonstrated the stability of
tion in patients with hypovitaminosis36 but also improved the pooled results of the serum 25(OH)D levels and SLE-
the degree of fatigue in patients with SLE.5 However, this DAI scores. Considering the maturity and accuracy of vari-
pooled result must be viewed as tentative because it was ous assays to test the serum 25(OH)D levels and positivity
derived from only 2 included studies. of anti-dsDNA, the heterogeneity might not be attributed
Notably, the result of this meta-analysis does not to the alternative assays. Also, we adopted the SMD,
confirm that vitamin D supplementation has a significant which was used to pool the variables collected from differ-
effect on decreasing the disease activity of SLE, ent scales as the pooled effect estimates owing to the
although the previous meta-analysis showed that low different versions in SLEDAI score and FSS score in
serum vitamin D levels correlated with high disease activ- the included studies. In addition, the baseline in each
ity of SLE.3 The association between vitamin D levels and included RCT was well-matched between the vitamin D
disease activity is still controversial.17,37 In addition, the supplementation and placebo treatment groups, despite
pooled result showed a noticeable tendency of decreas- different populations, initial disease activity and doses
ing SLEDAI scores by vitamin D supplementation, albeit of vitamin D supplementation, which might be the origin
without a significant difference. Thus, additional studies of heterogeneity.
are essential to validate the pooled result. Nevertheless, this meta-analysis has several limita-
A previous meta-analysis focused on the various tions. First, although only RCTs, which are the most rigor-
immune-mediated rheumatic diseases, however, it ous trials to assess efficacy, were included in this meta-
included only 3 studies of SLE and pooled only 1 out- analysis, a limited number of RCTs existed in each pooled
come of the positivity of anti-dsDNA.38 The result of the analysis. Second, the unidentified sources of heterogene-
meta-analysis was converse to our pooled result of the ity remain a concern, and the small number of studies
positivity of anti-dsDNA. Risk difference (RD), an abso- could not allow further meta-regression analysis. Third, 1
lute effect measurement, was used to assess the pooled study,25 in which 3 domains of bias were assessed as
estimate of the positivity of anti-dsDNA in the previous unclear or high, was included in some pooled analyses,
meta-analysis.38 However, the positivity of anti-dsDNA, which might provide information on the deviation and
as dichotomous data, should be avoided performing the influence the stability of the pooled results. Fortunately,
meta-analysis of RD because the relative effect measure sensitivity analyses did not validate this influence on the
RR is more consistent than absolute measure RD to serum 25(OH)D levels and SLEDAI scores because the 2
assess the pooled effect estimate of dichotomous pooled results were not altered upon exclusion of the
data.30 Therefore, the differences in pooled effect esti- study. Fourth, some unattainable data were not pooled for
mates might underlie the pooled result of the positivity of the analyses on the SLEDAI scores and serum calcium
anti-dsDNA, which is inconsistent with the result of that levels, although multiple attempts to contact the corre-
meta-analysis. Importantly, the current pooled result of sponding authors of individual studies were made; this
the positivity of anti-dsDNA, derived from the meta-anal- might also bias the 2 pooled results. Fifth, the small num-
ysis of RR, is reasonable and accurate. ber of studies limited our ability to further analyze the other
Vitamin D supplementation has been demonstrated to crucial outcomes, especially those associated with low
be relatively safe in patients with SLE throughout this serum vitamin D levels, as our search strategies were
meta-analysis. Four of the included studies, along with comprehensive without any language and date restric-
other studies involving vitamin D supplementation in tions. Sixth, SLE is a heterogeneous syndrome, which dif-
patients with SLE that reported the adverse events, fers significantly in the characteristics of the patients.
reported no serious adverse events during vitamin D sup- Vitamin D levels are also affected by many variables such
plementation.12,13,16,18-20,25,27 The toxicity of vitamin D as season, body mass index, geographic area, ethnicity
mainly occurred as a result of the increased level of serum and levels of proteinuria. Furthermore, vitamin D occurs in
calcium; however, the pooled result from 2 included stud- various forms, and vitamin D supplementation follows dif-
ies16,18 suggested that serum calcium levels are not ferent treatment strategies worldwide. Therefore, the trials
affected by vitamin D supplementation in patients with published to date might not be able to accurately assess
SLE. Herein, the included studies demonstrated that the the effects of vitamin D supplementation in patients with

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SLE. Hence, the findings in this meta-analysis should be 5. Ruiz-Irastorza G, Gordo S, Olivares N, et al. Changes in vitamin D lev-
interpreted carefully, and additional RCTs are required to els in patients with systemic lupus erythematosus: effects on fatigue, dis-
ease activity, and damage. Arthritis Care Res. 2010;62:1160–1165.
address these issues.
6. Reynolds J, Ray D, O'Neill T, et al. Role of vitamin D in endothelial repair
mechanisms in systemic lupus erythematosus. Lancet. 2014;383:S89.
7. Petri M, Magder LS. Benefits of vitamin D in SLE depend on the organ
CONCLUSIONS
system. Annals Rheum Dis. 2017;76:1211–1212.
