406 Acta Med Indones - Indones J Intern Med • Vol 54 • Number 3 • July 2022
ORIGINAL ARTICLE
Effect of Cholecalciferol Supplementation on Disease
Activity and Quality of Life of Systemic Lupus Erythematosus
Patients: A Randomized Clinical Trial Study
Fiblia1, Iris Rengganis2*, Dyah Purnamasari3, Alvina Widhani2,
Teguh H. Karjadi2, Hamzah Shatri4, Rudi Putranto4
1Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital,
Jakarta, Indonesia.
2Division of Allergy Immunology, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia
-Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
3Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine Universitas
Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
4Division of Psychosomatics and Palliative Care, Department of Internal Medicine, Faculty of Medicine Universitas
Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
*Corresponding Author:
Prof. Iris Rengganis, MD., PhD. Division of Allergy Immunology, Department of Internal Medicine, Faculty of
Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital. Jl. Diponegoro 71, Jakarta 10430, Indonesia.
Email:irisrengganis@yahoo.com.
ABSTRACT
Background: Increase in the prevalence and survival rates has led to the assessment of disease activity
and quality of life of SLE patients as targets in treatment. Cholecalciferol was considered as having a role in
reducing disease activity and improving quality of life. Methods: A double blind, randomized, controlled trial
was conducted on female outpatients aged 18-60 years with SLE, consecutively recruited from September to
December 2021 at Cipto Mangunkusumo Hospital. Sixty subjects who met the research criteria were randomized
and equally assigned into the cholecalciferol and placebo groups. The study outcomes were measured at baseline
and after 12 weeks of intervention. Results: Out of 60 subjects, 27 subjects in cholecalciferol group and 25
subjects in placebo group completed the intervention. There was a significant improvement on the level of vitamin
D (ng/ml) after intervention in the cholecalciferol group, from an average of 15,69 ng/ml (8.1-28.2) to 49,90
ng/ml (26-72.1), and for the placebo group from 15,0 ng/ml (8.1-25,0) to 17.35 ng/ml (8.1-48.3) (p<0,000).
Results of the MEX-SLEDAI score showed significant differences in both groups after the intervention, with a
significant decrease in the cholecalciferol group from 2,67 (0-11) to 1,37 (0-6), compared to the placebo group
from 2,6 (0-6) to 2,48 (0-6) (p<0,001). There were no significant differences on the quality of life in both groups.
Conclusion: Supplementation of cholecalciferol 5000 IU/day for 12 weeks was statistically significant in
increasing vitamin D levels and improving disease activity, but did not significantly improve the quality of life
of SLE patients.
Keywords: cholecalciferol, disease activity, quality of life, systemic lupus erythematosus.
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INTRODUCTION
Systemic lupus erythematosus (SLE)
is a chronic systemic autoimmune disease
characterized by autoantibody deposits in
tissues, organ damage and various clinical
manifestations. SLE is better known as a
syndrome than a single disease and the course of
SLE is still unpredictable; it can persist, recure,
or recover.1
The diagnosis and therapy of SLE had
improved and made a significant impact on
increasing the survival rate of SLE patients.2
By increasing the survival rate, the target of
treatment is not only to control disease activity
and prevent organ damage but also to pay
attention to the patient’s quality of life.3
Vitamin D deficiency has a role in the
pathogenesis of SLE, especially in the regulation
of growth, proliferation, apoptosis, and immune
system function. Low vitamin D is associated
with decreased Regulatory T-cells (Tregs), which
function to increase tolerance to self-antigens.
In addition, it also increases the auto reactive
activation of B cells to produce autoantibodies,
increases the activation and proliferation of
Th1 helper cells and produces Interferon-alpha
(IFN-α) through plasmatocytoid Dendritic
Cells (pDC), producing an excess of pro
inflammatory cytokines through macrophages.