This meta-analysis demonstrated that vitamin D sup- 8. Birmingham DJ, Hebert LA, Song H, et al. Evidence that abnormally
plementation is relatively safe and significantly increases large seasonal declines in vitamin D status may trigger SLE flare in non-
the levels of serum 25(OH)D in patients with SLE. The African Americans. Lupus. 2012;21:855–864.
result from 2 included studies suggested that vitamin D 9. Adorini L. Intervention in autoimmunity: the potential of vitamin D receptor
agonists. Cellul Immunol. 2005;233:115–124.
supplementation may improve fatigue in patients with 10. Piantoni S, Andreoli L, Scarsi M, et al. Phenotype modifications of T-
SLE. Considering the high prevalence of vitamin D defi- cells and their shift toward a Th2 response in patients with systemic lupus
ciency in SLE, administration of vitamin D in patients erythematosus supplemented with different monthly regimens of vitamin
with SLE, especially in those with fatigue, is recom- D. Lupus. 2015;24:490–498.
11. Calton EK, Keane KN, Newsholme P, et al. The impact of vitamin D
mended. However, vitamin D supplementation does not
levels on inflammatory status: a systematic review of immune cell studies.
seem to significantly decrease the positivity of anti- PLOS ONE. 2015;10: e0141770.
dsDNA and disease activity. Due to the limitations of this 12. AlSaleem A, AlE'ed A, AlSaghier A, et al. Vitamin D status in children
meta-analysis, the results of this meta-analysis should with systemic lupus erythematosus and its association with clinical and
be viewed as tentative and further well-designed studies laboratory parameters. Clin Rheumatol. 2015;34:81–84.
13. Petri M, Bello KJ, Fang H, et al. Vitamin D in systemic lupus erythemato-
with large sample sizes are required to validate the pres- sus: modest association with disease activity and the urine protein-to-cre-
ent findings. atinine ratio. Arthr Rheum. 2013;65:1865–1871.
14. Lima GL, Paupitz JA, Aikawa NE, et al. A randomized double-blind pla-
cebo-controlled trial of vitamin D supplementation in juvenile-onset sys-
AUTHOR CONTRIBUTIONS temic lupus erythematosus: positive effect on trabecular microarchitecture
R.Z. and X.W. designed the protocol and reviewed using HR-pQCT. Osteoporosis Int. 2018;29:587–594.
the manuscript. R.Z. and J.Y. performed study selection 15. Lomarat W, Rattapol Pakchotanon R, Chaiamnuay S, et al. A ran-
domized double-blind comparative clinical trials to evaluate efficacy of vita-
and data extraction, and assessed the study quality.
min d in systemic lupus erythematosus (SLE) patients. Ann Rheum Dis.
X.W. reviewed the study selection and the assessment of 2016;75:165.
study quality. R.Z. performed the statistical analysis and 16. Lima GL, Paupitz J, Aikawa NE, et al. Vitamin D supplementation in
drafted the manuscript. AG reviewed the data extraction adolescents and young adults with juvenile systemic lupus erythematosus
and statistical analysis, prepared figures, and drafted for improvement in disease activity and fatigue scores: a Randomized,
Double-Blind, Placebo-Controlled Trial. Arthr Care Res. 2016;68:91–98.
and reviewed the manuscript. R.Z., J.Y., S.Z., L.G., M.Q. 17. Karimzadeh H, Shirzadi M. The relation of vitamin D deficiency and
and L.H. searched the databases and prepared tables. activity of systematic lupus erythematosis. J Isfahan Med School.
All authors discussed the results and contributed to the 2016:784–790.
final manuscript. 18. Aranow C, Kamen DL, Dall'Era M, et al. Randomized, Double-Blind,
Placebo-Controlled Trial of the Effect of vitamin d-3 on the interferon signa-
ture in patients with systemic lupus erythematosus. Arthr Rheumatol.
ACKNOWLEDGMENTS 2015;67:1848–1857.
19. Andreoli L, Dall'Ara F, Piantoni S, et al. A 24-month prospective study
We wish to thank Dr. Cynthia Aranow for providing
on the efficacy and safety of two different monthly regimens of vitamin D
the required data for certain pooled analyses. We also supplementation in pre-menopausal women with systemic lupus erythe-
would like to thank Dr. Laura Andreoli for sending the matosus. Lupus. 2015:499–506.
data for assessment of eligibility. 20. Abou-Raya A, Abou-Raya S, Helmii M. The effect of vitamin D supple-
mentation on inflammatory and hemostatic markers and disease activity in
patients with systemic lupus erythematosus: a randomized placebo-con-
SUPPLEMENTARY MATERIALS trolled trial. J Rheumatol. 2013;40:265–272.
21. Yeap SS, Fauzi AR, Kong NCT, et al. A comparison of calcium, calci-
Supplementary material associated with this article
triol, and alendronate in corticosteroid-treated premenopausal patients
can be found in the online version at https://doi.org/ with systemic lupus erythematosus. J Rheumatol. 2008;35:2344–2347.
10.1016/j.amjms.2019.04.020. 22. Lambrinoudaki I, Chan D, Lau C, et al. Effect of calcitriol on bone min-
eral density in premenopausal Chinese women taking chronic steroid ther-
apy. A randomized, double blind, placebo controlled study. J Rheumatol.
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