This process forms immune complexes, which
leads to tissue damage and continuous release
of self-antigens.4,5 In vitro studies have shown
that 1,25 dihydroxy vitamin D can inhibit the
differentiation of Dendritic Cells (DCs), T cell
proliferation, cytokine production, activated B
cell proliferation and plasma cell formation.5,6
The relationship between vitamin D and SLE
is complex since SLE can cause low levels of
vitamin D and vitamin D deficiency further
plays a role in the etiology and worsening of
SLE symptoms.6,7 However, the relationship
between vitamin D levels and SLE disease
activity has been reported to be inconsistent and
is still debated.8 Several studies have shown that
vitamin D is associated with SLE disease activity
through several mechanisms; meanwhile,
other studies have reported that there was no
relationship between vitamin D levels and SLE.
Effect of vitamin D supplementation on
SLE disease activity is still controversial, and
its role on the quality of life of Indonesian SLE
patients has never been studied. As a result, this
study aims to examine the benefits of vitamin D
supplementation on disease activity and quality
of life of SLE patients in Indonesia.
METHODS
This study is a double blind randomized
controlled trial. Subjects were allocated in
each treatment arm using permuted block
randomization, with a block size of four and
concealed code lists. Investigators, doctors, and
subjects were blinded to treatment allocation
(double blind).
Study Participants
Women with systemic lupus erythematosus
aged 18-60 years old with hypovitaminosis
D as inclusion criteria. Exclusion criteria
included declining consent to participate, late
stage chronic kidney disease (staged 4-5),
decompensated liver cirrhosis, consumption of
glucocorticoids (equivalent to prednisone 20 mg/
day) in the past 30 days, pregnant or lactating,
patients with acute infection, hypercalcemic
patients, anticonvulsant consumption. Dropout
criteria included unwillingness to continue
participation in the study, compliance rate <70%
for both arms, side effects to vitamin D such as
nausea, vomiting, diarrhea, cramps that could
not be controlled with medication, hospitalized
due to infection, changes in the regiment or
dose of immunosuppressant or glucocorticoids
(equivalent to prednisone 20 mg/day) during the
trial. Subjects were consecutively recruited from
September 2021 to December 2021 at Allergy
and Immunology Outpatient clinic in Cipto
Mangunkusumo Hospital, Jakarta.
Intervention Protocol
After providing written consent, eligible
subjects were randomly assigned to either
the cholecalciferol (Prove D3 1x5000 IU) or
placebo (Saccharum lactis 1x5000 IU) arm.
Both the cholecalciferol and placebo tablets were
indistinguishable by appearance.
The allocated treatment was dispensed to
the subjects every four weeks. The collected
data consisted of subjects’ demographic data
Fiblia Acta Med Indones-Indones J Intern Med
408
(age, income, level, duration of illness, Body
Mass Index, organ involvement, treatment,
comorbidities, initial methylprednisolone dose,
initial MEX-SLEDAI score), clinical data (level
of hemoglobin, white blood cell, platelets,
Erythrocyte Sedimentation Rate, Creatine
Kinase (CK), estimated Glomerular Filtration
Rate (eGFR), micro-albuminuria, anti-dsDNA,
vitamin D levels, blood calcium levels). Quality
of life was assessed using the lupus quality of
life (Lupus QoL) questionnaire with a 5-point
Likert scale.
Measurement of study outcomes was
conducted at baseline and after 12 weeks of
intervention. Levels of vitamin D were measured
using the ELISA kit, and disease activity was
measured using the MEX-SLEDAI score, with
a score ranging from 0 to 34. Quality of life
was assessed using the Lupus Quality of Life
(Lupus QoL) questionnaire with a 5-point Likert
scale ranging from 0 to 100. All variables were
measured initially and 12 weeks after intervention.
Adverse events, side effects, and compliance rates
were evaluated every four weeks.
Sample Size
The minimum sample size required to assess
disease activity of SLE was 10 subjects in each
treatment arm. A minimal sample to assess
the quality of life was not determined due to
the novel nature of the study. Total number of
subjects in each treatment group was 30 subjects.
Ethics
This study was approved by the Ethical
Committee of Faculty of Medicine Universitas
Indonesia / Cipto Mangunkusumo Hospital (No.
KET-745/UN2F1/ETIK/PPM.00.02/2021). The
study procedure was performed in accordance
with the Declaration of Helsinki. This study has
been registered in clinicaltrial.gov (Registered
no. NCT05326841).
Statistical Analysis
Data analysis was performed using Statistical
Package for the Social Sciences (SPSS) version
20. Dropout subjects were excluded from the
analyses (per-protocol analysis). Mean and
standard deviation values were calculated for
normally distributed numerical data. Calculation
of median and interquartile range values was
performed for numeric data with non-normal
distributions. Unpaired independent T tests were
performed to analyze the changes in the variables
between the vitamin D (Prove D3) group and
placebo when the data distribution was normal.
In cases of non-normal data distribution, Mann-
Whitney tests were performed.
RESULTS
Despite recruiting 70 SLE subjects to
participate in the study, as many as 10 subjects
were excluded from this clinical trial, based on
the research criteria, which resulted in 60 subjects
who were randomized and equally assigned into
cholecalciferol (Prove D3) and placebo groups.
A total of 27 subjects in the cholecalciferol
group and 25 subjects in the placebo group had
completed the intervention trial (Figure 1).
From 27 subjects who completed the
intervention in the cholecalciferol group, the
mean age was 32,9 (20-40) years old, and most
(60%) had an education level of up to senior high
school. Eighteen subjects (40%) had a duration
of disease greater than 5 years. Most subjects
(30%) weighed within normal ranges of BMI. In
the placebo group, the mean age was 29.5 (19-49)
years old, with a majority (56.7%) having middle
school education level. A plurality (46.7%) of
subjects in this group had a duration of disease
greater than 5 years, and normal weight was
observed in 13 subjects (43.3%).
In the cholecalciferol group, mucocutaneous
organ involvement was found in all subjects,
followed by musculoskeletal involvement in 29
subjects (96.7%). Hydroxychloroquine (HCQ)
was the most commonly prescribed treatment,
given to 21 subjects (70%), followed by Myfortic
(63.3%) and Imuran (23.3%). Most patients
had at least one comorbidity with 5 subjects
(31.3%) having only one. In the placebo group,
mucocutaneous involvement was present in 29
subjects (96.7) followed by musculoskeletal
involvement in 25 subjects (83.3%). Treatment
by HCQ was standard for 23 subjects (76.7%),
followed by myfortic in 17 subjects (56.7%) and
imuran in 3 subjects (10%). Ten subjects (33.3%)
had one comorbidity, with most having more than
one. Results of the demographic characteristics
are summarised in Table 1.
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Figure 1. Flow diagram of randomized control trial.
Enrollment: Assessed for eligibility (n = 70)
10 patients excluded:
lLevel of vitamin D
(25(OH)D) ≥ 30 ng/ml
Randomized (n=60)
Allocated to Cholecalciferol (n=30) Allocated to placebo (n=30)
3 patients drop out
1 death caused by sepsis pneumonia
2 resigned
5 patients drop out
l1Lossof follow up
l2 admitted to hospital and
changed
immunosuppressant
l1 admitted due to Dengue
Hemorragic Fever
l1 resigned Analyzed (n=27)
Analyzed (n=25)
Table 1. Characteristic study subjects.
Variables Intervention (n=30) Placebo (n=30)
Age (year), median (IQR) 32.9 (20-46) 29.5 (19-49)
Level of education, n (%)
Low 3 (10.0) 3 (10.0)
Middle 18 (60.0) 17 (56.7)
High 9 (30.0) 10 (33.3)
Income, n (%)
<UMR 16 (53.3) 19 (63.7)
>UMR 14 (46.7) 11 (37.3)
Disease of duration, n (%)
<1 year 6 (20.0) 7 (23.3)
1-5 year 6 (20.0) 9 (30.0)
>5 year 18 (40.0) 14 (46.7)
IMT, n (%)
Underweight 6 (20.0) 4 (13.3)
Normoweight 9 (30.0) 13 (43.3)
Overweight 8 (26.7) 8 (26.7)
Obesity 7 (23.3) 5 (16.7)
Organ involvement, n (%)
Mucocutaneous 30 (100) 29 (96.7)
Musculosceletal 29 (96.7) 25 (83.3)
Renal 18 (40.0) 10 (33.3)
Hematology 15 (50.0) 8 (26.7)
Neuropsychiatric Systemic Lupus Erythematosus (NPSLE) 1 (3.3) 2 (6.7)
Serositis 2 (6.7) 0
Treatment, n(%)
Hydroxyichloroquine (HCQ) 21 (70.0) 23 (76.7)
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410
Quality of life in the two groups had
similar median values across the 8 domains.
In the physical health domain, the average
cholecalciferol group score was 79.6 (50-100),
which was slightly higher than the average
placebo group, which was 79.0 (21-100). Pain
scores in the cholecalciferol group (median
73.3 [33-100]) were on average lower than
the placebo group (median 78.5 [25-100]). On
average, the planning score in the cholecalciferol
group was 79.1 (25-100), which was lower than
the placebo group score of 84.4 (25-100). The
median intercourse score in the cholecalciferol
group was 86.2 (12.5-100), which was higher
than the placebo group (median 81.4 [0-100]).
Emotional health scores in the cholecalciferol
group (median 65.4 [8-95]) were lower than
the placebo group (median 75.4 [25-100]),
and median self-image scores in both groups
were 66.4 (15-100) and 77.1 (15-100) for the
cholecalciferol and placebo arm respectively.
Fatigue score in the intervention group (median
57.7 [12.5-93]) was lower on average, compared
to the placebo group (median 70.2 [18-100]).
Quality of life scores is summarised in Table 2.
Myfortic 19 (63.3) 17 (56.7)
Imuran 7 (23.3) 3 (10.0)
Methotrexate (MTX) 0 1 (3.3)
Comorbidity, n (%)
None 3 (18.8) 11 (36.7)
One 5 (31.3) 10 (33.3)
Two 3 (18.8) 4 (13.3)
Three 2 (12.5) 4 (13.3)
Four 2 (12.5) 3 (3.3)
Five 1 (6.3) 0 (0.0)
Initial dose of methylprednisolone mg/day, median (IQR) 3.53 (0-16) 5.13 (0-16)
Initial MEX-SLEDAI score, median (IQR) 2.67 (0-11) 2.6(0-6)
IQR: Interquartile Range ; n= total subjects
The initial levels of vitamin D 25 (OH) in
the two groups before intervention were similar.
After an intervention, the cholecalciferol group
had an increase of average vitamin D 25(OH)
levels from 15.69 ng/ml (8.1-28.2) to 49.90 ng/
ml (26-72.1), resulting in an average increase of
33.8 ng/ml. In the placebo group, average vitamin
D levels also increased slightly by 2.5ng/ml from
15.0 ng/ml (8.1-25,0) to 17.35 ng/ml (8.1-48.3).
The difference in the increase in average vitamin
D 25(OH) levels between the two groups was
statistically significant (p<0.000). Results of
initial laboratory values and analysis of vitamin
D changes are summarised in Table 3 and Table
4, respectively.
The effect of giving cholecalciferol on SLE
disease activity, based on the MEX-SLEDAI
results, showed a significant difference between
the cholecalciferol group and the placebo group.
An average decrease in the MEX-SLEDAI value
of about 1.29 in the intervention group was
observed, compared to the average decrease of
0.12 in the MEX-SLEDAI value of the placebo
group. This indicates that the intervention with
cholecalciferol provided an improvement, in the
Table 2. Characteristic initial quality of life.
Variables Intervention (n=30) Placebo (n=30)
Lupus QoL, median (IQR)
Physical health 79.6 (50-100) 79.0(21-100)
Pain 73.3 (33-100)) 78.5 (25-100)
Planning 79.1 (25-100) 84.4 (25-100)
Intimate relationship 86.2 (12.5-100)) 81.4 (0-100)
Burden to others 63.0 (7-100) 72.1 (10-100)
Emotional health 65.4 (8-95) 75.4 (25-100)
Body image 66.4 (15-100) 77.1 (15-100)
Fatique 57.7 (12.5-93) 70.2(18-100)
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Table 3. Initial laboratory characteristics.
Variables Intervention (n=30) Placebo (n=30)
Hemoglobin (g/dl), median (IQR) 11.9 (7.2-14.1) 12.0 (7.8-14.3)
White Blood Cell (/uL), median (IQR) 6639
(4100-10670)
7048
(3190-13110)
Platelets (/uL), median (IQR) 298966
(202000-396000)
320066
(139000.0-549000)
LED (mm), median (IQR) 38.1 (0-140) 41.8 (0-144)
CK (U/L), median (IQR) 66.0 (16.0-167.0) 54.7(16-178)
eGFR (ml/min/1.73m2), median (IQR) 111 (68-140) 105.7 (12-131)
Microalbuminuria (mg/g kreatinin), median (IQR) 169 (0-2085) 118.3 (0-792)
Anti dsDNA (IU/mL), median (IQR)
Initial Vitamin D (ng/ml), median (IQR)
Calsium level mg/dl, mean (SD)
266.7 (1.1-1235)
15.69 (8.1-28.2)
9.27 (0.49)
223.1 (1.9-967.0)
15.0 (8.1-25.0)
9.40(0.30)
IQR= Rentang Interquartile; SD= Standard Deviation
Table 4. Changes in pre and post intervention vitamin D
Levels.
Variables
Group [Mean (SD)]
PIntervention
(n=30)
Placebo
(n=30)
Vitamin D
(ng/ml)
33.8 (SD 12.04) 2.5 (SD 10.58) <0.000
Unpaired T-test.
Table 5. Effect of cholecalciferol supplementation on SLE
disease activity using MEX-SLEDAI.
Variable
Group [Median (IQR)]
p
Intervention (n=30) Placebo (n=30)
MEX-
SLEDAI
-1.29 (-5.0; 4.0) -0.12 (-5.0; 6.0) 0.015
form of a decrease in SLE disease activity (p =
0.015). The analysis of the SLE disease activity
post intervention is described in Table 5.
The effect of giving cholecalciferol compared
to placebo on the Lupus Quality Of Life (Lupus
Qol) scores showed that there was no significant
difference in the quality of life between the two
groups across all domains including physical
health, pain, planning, intimate relationships,
burden to others, emotional health, self-image
and fatigue (Table 6).
Table 6. Changes in the total quality of life of SLE patients
pre and post intervention.
Lupus QoL Intervention (n=30)
Placebo
(n=30)
p
Total QoL
Mean (SD)
21.32 (90.57) 14.4 (78.2) 0.773
DISCUSSION
In this study, the results in the vitamin D
group showed a significant increase in 25(OH)
D levels when compared to the placebo group.
These results are in accordance with the
randomized trial by Abou-Raya et al. where SLE
patients receiving vitamin D 2000 IU/day and had
a greater increase in post-intervention vitamin D
25(OH)D levels, compared to the placebo group.
On average, the vitamin D 25(OH) level was
greater by 17.9 ng/ml with a mean of 37.8±16.3
ng/ml in the intervention group, compared to
19.9±16.2 ng/ml in the placebo group (p<0.05).9
The effect of cholecalciferol supplementation
on SLE disease activity, showed that there was
a greater decrease in average MEX-SLEDAI
values of the intervention group compared to
the placebo group. The results of this study are
concordant with the research by Kalim et al,
where a double-blinded randomized clinical
trial was conducted involving 20 SLE patients
who were given vitamin D supplementation of
1200 IU/day for 3 months, compared to 19 SLE
patients who received a placebo. The results of
this study showed a significant decrease in the
SLEDAI scores from an average of 12.65 ± 4.85
to 6.20 ± 2.67 in the vitamin D group, compared
to the slight decrease in SLEDAI scores of the
placebo group (10.74±2,75 to 9.68±2.26).10
Vitamin D plays a role in regulating Treg
cells through the process of tolerogenic induction
of dendritic cells, which will produce IL-
10 through CD4+ T cells and Treg-specific
antigens. High levels of vitamin D can stimulate
the transcription factor FOXP3, which plays
Fiblia Acta Med Indones-Indones J Intern Med
412
a role in the formation and enhancement of
Treg function. High vitamin D levels are also
associated with anti-inflammatory lymphoid
polarization. Tregs stimulated by vitamin D
will function to control the immune response
of T cells, both alloreactive or autoreactive, by
producing inhibitory cytokines, namely IL-10
and TGF-beta, through the release of granzyme
and perforin or expression of CTLA-4 to
prevent antigen presentation or proinflammatory
response. Vitamin D can increase Tregs both
directly or indirectly. The results of the study
showed that there was a relationship between
high Treg levels and immunosuppressive
phenotypes. Vitamin D supplementation can
decrease SLE activity. This is due to the role of
vitamin D in inhibiting Th1, Th17 and increasing
Tregs and Th2. Vitamin D also decreases the
differentiation and proliferation of B cells.12
After the intervention, there was an increase
in the Lupus QoL score in the cholecalciferol and
the placebo group, but the differences between
the two results were not significant (p=0.773).
This was due to the good baseline quality of life
in both groups since both groups had a median
score greater than 50 in each domain prior to
intervention. In addition, several factors can
affect the quality of life in this study such as age,
duration of illness, level of education, disease
activity. In this study, the difference in age
between the two groups was not much different
and on average subjects were relatively young.
In addition, the duration of illness and level of
education may also play a role in the quality of
life since a patient with longer duration of disease
may have better physical health, mental health and
emotional regulation. Higher education levels on
average will lead to a better quality of life. Quality
of life in this study was good and not related to
disease activity and organ involvement.14
Although there were three serious adverse
events (SAEs) reported in the vitamin D group
(nausea, pneumonia, iron deficiency anemia),
further investigation showed that they were not
related to vitamin D administration.
The advantage of this study was that it
used a double-blinded randomized trial design,
with a long observation time of 12 weeks. In
addition, the use of cholecalciferol tablets in this
study at a dose of 5000 IU was in accordance
with the guidelines of the European Food
Safety Authority, which recommends the use
of vitamin D at a daily average of 4000 IU/
day (100µg/day) for adults and the elderly with
normal weights. The tablet preparations taken
are also small, tasteless, and odorless, making it
easier for patients to consume. This study was
also successful in increasing vitamin D levels,
achieving sufficient values, and succeeded in
significantly improving disease activity. The
study also succeeded in improving the quality
of life of the subjects, albeit slightly.
The weakness of this study is a large number
of tablets that have to be consumed per day and
the absence of specific inflammatory marker
examinations that can explain the decrease
in SLE disease activity. With respect to the
quality of life study, the sample size needs to
be increased, and the research time needs to be
longer than at least 6 months.
CONCLUSION
In this study, the results showed that daily
cholecalciferol (5000 IU) supplementation for
12 weeks improved disease activity, but did not
significantly improve the quality of life of SLE
patients.
From this study, it can be proven that
cholecalciferol (5000 IU)/day supplementation
for 12 weeks increases vitamin D levels and
improves disease activity in SLE patients.
However, it is necessary to conduct an assessment
in the form of inflammatory markers that are
more specific for inflammatory conditions in the
LES so that they can explain the activity of the
LES. And related to the role of cholecalciferol
supplementation on the quality of life of SLE
patients, it is still not significant in this study, so
further research is needed with a larger sample
size and a longer time of at least 6 months.
ACKNOWLEDGMENTS
Acknowledgments and affiliations. Individuals
with direct involvement in the study but not
included in authorship may be acknowledged. The
source of financial support and industry affiliations
of all those involved must be stated.
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